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Relationship Between Periodontitis and Oral Hygiene Habits with UADT Cancers


Squamous cell carcinomas of upper aero-digestive tract (UADT: lip, oral cavity, oropharynx, hypopharynx, larynx and oesophagus) are, collectively, the nth most common cancer site globally, accounting for 1,277,815 cases and 866,729 deaths per annum.1, 2 These cancers usually present late and progress rapidly, resulting in death within a few years of initial diagnosis, as achieving local control at the cancer site is extremely difficult with late presentation.3 Exposure to tobacco, areca nut and alcohol, as well as diets insufficient in fresh fruits and cruciferous vegetables, remain the major risk factors, along with persistent infection by “high risk” genotypes of human papillomavirus (HPV) in a substantial subset of cases. Emerging risk factors include chronic oral infections, especially periodontitis, poor oral hygiene and inadequate personal and professional dental care.3-5 Malignant neoplasms of the nasopharynx and of salivary glands are not been included in our description of UADT neoplasms as these have different biology and risk factors.6, 7

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Periodontitis (chronic and destructive of the periodontium) is characterised by chronic inflammation of both the soft tissues of the attachment apparatus and of alveolar bone.8 It is caused by the metabolic activity of the total microbiota of the subgingival biofilm.9-11 In addition, periodontal pockets may act as reservoirs for HPV, and Human herpesviruses including cytomegalovirus and Epstein-Barr virus, which have been associated with oral cancer, the commonest UADT cancer site.12, 13 High levels of inflammatory markers associated with carcinogenesis, in particular IL1-ß and TNF-α, have also been measured in the lesions of chronic periodontitis.14

The tissue characteristics relating cancer to inflammation include presence of inflammatory cells and inflammatory mediators (e.g. cytokines and prostaglandins) in tumour tissue as well as tissue remodelling and angiogenesis in tumours which is similar to the changes observed in chronic inflammatory response and tissue repair.15 It is estimated that up to 20% of all malignant neoplasms are initiated by infection/inflammation.16 Chronic inflammation poses an increased risk for malignant transformation of affected epithelia.14 Multiple examples of this possible aetiology include: oral lichen planus, which may transform into malignancy in 0.4-5.3% cases.17 Similarly, Barrett’s oesophagus, another chronic inflammatory condition, is a precancerous condition for adenocarcinomas of oesophagus.18 Although the microbiome (viral, bacterial, and fungal) inhabiting the oral cavity also differs between healthy individuals and patients with cancer, a causal association between oral microbial infections and UADT cancers is yet to be firmly established, though it is being increasingly

explored.19 Whilst there is no uniformity between individual species of the oral bacteriome associated with oral squamous cell carcinoma, there is a common pro-inflammatory metabolic outcome, which one of us has recently characterised as a “passenger turned driver” scenario, in which the presence of an invasive neoplasm encourages a proinflammatory and procarcinogenic flora.11, 20

With increasing evidence supporting the association between chronic infection/inflammation and cancer, a potential link between periodontitis and UADT cancers seems probable. To the best of our knowledge, this is the first study from India which aimed to study the possible association and presence and severity of periodontitis and oral hygiene habits with UADT cancers.

n this study, we estimate the extent to which high levels

of peri odontal diseases, measured by gingival inflammation

and recession, are associated with oral cancer risk in a sam-

ple of subjects living in Kerala, Southern India, using a com-

prehensive adjustment approach for confounding with a large

set of life course variables

n this study, we estimate the extent to which high levels

of peri odontal diseases, measured by gingival inflammation

and recession, are associated with oral cancer risk in a sam-

ple of subjects living in Kerala, Southern India, using a com-

prehensive adjustment approach for confounding with a large

set of life course variables



2.1 Study design and recruitment of study subjects

This study is based on data collected in a hospital-based case-control study on UADT cancers diagnosed between June 2014 – May 2015 at Pune, Maharashtra, India.21-23 The details of identification, selection and recruitment of study subjects has been described elsewhere.21-23 Study subjects ranging in age from 30 to 80 years old and above were recruited from two different multidisciplinary hospitals in Pune: Sadhu Vaswani Mission’s Medical Complex and Command Hospital. These two hospitals are tertiary care centres (including oncology care) for the residents of Pune city and nearby villages within the state of Maharashtra. A total of 240 incident UADT cancer cases with histopathologically confirmed diagnoses were recruited irrespective of sex, age and stage of cancer. UADT cancer subsites were coded using the International Classification of Diseases (ICD-10 C01-06).24

A total of 240 controls were randomly selected patients with non-neoplastic diseases unrelated to tobacco or alcohol consumption, attending or hospitalized at the study sites. They were recruited within the same time frame as the cases. Controls were frequency-matched to cases by sex and age distribution (±5 years). Potential cases and controls were excluded if they were unable to speak or write due to their state of health and provide consent in the presence of a witness. This study and the consent statement was approved by Griffith University Human Research Ethics Committee (Reference No: DOH/10/14/HREC) and by the ethics committee of both the participating hospitals in India. All patients gave verbal informed consent in the presence of a witness on the date and time of interview.


