|Year : 2014 | Volume
| Issue : 3 | Page : 499-505
Betel nut chewing and its deleterious effects on oral cavity
Richa Anand1, Chandan Dhingra2, Sumanth Prasad3, Ipseeta Menon4
1 Department of Public Health Dentistry, I.T.S Dental College, Hospital and Research Centre, Greater Noida, India
2 Department of Public Health Dentistry, Sudha Rustagi College of Dental Scinces and Research, Faridabad, Haryana, India
3 Department of Public Health Dentistry, Sri Gobind Tricentenary Dental College, Hospital and Research Institute, Gurgaon, India
4 Department of Public Health Dentistry, I.T.S Centre for Dental Studies and Research, Ghaziabad, Uttar Pradesh, India
|Date of Web Publication||14-Oct-2014|
5E 46 BP, New Industrial Township, Faridabad - 121 001, Haryana
Source of Support: None, Conflict of Interest: None
The habit of chewing betel nut has a long history of use. Betel nut and products derived from it are widely used as a masticatory product among various communities and in several countries across the world. Over a long period, several additives have been added to a simple betel nut preparation; thus, creating the betel quid (BQ) and encompassing chewing tobacco in the preparation. Betel nut has deleterious effects on oral soft tissues. Its effects on dental caries and periodontal diseases, two major oral diseases are less well-documented. Betel-induced lichenoid lesions mainly on buccal mucosa have been reported at quid retained sites. In chronic chewers, a condition called betel chewers mucosa is often found where the quid is placed. Betel nut chewing is implicated in oral submucous fibrosis (OSF) and its use along with tobacco can cause leukoplakia, both of which are potentially malignant in the oral cavity. Oral cancer often arises from such precancerous changes. Thus, public health measures to quit betel use are recommended to control disabling conditions such as OSF and oral cancer.
Keywords: Betel nut chewing, betel quid, oral health
|How to cite this article:|
Anand R, Dhingra C, Prasad S, Menon I. Betel nut chewing and its deleterious effects on oral cavity. J Can Res Ther 2014;10:499-505
| > Introduction|| |
The habit of chewing betel (or areca) nut is a habit of great antiquity. Its use is globally acceptable among all sections of society, including women and quite often children.  Four factors form the foundation for the popularity of chewing betel nut are: Social acceptability, religious beliefs, perceived health benefits, and addiction. 
Betel nut is the fourth most commonly used psychoactive substance in the world after caffeine, alcohol, and nicotine. Betel nut is present in a number of chewing products like mawa, paan, gutkha, khaini, and paan masala. Reasons for using betel nut include achieving euphoria, combating fatigue, increasing salivation, attaining satiation, and even seeking relief of toothaches. ,
Chewing betel nut on a habitual basis is known to be deleterious to human health.  The World Health Organization and International Agency for Research on Cancer classified betel nut as a group 1 human carcinogens.  The International Agency for Research on Cancer considers paan and gutkha as substances containing known human carcinogens, of which the betel nut is believed to be the main culprit.  A growing body of evidence over the last 40 years, mainly in the form of large-scale epidemiological and experimental studies, has shown that even when consumed in the absence of tobacco or lime betel may have potentially harmful effects on the oral cavity. These effects can be divided into two broad categories: Those affecting the dental hard tissues, which include teeth, their supporting periodontium and the temporomandibular joint (TMJ) and the soft tissues, which make up the mucosa that lines the oral cavity.  This article aims to review the effects of chewing betel nut on oral health.
| > Effects on hard tissues|| |
Excessive tooth abrasion and fractured teeth
The hard fibrous nature of the betel nut causes fractured teeth and extensive abrasion of the occlusal tooth surface of regular users. The molars, premolars, and canine teeth frequently completely lose their cuspal form and the incisors become shortened.  The loss of enamel may also expose the underlying dentine and as this is softer than enamel wears at an increased rate. The exposure of dentine may also result in dentinal sensitivity. 
