|HEAD AND NECK SYMPOSIUM: REVIEW ARTICLE
|Year : 2014 | Volume
| Issue : 3 | Page : 200-208
A review of Indian literature for association of smokeless tobacco with malignant and premalignant diseases of head and neck region
S Datta1, P Chaturvedi1, A Mishra2, P Pawar1
1 Department of Head and Neck Surgery, Tata Memorial Hospital, Mumbai, Maharashtra, India
2 Department of Otorhinolaryngology, Seth G.S. Medical College, Mumbai, Maharashtra, India
|Date of Web Publication||10-Dec-2014|
Department of Head and Neck Surgery, Tata Memorial Hospital, Mumbai, Maharashtra
Source of Support: None, Conflict of Interest: None
In India, about 60% of tobacco users use smokeless tobacco (ST) alone. Head and neck squamous cell carcinoma is one of the most common cancers in India. International Agency for Research on Cancer (IARC) monograph (Vol 89) found a significant association between ST use and oral cancer. However, only a few articles from India were included in this monograph. To overcome this lacuna, we have reviewed the articles published from India investigating the association between ST use and malignant and premalignant diseases of head and neck region. Data collection has been performed by computer-aided search of the MedLine and PubMed databases using different combinations of the key words. For malignant lesions, only cohort and case control studies were considered for review. For premalignant lesions and dental diseases other than case control studies, some cross-sectional studies have also been reviewed. Studies found a significant association between ST use and cancer of the oral cavity. The association was stronger for the buccal mucosa compared to tongue and for females compared to males. Significant association noted between cancer of the hypopharynx and oropharynx with ST use but no definitive association noted for cancer of the larynx and nasopharynx. Some dental disease and oral premalignant conditions were also associated with ST use. Indian studies suggest ST use is strongly associated with cancer of the oral cavity, oropharynx and hypopharynx.
Keywords: Dental diseases, head and neck cancer, oral cancer, oral premalignant lesion, smokeless tobacco
|How to cite this article:|
Datta S, Chaturvedi P, Mishra A, Pawar P. A review of Indian literature for association of smokeless tobacco with malignant and premalignant diseases of head and neck region. Indian J Cancer 2014;51:200-8
|How to cite this URL:|
Datta S, Chaturvedi P, Mishra A, Pawar P. A review of Indian literature for association of smokeless tobacco with malignant and premalignant diseases of head and neck region. Indian J Cancer [serial online] 2014 [cited 2021 Mar 5];51:200-8. Available from: https://www.indianjcancer.com/text.asp?2014/51/3/200/146713
| » Introduction|| |
Smokeless tobacco (ST) is a major public health problem in Indian subcontinent and India is considered as the global capital of ST use. As per the Global Adult Tobacco Survey (GATS - 2010), more than one-third (35%) of adults in India are tobacco users. Of them, 21% are addicted only to ST products where as 9% are addicted to smoking alone. Rest 5% are addicted to both forms; i.e. smoking as well as ST.  Contrary to this, in the United States, 20.6% of adults are smokers, whereas only 4.4% of men and 0.7% of women are ST users.  This data clearly shows that unlike western countries, ST use is far more common than smoking in India. As per the World Health Organization report, the most significant risk factor for cancer is tobacco use, which alone is responsible for 22% of cancer deaths world over.  According to the IARC monograph on ST, which was published in 2007, among the different sub-sites of the head and neck region, tobacco chewing is associated with only cancer of the oral cavity.  The studies, which were reviewed by the IARC working group were mainly from the North America and Europe. Only a handful of studies from India, which were published a long time back, were considered for review by the IARC group for the monograph of ST. For oral and oropharyngeal cancer, only four case control studies from India were discussed in the monograph. Similarly, for premalignant lesions, only one case control study from India was discussed, whereas no case control or cohort studies from India for laryngeal, hypopharyngeal or nasopharyngeal cancer were discussed in the monograph. 