2.2 Exposure assessment/Data collection

Multiple methods were used for data collection including medical records, interviews and intra-oral examination. Diagnostic information was retrieved from medical records, including the incidence date and basis of diagnosis, histologic type, site and stage of cancer. Patient’s self-reported information was collected through face-to-face interviews using a questionnaire and a life-grid. Life-grid is an interview tool used to visualize lifetime data and to improve the reliability of retrospective data in a case-control study.25 Patients’ self-reported information included their sociodemographic profile, oral hygiene habits (bleeding gums, frequency of cleaning teeth, instrument and substance used for cleaning and frequency of dental check-ups) and lifetime history of behavioural risk factors (chewing and smoking tobacco, consumption of areca nut, and alcohol drinking, all prior to their cancer diagnosis or other disease which had brought them to hospital, as well as their current co-morbidity status and any family history of cancer). Intra-oral examinations were conducted to record the number of missing teeth and periodontal status. The primary author (BG, a qualified dental surgeon) collected all the information on site. All the risk factors were initially classified into ‘never’, ‘yes’ and ‘yes only in the past’ categories. As there were very few patients in the latter category, these were combined with affirmative grouping leading to the dichotomy of ‘ever (yes)’ and ‘never’ categories in analysing and presenting the results. The definition of ever- or never-users of tobacco and alcohol has been described in detail previously.21 In brief, ever-tobacco chewers and smokers were defined as those who self-reported as having smoked bidis or cigarettes, chewed any form of tobacco including mishri at least once a day for a minimum of six months prior to the diagnosis of cancer. There were very few users of areca nut/betel quid in this population. Ever-alcohol drinkers were defined as those who drank alcoholic beverages at least once a week for a minimum of six months. Study subjects who had abstained or self-reported as rare users of smoked or chewing tobacco and alcohol in their lifetime were recorded as never-users of the respective habits.



2.3 Basic periodontal examination

For assessment of the of periodontal tissues, the Basic Periodontal Examination was used.26 The dentition was divided into sextants: upper right (17 to 14), upper anterior (13 to 23), upper left (24 to 27), lower right (47 to 44), lower anterior (43 to 33) and lower left (34 to 37). Third molars were excluded. Recordings were made only if there were at least two teeth present in a sextant. In case of presence of only one tooth in a sextant, the score for that tooth was included in the recording for the adjoining sextant.26

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Periodontal status was assessed quantitatively using a World Health Organization periodontal probe. The probe has a “ball end” 0.5 mm in diameter, and a black band from 3.5 to 5.5 mm. Light probing force was used (20-25 grams). The probe was “walked around” the sulcus/pockets in each sextant, and the highest score recorded. As soon as a code 4 was identified in a sextant, the examination moved directly on to the next sextant. If a code 4 was not detected, then all sites were examined to ensure that the highest score in the sextant was recorded.26


2.4 Statistical analysis

Differences between cases and controls in the distribution of covariates were tested using the Pearson’s 2 test for categorical variables. An unconditional logistic regression model was used to derive fully-adjusted odds ratios (OR) and 95% confidence intervals (95% CI) for the risk of UADT cancer associated with periodontitis, after adjusting for potential confounders (age, education, family income per month, smoking and chewing tobacco and drinking alcohol habits (never/ever). The effect modification of periodontitis with risk of UADT cancer was assessed by stratifying on the tobacco chewing as never- or ever-chewers. Two-sided p-values<0.05 were considered statistically significant. The Hosmer-Lemeshow index was used to assess the overall model fit. All the statistical analyses were performed using the Statistical Package for Social Sciences (version 22, II, USA).


A total of 480 patients participated in the study, of whom 67% were males and 32.9% females. The distribution of socioeconomic status and the medical and family history of UADT cancers among the cases and controls are shown in Table 1. Compared to controls, cases had significantly lower levels of education and monthly family income. Chewing tobacco was the most common behavioural habit reported among the cases as compared to controls (p<0.001). The co-morbidity status and the family history of any type of cancer did not show any significant differences among the cases and controls. Table 2 shows that nearly 78% of the cases presented with histopathological diagnosis of lip and oral cavity cancer. Forty-five percent of the UADT cancer cases were diagnosed at Stage II.