The degree of attrition is dependent upon several factors, which include the consistency (hardness) of the betel, the frequency of chewing, and the duration of the habit. Root fractures have also been demonstrated in chronic betel chewers and this is likely to be a consequence of the increased masticatory load that is placed upon the teeth and is not direct effect of betel. 
Chewing betel nut produces copious red saliva. With regular betel quid (BQ) chewing, this stain becomes embedded in the teeth, gingival, and oral mucosa  [Figure 1]. The color ranges from red to black depending on the preparation and the number of years of use. The darkening has been reported to be caused by polymers of orthoquinones. Traditionally, this tooth coloration was regarded as esthetically pleasing by some societies, but with western influence it seems to be becoming less. 
It has been suggested that betel chewing may confer protection against dental caries. Epidemiological studies carried out in southeast Asia suggest that the prevalence of dental caries in betel chewers is lower than in non-chewers. , The possible reasons that BQ chewing diminishes dental caries are:
- Betel stain which often coats the surface of the teeth, may act as a physical barrier to tooth demineralization 
- Tannin content of betel may have antimicrobial properties and this may contribute to the cariostatic role of betel 
- Chronic chewers have marked attrition of cusps of teeth leading to loss of occlusal pits and fissures, which may reduce the risk of pit and fissure caries by eliminating potential stagnation areas
- The process of chewing itself brings copious amounts of saliva to the mouth and in the presence of added slaked lime may increase the pH in the oral environment
- The increased production of sclerosed dentine in response to attrition may confer protection against microbial invasion.
Some investigators, however, have shown that there is no difference in the prevalence of dental caries between betel chewers and non-chewers in other Asian populations. 
It has been speculated that the chewing forces generated during habitual betel nut use could give rise to deterioration of the TMJ. However, there is no reliable data to substantiate an increased prevalence in betel users and further studies are required. Furthermore, this is difficult to prove because many of the symptoms associated with TMJ pathology, e.g. trismus, also occurs in fibrotic conditions linked to betel nut use. It is difficult to distinguish a direct effect on the TMJ from the fibrotic involvement of the oral musculature that may contribute to limitation of mouth opening in chronic chewers. 
| > Effects on soft tissues|| |
The betel nut may be cytotoxic to periodontal fibroblasts and may exacerbate preexisting periodontal disease as well as impair periodontal reattachment. Some investigators have shown that loss of periodontal attachment and calculus formation is greater in betel chewers. ,,, However, it is difficult to interpret such facts, as there are several confounding variables such as the level of oral hygiene, dietary factors, general health, and dental status, not to mention tobacco smoking, which may have a significant influence on periodontal status.
Oral mucosal lesions and conditions associated with BQ chewing habits
Definition of quid
The term "quid" may be defined as "a substance or mixture of substances (in any manufactured or processed form), placed in the mouth or chewed and remains in contact with the mucosa, usually containing one or both of the two basic ingredients, tobacco, or betel nut, in raw or any manufactured or processed form". Thus, BQ is to be considered as a specific variety of quid; it indicates any type of mixture or quid that includes betel leaf. 
Categories of quid
- Quid with betel nut but without tobacco products (betel nut quid) which may involve chewing only the betel nut or betel nut quid wrapped in betel leaf (paan)
- Quid with tobacco products but without betel nut (tobacco quid) including chewing tobacco, chewing tobacco plus lime, mishri (burned tobacco applied to the teeth and gums), moist snuff, dry snuff, niswar (a different kind of tobacco snuff), and naas (a stronger form of niswar)
- Quid with betel nut as well as tobacco products (tobacco and betel nut quid). 