There is a difference in the incidence of tobacco related cancer between India and the western world. According to the report of the American Cancer Society, an estimated 228,190 new cases of lung cancer are expected in 2013, which will account for about 14% of all cancers diagnosed in the United States. Whereas, estimated new cases of cancer of the oral cavity and pharynx in the United States are 41,380; which is less than one-fifth of the estimated lung cancer cases.  In a sharp contrast to this, according to the population based cancer registry published by Indian Council of Medical Research (ICMR), in India, oral cavity and pharynx cancer accounts for about 12-32% of all cancer in males and about 3.5-10% of all cancers in female. Whereas, lung cancer accounts for only about 5-11% of all cancer in males and about 1.5-3% of all cancer in females.  There is also difference between incidence of cancer in different subsites of head and neck region among different parts of the world. Oral cancer is by far the most common cancer in India; laryngeal cancers are common in western world and the nasopharyngeal cancers in Chinese and south east population.  The difference of incidence and site wise distribution of head and neck cancer between India and most parts of the world is believed to be due to the difference in tobacco consumption pattern, i.e., smoking vis-a-vis ST use. According to a recently published study from India, the mortality rate in tobacco chewers has increased by 5 times due to oral cancer, in sharp contrast to the non-chewers. Increased mortality rate due to cancer of the pharynx, larynx, esophagus, stomach, and cervix were also noted among the chewers. 
In this review, we have included studies that have been conducted among the Indian population to find the association between ST use and malignant and premalignant diseases of head and neck region. In India, it is a common practice to chew tobacco in a mixture form along with areca nut and other ingredients. As areca nut is also a known carcinogen, so it is very difficult to say which ingredient of such mixture is more harmful or carcinogenic. To rule out any bias, we have reviewed all articles, which have investigated for association of head and neck cancer and premalignant lesions with usages of chewable form of tobacco with or without areca nut. We have also compared the result of our study with the result found by the IARC work committee on ST to find any difference, which may have happened due to the inclusion of less number of articles from India by the IARC working group.
| » Methodology|| |
Data collection has been performed by computer-aided search of the MedLine and PubMed databases using different combinations of the following key words "ST," "tobacco chewing," "India," "head and neck cancer," "oral cancer," "oropharyngeal cancer," "hypopharyngeal cancer," "laryngeal cancer," "nasopharyngeal cancer," "oral premalignant," "leukoplakia," "erythroplakia," "oral submucous fibrosis (OSMF)," and "dental disease." Only cohort and case control studies looking for association between ST use and cancer of different sites of the head and neck region were considered for further evaluation, as the evidence produced by them is stronger than that by cross-sectional studies. We have also reviewed some of the studies where the association between oral premalignant diseases and dental diseases with tobacco chewing has been investigated. As only a limited number of case control studies are available for premalignant diseases and dental diseases; we have also discussed some of the cross-sectional studies in this regard. Though we have primarily concentrated on the studies published exclusively from India; however, there are instances where references have been made to the IARC monogram for comparative purposes. To rule out any bias, we have reviewed all articles, which have searched for association of head and neck cancer and premalignant lesions with usages of chewable form of tobacco with or without areca nut. In tables, wherever applicable we have mentioned the form of tobacco usage.
| » Result and Discussion|| |
Oral cancer is one of the most common forms of cancer in India. Almost all published literature from different parts of the world reveals a strong association between oral cancer and chewing tobacco. 
Karunagappally cohort was established in 1990 at a rural coastal area in Kollam district of Kerala covering 93% of population. The baseline data were collected between 1990 and 1997. The incidence of oral cancer between 1990 and 2005 was documented in this cohort.  From this cohort, one study examined the association of oral cancer with tobacco chewing among females. The study found tobacco chewing as a significant risk factor for oral cancer among females. Oral cancer incidence was strongly related to daily frequency and duration of chewing habit, though the age of starting the habit was not a significant risk factor  [Table 1]. A separate analysis for males was also performed from the same cohort and it was found that tobacco chewing was a significant risk factor for oral cancer among males too. The risk of having cancer of mouth and gum was very high (relative risk [RR] 4.7) among the current tobacco chewers, whereas the risk of having tongue cancer was only slightly higher (RR 1.1). Alcohol consumption was not found to be a significant risk factor for oral cancer, whereas bidi smoking was a significant risk factor only for those who did not chew tobacco  [Table 1].