Table 3 presents OR and their corresponding CIs for periodontal status and oral hygiene habits among UADT cancer cases and controls. Significant risk for UADT cancers was observed with severe periodontitis (adjusted OR= 2.35; 95% CI: 1.12-4.91) in comparison with no, mild and moderate periodontitis. More than five missing teeth also showed an elevated risk for UDAT cancers (adjusted OR= 3.28; 95% CI: 1.95-5.49). Among the self-reported oral hygiene habits, dental check-ups only at the time of pain showed the highest risk associated with UADT cancers (adjusted OR=4.12; 95% CI: 2.63-6.47). Topical application of mishri to clean the mouth was also associated with an increased risk (adjusted OR=3.06; 95%CI:1.75-5.35). Among the UADT cancer cases and controls, ever tobacco chewers were associated with an increased risk of severe periodontitis (p<0.001) (Table 4).

To the best of our knowledge, the novel findings in this study are the increased risk of UADT cancers with severe periodontitis and with presence of poor oral hygiene habits (dental check-ups only at time of pain, topical application of mishri on gums, minimal frequency of cleaning teeth, more than five missing teeth) as compared to no, mild, moderate periodontitis and good oral hygiene habits.



Because of the high morbidity and mortality associated with UADT cancers, primary prevention remains the most effective strategy to improve disease outcomes. Though excessive use of tobacco and alcohol remain the most important risk factors for these cancers, and primary control based on this knowledge is accepted universally, chronic inflammatory disorders are gaining attention as independent risk factors for these cancers.27, 28 If additional risk factors contributing to a high-risk profile for development of UADT cancers could be identified, this should improve screening and early detection, as well as public health messages for primary prevention.

Chronic periodontitis causes continuous release of inflammatory mediators into surrounding tissues, the bloodstream, and into oral fluid. Mediators such as TNF-α and IL1-ß are characteristic of early carcinogenesis.6, 29 The reduction of risk of certain cancers by non-steroidal anti-inflammatory drugs further demonstrates the association of cancer and chronic inflammation.14

The present case-control study aimed to determine the risk of UADT cancers associated with periodontitis and its severity. Although periodontitis emerged as a significant risk indicator for UADT cancers, the association was determined by the severity of the periodontitis and not merely by its presence. Severe periodontitis remained a potential independent risk indicator for UADT cancers, even after adjusting for tobacco use and alcohol consumption, whereas mild and moderate periodontitis did not pose a significant risk after similar adjustment. The strength of association was strongest amongst concurrent tobacco chewers. This is consistent with previous studies.30, 31 Since periodontitis generates proinflammatory cytokines which induce continuous cell proliferation, including of local keratinocytes, the chances of replication errors and of erroneous DNA repair are increased.14, 20, 32, 33

Interviewer and self-reported oral hygiene variables associated with increased risk of UADT cancers included tooth-brushing frequency less than once daily, having more than five missing teeth, topical application of mishri for cleaning the mouth and dental check-ups only when in pain. Mishri is a roasted preparation made by baking tobacco on a hot metal plate until it becomes a uniformly black powder used as a dentifrice on the teeth and gums with

fingers.34 Chewing tobacco strengthened the association between UADT cancers and periodontitis, whereas gender and age did not have any significant association.

Regular dental check-ups were associated with a lower incidence of UADT cancers. Such individuals maintain better oral hygiene. Also, regular dental visits give an opportunity to dentists to screen for any suspicious oral lesions. A recent systematic review and meta-analysis exploring the relationship between past dental visits and incidence of head and neck cancers confirms this protective effect.35

In the present study there was a significant association between toothbrushing less than once daily as well as topical application of mishri on gums with incidence of UADT cancers. Less frequent cleaning of mouth and teeth allows increased load of biofilm, with ecological shifts towards more pathogenic metabolism.36

The major strength of this study is that it used full mouth examination as well as interviewer-based questionnaires to assess periodontal status. Parameters considered in other studies4, 37, 38 may not be as reliable as tooth loss may not be related to periodontal disease, and periodontal indices as well as self-assessment questionnaires may underestimate the prevalence of periodontitis. status. Nevertheless, this study has limitations: as it was not possible to blind the interviewers to case/control status during assessment of severity of periodontitis. The presence of cancer itself adversely affects oral hygiene. Our study did not assess radiological features of oral health and disease. Due to limited sample size of some UADT cancer cases, it was not possible to analyse cancer sub-sites in relation to hypothesized risk factors.


Our case-control study results suggest that severe periodontitis may be an independent risk factor for UADT cancers and chewing tobacco strengthens this association in this population in Maharashtra, India. As severe chronic periodontitis is common, regular monitoring and early treatment of this may contribute to prevention of UADT cancers, and to early diagnosis and management thereof. Further, prospective clinical and confirmatory basic science studies are required to fully understand the relationship, and the mechanisms involved. There are considerable public health implications.


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