Some oral mucosal lesions and conditions are specifically associated with BQ chewing habits. Two categories of quid-related lesions are recognized:
- Lesions or conditions that are diffusely outlined, that involve more than one site or that represent a widespread alteration, such as those due to mechanical or chemical trauma. Clinical lesions or conditions such as chewer's mucosa fall into this category, but transient states of the mucosa, such as quid stains, are excluded 
- Lesions that are localized to the site where quid is regularly placed. These lesions are equivalent to snuff induced lesions or tobacco lime user's lesions, which arise only on the mucosa in contact with the quid. ,
Betel chewer's mucosa
A condition of the oral mucosa where, because of either direct action of the quid or traumatic effect of chewing, or both, there is a tendency for the oral mucosa to desquamate or peel [Figure 2]. Loose and detached tags of tissue can also be seen and felt. The underlying areas assume a pseudomembranous or wrinkled appearance. The area may also show evidence of incorporation of ingredients of the quid in the form of yellowish or reddish-brown encrustations.  The lesion is usually localized and is associated strongly with the habit of BQ chewing, particularly in elderly women who have been chronic chewers for long durations.  Several epidemiological studies have shown that the prevalence of betel chewer's mucosa may vary between 0.2 and 60.8% in different southeast Asian populations. ,,,
|Figure 2: (a) Betel chewers mucosa, (b) betel-quid lichenoid lesion, (c) oral leukoplakia, and (d) oral submucous fibrosis|
Click here to view
This lesion should be distinguished from morsicatio buccarum and/or labiorum, cheek or lip biting, which are very similar to betel chewer's mucosa in terms of clinical appearance (without stains) and histology. The differences are: Cheek biting is unintentional; whereas, chewer's mucosa results from an intentional habit and the average age of the individuals with chewer's mucosa is usually higher, 50 years and older;  whereas, in cheek biting it is generally younger, around 20-35 years. ,,
Although the exact mechanisms underlying the development of this condition are not fully understood, it is thought that the chemical and traumatic effects of the BQ on the oral mucosa may be significant factors. Betel chewing produces reactive oxygen species (ROS) that is detrimental to oral mucosa and can be directly involved in tumor initiation process, by inducing mutation, or by making the mucosa susceptible to BQ ingredients and environmental toxicants. The production and release of ROS occurs under alkaline conditions during the autoxidation of betel nut polyphenols, in the BQ chewer's saliva. The ROS can be directly involved in the tumor initiation process, by inducing genotoxicity and gene mutation, or by attacking the salivary proteins and oral mucosa, leading to structural change in the oral mucosa that may facilitate the penetration by other BQ ingredients and environmental toxins. The nitrosation of betel alkaloids to AN-specific nitrosamines occurs in the saliva of BQ chewers. These AN-specific nitrosamines are mutagenic, genotoxic, and capable of inducing tumors in animal model. 
Furthermore, there is also evidence that the presence of tobacco in the quid is not essential for the development of betel chewers mucosa. At present betel chewers mucosa is not considered to be potentially malignant, although the condition often co-exists with other mucosal lesions such as leukoplakia and oral submucous fibrosis (OSF), which are well known for their potential for malignant change. 
A quid-induced lesion is a localized lesion of the oral mucosa corresponding to the regular site of placement of quid. It is characterized by one or more of the following characteristics: change of normal color, wrinkled appearance, thickening of the mucosa, scrapable or non-scrapable epithelial surface, and presence of ulceration. Examples of such quid-induced lesions are: Tobacco and lime user's lesion, snuff-induced lesions, and BQ lesions. ,
Betel nut-related lesion
Betel nut chewers, as in chewers of other kinds of quids, may have clinically healthy mucosa with no textural or color changes. However, buccal mucosa, either bi- or unilaterally, may show an ill-defined whitish gray discoloration that cannot be rubbed off. The mucosa, in addition, may show a rough linen-like texture and histologically show ortho- and/or para-keratinized epithelium. 
BQ lichenoid lesion
A quid-induced lichenoid oral lesion has been reported exclusively among BQ users.  It resembles oral lichen planus but there are specific differences. It is characterized by the presence of fine, white, wavy, parallel lines that do not overlap or criss-cross, are non-elevated, and in some instances radiate from a central erythematous area [Figure 2]. The lesion generally occurs at the site of placement of the quid. This lesion was described as a lichen planus-like lesion, but it is now termed a "betel-quid lichenoid lesion". This lesion may regress with decrease in frequency, duration, or change in site of placement of the quid. There may be complete regression when the quid habit is given up. This lesion has been found to demonstrate a different natural history from lichen planus in intervention studies, and therefore it should be recognized as a specific entity. 