A number of case control studies are available from different parts of India and all of them reveal a strong association between tobacco chewing and oral cancer [Table 2].
Of the 12 case control studies, ,,,,,,,,,,, seven were from South India. ,,,,,, Most of these studies confirmed that the risks involved in tobacco chewing were higher than the risks associated with smoking, but only one study found the RR of oral cancer among bidi smokers to be higher than that for tobacco chewers. This study from Tamil Nadu indicated that the chewing of betel-nut and tobacco (odds ratio [OR] =3.19), chewing of tobacco alone (OR = 2.89), bidi smoking (OR = 4.63) and alcohol consumption (OR = 1.65) were all significant risk factors for oral cancer. People addicted to all three habits, had a very high RR for oral cancer (OR = 11.34).  A study from Kerala found tobacco chewing as the most potent risk factor associated with oral cancer. The adjusted OR of chewing tobacco was much higher than bidi smoking (3.3 vs. 1.9). Significant increased risk was observed among all categories of tobacco chewers, i.e. ever chewer, past chewer or present chewer.  The similar type of result was also depicted by other studies. A study found current smokers had about 2 fold increased risk of oral cancer, whereas tobacco chewers had about 5 fold increased risk of oral cancer. According to this study, the joint effect of smoking, chewing, and drinking alcohol was greater than additive but less than multiplicative. However, alcohol and tobacco chewing showed multiplicative interaction, inducing a 24 fold increased risk of oral cancer.  A study from Bangalore found RR associated with smoking (OR = 1.9) was much lower than RR associated with tobacco chewing (OR = 14.6). The study also reported that though smoking had only slightly increased risk of developing oral cancer, alcohol consumption and snuff inhalation did not increase any risk of oral cancer.  A study found the RR of oral cancer among men caused by smoking > 20 bidi/day was 2.5 (95% confidence interval [CI]: 1.4-4.4), and for alcohol consumption was 2.2 (95% CI: 1.4-3.3); whereas, for chewing paan with tobacco it was 6.10 (95% CI: 3.84-9.71). 
Two of these 12 studies were from Tata Memorial Hospital (TMH), Mumbai. Being the Apex Centre for Cancer Care in India, it actually represents patients from almost every region of the country. One of these studies from TMH found tobacco chewing to be a significant risk factor for oral cancer among males (OR = 2.95, 95% CI: 2.34-3.71). This study also found bidi smoking and alcohol consumption as a significant risk factor for oral cancer among males.  In the second study from TMH, the cases included tongue cancer patients (both oral and base of the tongue). According to this study, tobacco chewing was a significant risk factor for anterior tongue cancer, whereas bidi smoking was a significant risk factor for a base of the tongue cancer. The study concluded that the type of the tobacco used had a direct relationship with the site of the cancer. 
A study from Wardha, found the habit of gutka chewing to be significantly associated to oral cancer. The same study also found a strong association between oral cancer and sleeping with quid of tobacco in the mouth.  A recently published study from Pune, Maharashtra reported chewing tobacco, mishiri as well as consumption of gutka and betel-nut to be significant risk factors for oral cancer. Smoking of bidi was also a significant risk factor for oral cancer according to this study.  A study from Bhopal found about six-fold increase in the risk of oral cavity cancer among the tobacco quid chewers. Population attributable risk percent was found to be 66.1% for tobacco chewers for the development of oral cancer. 
Three of these twelve studies found that, though the RR for oral cancer associated with tobacco chewing was elevated in both the sexes; its effect was much higher among females. In one study, the adjusted OR for males was 3.1 (95% CI: 2.1-4.6), whereas for females it was 11.0 (95% CI: 5.8-20.7).  According to the second study, RR was 25.3% for females and 3.6% for males;  whereas the third study revealed 49% of oral cancer of male patients was attributable to paan chewing, on the other hand, for females, paan chewing attributed 87% of the oral cancer. 
One of these studies had also looked for association of tobacco chewing with cancer of the different subsites of the oral cavity. This study found that the RR of tongue cancer (2.74) was less than the RR of mouth cancer (6.95) among tobacco chewers. 
