|Year : 2012 | Volume
| Issue : 2 | Page : 74-78
Smokeless tobacco and oral cancer: A review
Jagriti Gupta1, Krishna Kumar Gupta2, Fahad Mansoor Samadi1, Arpita Kabiraj1
1 Department of Oral Pathology and Microbiology, Sardar Patel Post Graduate Institute of Dental & Medical Sciences, Lucknow, Uttar Pradesh, India
2 Department of Periodontology and Implantology, Sardar Patel Post Graduate Institute of Dental & Medical Sciences, Lucknow, Uttar Pradesh, India
|Date of Submission||03-Jul-2012|
|Date of Acceptance||26-Jul-2012|
|Date of Web Publication||24-Jan-2013|
C/O Gupta Dental Clinic, 3A Vijaynagar, Kanpur Road, Lucknow, Uttar Pradesh
Source of Support: None, Conflict of Interest: None
Smokeless tobacco (ST) is not burnt when it is used and is usually placed in the oral or nasal cavities against the mucosal sites that permit the absorption of nicotine into the human body. Health risks related to ST have received comparatively little attention, in spite of widespread use in many parts of the world. With the current emphasis on adverse health consequences of tobacco smoking, including exposure to environmental tobacco smoke, there may be a shift to increased use of ST. Habitual use of oral tobacco can increase the risk of oral cancer. Increasing use has been reported not only among men, but also among such vulnerable groups as children, teenagers, women of reproductive age, and by immigrants of the South Asian origin wherever they have settled. However, the known and suspected health risks associated with ST indicate that it should not be viewed as an alternative to smoking. The present review portrays a vivid description of the various ill effects of ST usage.
Keywords: Carcinogenicity, nitrosamines, oral cancer, smokeless tobacco
|How to cite this article:|
Gupta J, Gupta KK, Samadi FM, Kabiraj A. Smokeless tobacco and oral cancer: A review. Indian J Oral Sci 2012;3:74-8
| Introduction|| |
Smokeless tobacco (ST) has been associated with oral cancer for many decades. The types of tobacco that people dip or chew are sometimes called "smokeless" tobacco. The term "smokeless" does not mean "harmless." Advertisements for ST imply that the habit is less harmful than smoking. Unfortunately, this impression is common among the public and even among health professionals. The various ST habits practiced throughout the world include tobacco chewing and snuff dipping. Tobacco chewing is the practice of placing a portion of leaf, plug, cake, or thread twines of tobacco between the cheek and gingiva after it has been chewed. 
Loose-leaf chewing tobacco, moist snuff, and dry snuff are the three types of ST commonly used in the oral cavity.  The risk of oral cancer from long-term ST use is elevated, and much of this risk has been attributed to the presence of tobacco-specific N-nitrosamines (TSNAs). TSNAs are widely considered to be among the most important carcinogens in ST products and cigarette smoke. 
The high incidence of oral cancer in India tends to reflect the widespread use of tobacco. A study from the WHO International Agency for Research on Cancer concluded that ST users have an 80% higher risk of developing oral cancer and a 60% higher risk of developing pancreatic and esophageal cancer.
| Epidemiology|| |
Cancers of the oral cavity accounted for over 274,000 cases in 2002 and were the cause of death in over 127,000 cases. In India, cancer of the oral cavity is one of the five leading sites of cancer in either sex. It is estimated that 75,000-80,000 new oral cancer cases develop in India annually.  Oral squamous cell carcinoma is the most frequent tumor of oral cavity, statistically responsible for 90% of oral cancer world data diagnosed every year.  In countries of South Asia, particularly India, traditional values do not favor smoking by the young or by women, but there is no such taboo against using ST. Thus, most women who use tobacco use it in smokeless forms. Tobacco use, in whatever form, generally begins during adolescence. In India, it has been estimated that roughly one-third of women and two-thirds of men use tobacco in one form or another. In prevalence surveys, in eight rural areas of India, ST use was 3-53% among men and 3-49% among women. Also in these areas, 2-26% of men and 0-4% of women practised both smoking and ST habits.