Three of these 12 studies were done for specific sub-sites of oral cancer. One study found substantial cases of cancer of the buccal and labial mucosa were attributable to paan-tobacco chewing. Duration of chewing habit was a better predictor than daily frequency of chewing or total life time exposure. Another important finding of this study was the revelation that the current occasional chewers had very high-risk of cancer of these two subsites of the oral cavity compared to non-chewers.  One study found there was a significant positive association between paan-tobacco chewing and cancer of the gingiva. The strongest predictor was daily frequency of paan-tobacco chewing. Four predictors of gingivial cancer were yielded from stepwise logistic regression analysis; they were the daily frequency of paan-tobacco chewing, duration of bidi use, and alcohol and snuff use (regular versus ever).  According to a study from TMH, tobacco chewing was a significant risk factor for anterior tongue cancer, whereas bidi smoking was a significant risk factor for a base of the tongue cancer. 
Laryngeal and hypopharyngeal cancer
Laryngeal and hypopharyngeal cancers are common in India. Among the sub-sites of the larynx, unlike the Western world, supraglottic cancer is more common in India rather than glottic cancer. Among the subsites of the hypopharynx, pyriform sinus cancer is the most common.
Four case control studies from different parts of the country are available looking for association of tobacco chewing and cancer of the larynx and hypopharynx. Of them, two were only for laryngeal cancer, one was for different subsites of pharynx including hypopharynx and the other was for both laryngeal and hypopharyngeal cancer [Table 3].
The study which sought to associate the various risk factors of both laryngeal and hypopharyngeal cancer found that higher risk of hypopharyngeal cancer was associated with chewing of both tobacco (OR = 1.51, CI: 1.08-2.11) and non-tobacco (OR = 1.95, CI: 0.96-3.97) products. However when the same analysis was performed among the non-smokers only, the risk associated with chewing tobacco product increased in magnitude (OR = 3.18, CI: 1.92-5.27), whereas the risk associated with chewing non-tobacco product became non-apparent (OR = 1.21, CI: 0.39-3.78). The same study could not found any association between chewing tobacco products and the risk of laryngeal cancer (OR = 0.75, CI: 0.52-1.70 for all individuals, OR = 0.95, CI: 0.52-1.73 for never smokers). This study also found strong dose response relationship between tobacco chewing and hypopharyngeal cancer.  Results from a study from Southern India also suggested that tobacco chewing is a risk factor for pharyngeal cancer (both oro and hypopharynx), but the evidence was not conclusive. Smoking was the strongest risk factor for pharyngeal cancer in this study. 
The other two studies were specifically for laryngeal cancer. The result of one of these studies was quite surprising. In this study, paan-tobacco chewing was found to be an almost significant protective factor (0.1 > P < 0.05) for laryngeal cancer, on the other hand occasional chewing was a significant risk factor for the same (RR 13.74, 95% CI: 4.92-38.34; P < 0.001). The authors concluded that the protective role of tobacco chewing could be an artifact of the confounding effect of smoking. According to the authors, two other noteworthy findings of the same study, i.e., the high-risk associated with occasional use and low risk associated with a late start of the chewing habit were compatible with a moderate increase in risk associated with paan-tobacco chewing.  The other study found that on univariate analysis, there was a strong association between alcohol intake, smoking and chewing of tobacco with betel leaf and laryngeal cancer; however overall tobacco chewing (with or without betel leaf) was not a significant risk factor for laryngeal cancer. 
We could found three case control studies from India where the association between oropharyngeal cancer and use of chewable form of tobacco have been investigated. Of them, two were from Central India and one was from South India [Table 4].
The study from South India found that there was a marginally elevated risk of oropharyngeal cancer among tobacco chewers (OR = 1.74, 95% CI: 1.25-2.43), whereas the risk was much higher among current smokers (OR = 5.46, 95% CI: 3.46-8.61) and alcohol drinkers (OR = 2.51, 95% CI: 1.85-3.40). 