| Smokeless Tobacco|| |
ST is tobacco consumed orally, not smoked. It has been in use for as long as other forms of tobacco consumption and its use have dramatically increased. In developing countries, tobacco is mostly chewed with other ingredients. Chewing tobacco is practised in different ways. The main ingredients are usually areca nut (betel), betel leaf, lime, and tobacco.  Habitual betel quid chewing is commonly practised by men and women in Bangladesh, India, Pakistan, and Sri Lanka, while tobacco smoking is much more common among men in these countries compared to women, except for certain small geographic areas. 
In India and Pakistan, almost 100 million people use ST.  In India, some forms are called khaini, mishri, zarda, and kiwam, which constitute different preparations of tobacco (dried, roasted, or boiled). The habit of nass is common in Central Asia with prevalence rates of up to 20% in some countries. Nass is usually made with local tobacco, ash and cotton or sesame oil, but the composition varies in different regions. 
More than 2000 chemical compounds have been identified in processed tobacco. This includes original tobacco constituents and chemicals applied during cultivation, harvesting, and processing. Major classes of compounds identified in tobacco include aliphatic and aromatic hydrocarbons, aldehydes, ketones, alcohols, phenols, amines, amides, alkaloids, metals, and radioelements. Tobacco-specific nitrosamines are formed from alkaloids during the processing of tobacco leaves. The concentrations in chewing tobacco and snuff may exceed by two orders of magnitude levels found in other consumer products. The average consumption in regular users of snuff is about 10-15 g per day. In general, the snuff is kept in the oral cavity for several hours per day. This holds true also for many other types of ST. 
About 35-40% of tobacco consumption in India is in smokeless form, mostly of the species Nicotiana rustica, while most smoking tobacco is N. tabacum. Samples of N. rustica have been found to contain higher concentrations of tobacco-specific nitrosamines than N. tabacum. Two of the tobacco alkaloid-derived compounds, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N9-nitrosonornicotine (NNN), are consistently carcinogenic in laboratory animals, with NNK showing higher activity and the other two commonly measured TSNAs are N0?-nitrosoanabasine (NAB) and N?-nitrosoanatabine (NAT).  Hoffmann's group had identified 28 known carcinogens in ST analysed by them. TSNAs are the most abundant carcinogens identified in unburnt tobacco and are formed during the aging, curing, and fermentation of tobacco.  There is sufficient evidence for the carcinogenecity of 3-methylnitrosamino propionitrile to experimental animals. 
While carcinogenicity of ST to humans is well established, the oral lesions that precede development of cancer are less well characterized. The clinical appearances of ST-associated lesions are variable. Epidemiological studies show a strong significant association of risk with chronic daily use, but population differences are noted because of various commercial products in use. Morphological features observed are somewhat different to oral lesions caused by smoking and oral dysplasia in ST-associated lesions is less common. Effects of ST on oral keratinocytes observed in vitro include alterations in cell proliferation, apoptosis, and activation of inflammatory markers. 
| Pathophysiology|| |
The chemical carcinogens in ST include polynuclear aromatic hydrocarbons (usually benzo[a]pyrene), polonium 210, and N-nitrosamines. Other chemicals include radium-226 and lead-210.  Oral ST contains numerous carcinogens, including polonium 210, tobacco-specific N-nitrosamines, volatile aldehydes, and polycyclic aromatic hydrocarbons.
Approximately, twice as much as nicotine is absorbed per dose from ST than cigarettes (4 vs. 2 mg); orally absorbed nicotine also stays longer in the bloodstream. ST that is placed in the mucobuccal folds causes direct damage to the periodontium (e.g., gingivitis, periodontal recession) and oral soft tissue.
Tobacco and alcohol use are the major risk factors for cancers of the oral cavity and pharynx, accounting for more than 75% of these neoplasms. The use of oral tobacco (moist snuff and chewing tobacco) has been found to be associated with oral lesions in both young people and adults. Histologically, these "smokeless tobacco lesions" are characterized by hyperkeratinization and vacuolization of the epithelium, acanthosis, and proliferation of inflammatory cells. Clinically, ST lesions appear as changes in the color and texture of the oral mucosa. The terminology for these lesions varies. They have been called "smokeless tobacco keratosis," "snuff dipper's lesions," "oral leukoplakia," and "smokeless tobacco lesions." 
| Lesions Associated with Smokeless Tobacco Use|| |
The various oral lesions that are found to be associated with chronic usage of ST can be enumerated as under.
A precancerous lesion in the oral cavity has also been strongly associated with ST use both among young adults and adolescents.  Leukoplakia refers to a filmy white or yellow patch involving the oral mucosa. The patch may appear translucent or opaque and raised or ulcerated. It may be pumice like. Leukoplakia is a clinically descriptive term, and other diseases must be ruled out.
Erythroplasia appears as a patch with varying degrees of erythema. It most commonly occurs on the floor of the mouth. The term erythroplakia is used for a clinically and histopathologically similar process that occurs on the oral mucosa. Similar to the definition for leukoplakia, erythroplakia is a clinical term that refers to a red patch that cannot be defined clinically or pathologically as any other condition. 
Nicotine stomatitis and tobacco pouch keratosis
Two specific tobacco-related lesions of the oral mucosa, nicotine stomatitis and tobacco pouch keratosis, have often been included under the broad umbrella of leukoplakia. However, because these lesions have a specific known cause and prognosis, we prefer to classify them separately from leukoplakia.  Tobacco-associated keratosis is an ill-defined area of white thickening at the sites at which oral ST is habitually placed; most commonly, these areas involve the mandibular labial and buccal mucosal folds. The continued use of ST causes the affected areas to become corrugated and grayer. Microscopically, ST keratoses show hyperkeratosis and acanthosis of the mucosal epithelium. True epithelial dysplasia is uncommon; when dysplasia is found, it is usually mild in degree.  Such lesions typically occur in the buccal or labial vestibule where the tobacco is held, but they can also extend onto the adjacent gingiva and buccal mucosa. 
Oral submucous fibrosis
Oral submucous fibrosis (OSF) was initially described in 1966 by Pindborg and Sirsat as an insidious, precancerous, chronic disease that may affect the entire oral cavity and that sometimes extends to the pharynx. Although it is occasionally preceded by the formation of vesicles, OSF is always associated with a subepithelial inflammatory reaction followed by fibroelastic changes of the lamina propria, accompanied by epithelial atrophy. This process leads to stiffness of the oral mucosa, which results in trismus and inability to eat.  Both leukoplakia and submucous fibrosis are potentially malignant conditions in the oral cavity. 
A warty variant of squamous cell carcinoma characterized by a predominantly exophytic overgrowth of well-differentiated keratinized epithelium having minimal atypia and with locally destructive pushing margins at its interface with underlying connective tissue. Microscopically, there is marked epithelial proliferation with downgrowth of epithelium into connective tissue but without a pattern of invasion. 
Squamous cell carcinoma
It is a malignant epithelial neoplasm exhibiting squamous differentiation as characterized by the formation of keratin and/or the presence of intercellular bridges. In India, the majority of oral cancers are unequivocally associated with tobacco chewing habits and usually preceded by premalignant lesions, most often a persistent leukoplakia or OSF. 
Individual cases of acute necrotizing ulcerative gingivitis (ANUG), gingivitis, and periodontitis have been reported, but a clear relationship does not exist between a generalized periodontal condition and smokeless tobacco use. Gingival recession and attachment loss have been shown to occur in the area adjacent to where the smokeless tobacco is held, but some authors believe that gingival recession occurs only in ST users who exhibit coexisting gingivitis. The prevalence of dental caries, gingivitis, and plaque were not shown to be different in ST users and nonusers. 