One study from Bhopal showed marginally increased risk for oropharyngeal cancer (OR = 1.2; 95% CI: 0.8-1.8) among tobacco chewers, whereas the risk was very high for smokers (OR = 7.2; 95% CI: 4.7-11.2). Compared to the non-chewers, the risk of oropharyngeal cancer was not significant among those who chewed <10 tobacco quid/day. However, there was significant (3.6 fold) increased risk of oropharyngeal cancer among those who chewed >10 tobacco quid/day. Persons who chewed tobacco quid for more than 30 years, the risk of having oropharyngeal cancer was 3.1 times more than persons who did not chew tobacco quid at all.  The result of the other study from the same region (Nagpur, Central India) was quite different. According to this study, though tobacco chewing and smoking both were significant risk factors for oro-pharyngeal cancer, the OR was much higher for chewers (OR = 7.98, 95% CI: 4.11-13.58) compared to smokers (OR = 2.25, 95% CI: 1.22-3.70). 
A case control study from North-Eastern region of the India could not find any association of nasopharyngeal carcinoma with habits of ST product use, betel-nut chewing, smoking, and alcohol intake. 
Head and neck squamous cell carcinoma (HNSCC)
A case control study from Kolkata investigated the association between tobacco use and squamous cell carcinoma of the entire head and neck region. This study found 2.17 fold increase risk of developing HNSCC among current tobacco users. This study could not find any significant difference for the development of the disease between ST use and smoking. 
OSMF is a potentially malignant disorder which has been reported exclusively among Asian population, particularly among Indians. Though the major risk factor for OSMF is areca nut chewing, studies are available where the association between the chewing of tobacco and OSMF has been investigated.
A study from Kerala investigated the association of other habits with OSMF. This study found ever-tobacco chewing as a strong risk factor for OSMF (OR = 44.1, 95% CI: 22.0-88.2), whereas alcohol drinking as a possible risk factor (OR = 2.1, 95% CI: 1.0-4.4). 
A hospital-based case-control study compared 220 patients of OSMF with matched controls with regard to dietary habits, smoking history, and preference for chewing substrates. This study found the RR of developing OSMF was highest among gutka chewers (relative risk, 1,142.4). Another important finding of this study was, RR of OSMF increased with the frequency of chewing habit up to 15 times daily and with duration of habit up to 4 years. 
A case control study from All India Institute of Medical Sciences, New Delhi found chewing of areca nut/quid or pan-masala was directly related to OSMF; however, chewing or smoking did not increase the risk of OSMF. 
Some notable cross-sectional studies are also available from India, which are worth mentioning here. After evaluating 205 cases of OSMF, one study found a strong association between ST use, especially that of gutka (combination of ST and areca nut) and OSMF. The authors also found OSMF developed within 1 year of chronic use of gutka.  Another study conducted among 1000 patients with OSMF who visited a government dental college at Nagpur, Maharashtra found that 77.8% of patients had a history of multiple habits, where as 20.5% patients gave a history of only one habit. For patients who had only one habit, exclusive areca nut chewing habits were more common among females compared to men (OR = 44.5), whereas addiction to gutka (OR = 3.69) and kharra/mawa chewing was more common among men. Among patients who gave a history of multiple habits, increased incidence of areca nut chewing (OR = 24), kharra/mawa chewing (OR = 6.8), gutka chewing (OR = 2.33) and smoking (OR = 12.8) were observed in men compared with women.  A study conducted among 2017 consecutive patients who attended a dental college at Chennai found that the prevalence of OSMF was 0.55%. The prevalence of OSMF was more common among the chewers of paan-masala, gutka and betel-quid with or without tobacco. 
Other premalignant lesions
Other than OSMF, oral leukoplakia and erythroplakia are the other two important oral premalignant lesions. Case control studies are available from India, which establish the association of these premalignant lesions with tobacco chewing.
One such study was carried out in Kerala to find the risk factor associated with multiple oral premalignant lesions. The cases were patients having at least two or all the three major oral premalignant lesions, i.e. leukoplakia, erythroplakia and OSMF. The adjusted OR for continuous tobacco chewers was very high (OR = 37.8, 95% CI: 16.2-88.1). There was possible association of alcohol intake and multiple oral premalignant lesion (OR = 1.4, 95% CI: 0.7-2.7), but no association was found with smoking (OR = 0.9, 95% CI: 0.5-1.7).  Another study was conducted among patients with only oral leukoplakia lesions. The control group of this study was the same control group of the previous study. This study revealed tobacco chewing as a significant risk factor for oral leukoplakia (adjusted OR = 7.0, 95% CI: 55.9-8.3). The association was significantly higher for females (OR = 37.7 95% CI: 524.2, 58.7) compared with males (OR = 3.4, 95% CI: 2.8-4.1). 
Using the same control group of the two studies mentioned above, another study was conducted among patients with only oral erythroplakic lesion. This study found tobacco chewing as a significant risk factor for erythroplakia (OR = 19.8, 95% CI: 9.8-40). The risk associated with alcohol (OR = 3.0, 95% CI: 1.6-5.7) and smoking (OR = 1.6, 95% CI: 0.9-2.9) was much smaller. 
Poor dental hygiene and different oral lesions are common among chronic tobacco chewers. Several studies from different parts of India establish the association between different dental disorders and chewing habits.
A case control study conducted among the slum dwellers of Visakhapatnam revealed that saliva and mucous formation decrease in gutka chewers, which ultimately results in the reduction of normal oral microflora.  A case control study from Uttar Pradesh reported the incidence of dental caries were significantly lower among ST chewers compared to non-chewers, whereas the incidence of periodontal diseases were slightly higher among the chewers, but the difference was not statistically significant. The study concluded that the higher incidence of caries among the non-chewers might be due to the significantly higher number of lactobacillus found in their saliva compared to the chewers. 
A cross-sectional study from Ahmedabad, Gujarat found in spite of no statistically significant difference of oral hygiene measures adopted, only 14.9% of the chewers had good oral hygiene where as 49.2% of non-chewers had good oral hygiene. Different oral symptoms such as gum bleeding (OR = 1.38), halitosis (OR = 1.56), trismus (OR = 4.84), burning sensation (OR = 9.99), ulceration and difficulty in swallowing were more common among the chewers. They also found that different periodontal conditions such as periodontal pocket (OR = 1.64), gingivial lesion (OR = 2.86), gingivial recession (OR = 1.72) were more common among chewers.  A study conducted among 805 subjects in the age group 30-69 years revealed that the highest prevalence of oral mucosal lesions (22.7%) was found among tobacco chewers, compared to the smokers/non-tobacco users. The mean number of decayed teeth (6.96) and filled teeth (3.67) were also highest among tobacco chewers. 
A study compared periodontal status of 150 subjects who chewed paan without tobacco with an equal number of subjects who chewed paan with tobacco. With the probing depth of 6 mm, 30% of paan-tobacco chewers had community periodontal index code 4, whereas 7.3% of paan chewers without tobacco had Community Periodontal Index (CPI) code-4. Paan chewers with tobacco had 4.7 times increased risk of having pockets and 7 times increased risk of suffering loss of attachment than paan chewers without tobacco. They concluded that the addition of tobacco causes a synergistic effect on deleterious effect of betel-nut over periodontal tissue. 
| » Conclusion|| |
The studies from India suggest a strong association of tobacco chewing with oral and oropharyngeal cancer. There is also almost certain association between tobacco chewing and cancer of the hypopharynx. These findings are quite different from the finding of the IARC monograph. Both monograph and studies from India found a strong association between tobacco chewing and cancer of the oral cavity. However, studies from India suggest certain association of oropharyngeal and hypopharyngeal cancer with the use of chewable form of tobacco, which was not found by the Monograph. As tobacco chewing is exceedingly common in India compared to the western world, we believe the high incidence of hypopharyngeal and oropharyngeal cancer in this part of world is attributed to the rampant use of the smokeless form of tobacco. Both IARC monograph and studies from India could not find any association between ST use and cancer of the larynx and the nasopharynx. Indian studies suggest a strong association between tobacco chewing and different premalignant lesions such as leukoplakia and erythoplakia. However, the association between tobacco chewing and OSMF is not well-established. Studies from India also suggest association between different dental diseases and tobacco chewing.
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[Table 1], [Table 2], [Table 3], [Table 4]
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