Tobacco smoking is related to many types of health effects besides cancer and cardiovascular disease, which also could be of importance following ST use. Unfortunately, only few studies have investigated such effects. Most evidence relates to local lesions in the oral cavity. The role of ST for the development of gingivitis, parodontitis, and dental caries remains equivocal. 
The use of oral tobacco (moist snuff and chewing tobacco) has been found to be associated with oral lesions in both young people and adults. Histologically, these "smokeless tobacco lesions" are characterized by hyperkeratinization and vacuolization of the epithelium, acanthosis, and proliferation of inflammatory cells. 
| Diagnostic Modalities for Oral Cancer Detection|| |
The oral mucosa can be easily inspected and therefore oral cancer should be detected at a very early stage. A thorough examination of the oral mucosa of lips, tongue, alveolar mucosa, floor of the mouth, palate, cheek, and oropharynx should be routinely carried out for every patient presenting at a dental office. 
Toluidine blue (TB) staining is a simple and inexpensive diagnostic tool that uses a blue dye to highlight abnormal areas of mucosa. TB is a basic metachromatic nuclear stain which stains nuclear material of malignant lesions and premalignant lesions, but not normal mucosa. 
The biopsy should be sufficiently large to include suspect and apparently normal tissue to give the pathologist a chance to make a diagnosis and not to have to request a further specimen. Since red rather than white areas are most likely to show any dysplasia present in the lesion, a biopsy should include the former.
Carcinoma is diagnosed when histopathological examination shows that there is:
- Dysplasia extending through the full thickness of the epithelium (severe dysplasia) and with
- Extension of the rete pegs into the underlying lamina propria, i.e., invasion across the basement membrane. 
The concept of a saliva test to diagnose oral squamous cell carcinoma is even more appealing. Promoter hypermethylation patterns of TSG p16, O6-methylguanine-DNA-methyltransferase, and death-associated protein kinase have been identified in the saliva of head and neck cancer patients. Forensic science has since shown that saliva can contain a number of messenger ribo-nucleic acid (mRNA) fragments including salivary-specific statherin, histatin and the proline-rich proteins PRB1, PRB2, and PRB3, as well as the ubiquitously expressed spermidine N1 acetyl transferase (SAT), β-actin, and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). 
Other diagnostic adjuncts
Certain other diagnostic tests for early detection are autofluorescence, DNA analysis, biomarkers, spectroscopy, and newer adjuncts such as VeLscope, Vizilite system, etc. This state of the art review critically examines these tests and assesses their value in identifying oral squamous cell carcinoma and its precursor lesions. 
| Conclusion|| |
ST forms can serve as a gateway to cigarette smoking. Dual tobacco-product use or switching from smoked tobacco to ST may also result in establishment of novel mutational spectra in the target organ that may increase the number of genetic hits above a threshold considered essential for initiation and promotion of cancer in the oral cavity. Use of both products could also be far more toxic to oral mucosa than just one type of tobacco.
Government, non-government, NGOs, dentists, and other health professionals should discourage tobacco users to use tobacco products, and this is made effective at individual as well as community level with various approaches. The Government of India promulgated The Cigarette (Regulation of Production, Supply and Distribution) Act 1975 and The Cigarettes and Other Tobacco Products (COTPA) (Prohibition of Advertisement and Regulation of Trade and Commerce, Production, and Supply and Distribution) Act, 2003 which advocate a statutory warning on tobacco products, "Cigarette smoking is injurious to health." On October 2011, Ministry of Health and Family Welfare notified new rules through a Gazette notification, which firmly regulates the depiction of tobacco use in films. The current health warning appearing on tobacco products consist of a drawing of scorpion on smokeless form of tobacco. These pictorial representations are collectively known as "shock effect." The recent statutory warning for smoking and ST is "Tobacco kills."
However, further research and eventual implementation of such important health promotion programs will benefit populations addicted to ST use and contribute to the control of oral cancer.
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