These quid induced lesions are considered to be a type IV contact hypersensitivity-type lesion. 
Leukoplakia can be defined as a predominantly white patch or plaque on the oral mucosa that cannot be characterized clinically or pathologically as any other disease and is not associated with any other physical or chemical agent except tobacco [Figure 2]. Based on clinical appearance, leukoplakia can be divided into several subtypes: Homogeneous (white), speckled (red/white), nodular, or verrucous leukoplakia.  Although there is considerable controversy and debate about how to define oral leukoplakia there is little doubt that both tobacco, in any form, and betel nut use are major risk factors for developing this condition. Evidence of its relationship with betel chewing has come from epidemiological data. ,,,,
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 [Figure 2].  Various factors have been implicated in the development of OSF, the most common of which is chewing betel nut. ,,, Associations with tobacco use and vitamin deficiency have also been reported.  Other causes which have been proposed in the past but have not been substantiated include excessive consumption of chilies, autoimmune reaction, and nutritional factors, particularly iron deficiency. The potentially malignant nature of this condition has been well-documented. A malignant transformation rate of 7.6% over a period of 10 years was described in an Indian cohort. 
Clinically, the earliest sign of OSF is mouth soreness, with constant burning when eating spicy foods. OSF is categorized clinically into three stages: Stomatitis, fibrosis, and sequelae.  During the stomatitis phase, the oral mucosa contains areas of erythema in which vesicles appear. These vesicles later rupture and produce ulcers that heal via fibrosis (the second stage). During the sequelae stage, the fibrosis extends and thickens the floor of the mouth, decreasing tongue size, and causing difficulty in speech and mastication. The buccal mucosa has a mottled marble-like appearance, with thick vertical fibrous bands. These bands limit the mandibular range of motion and cause the characteristic trismus. In addition, the dentition often is stained as a scarlet color, and periodontal disease typically is associated with OSF. Loss of auditory acuity may occur secondary to fibrosis of the Eustachian tube More Detailss. Fibrosis can extend down the oropharynx to the esophagus, causing dysphagia when eating solid foods. The primary complaint of patients with this disease is progressive trismus resulting from fibrosis of the buccal submucosa [Table 1]. 
Pathogenesis of OSF
The betel nut has psychotropic and antihelminthic property due to presence of betel alkaloids. Four alkaloids have been conclusively identified in biochemical studies, arecoline, arecaidine, guvacine, and guvacoline, of which arecoline is the main agent. These alkaloids have powerful parasympathetic properties which produce euphoria and counteract fatigue. 
Recently suggested pathogenesis of OSF is by dual action of betel nut. It is suggested that arecoline not only stimulates fibroblastic proliferation and collagen synthesis, but also decreases its breakdown. This suggests that arecoline is the active metabolite in fibroblast stimulation. 
OSF results from increased production of collagen by fibroblasts. In addition to this there is decreased breakdown leading to accumulation of excessive amount of collagen. 
Increased collagen production
Under the influence of betel nut, fibroblasts differentiate into phenotypes that produce more collagen. The alkaloids present in betel nut, arecadine and arecoline are responsible for this. Arecoline gets converted in to arecadine which is the active metabolite. There is dose-dependent increase in production of collagen by fibroblasts under influence of these factors [Figure 3]. 
Various cytokines are increased in OSF. These are: Transforming growth factor beta (TGF-beta), platelet-derived growth factor (PDFG), and basic fibroblast growth factor (bFGF). These are fibrogenic growth factors that stimulate collagen production. Another cytokine that has anticollagen effect is interferon-alpha (IFN-alpha). This is decreased in OSF. Thus, overall there is stimulation of collagen synthesis through different mechanisms. 
Stabilization of collagen structure and decreased collagen breakdown
One of the mechanisms that can lead to increased fibrosis is by reduced degradation of collagen by forming a more stable collagen structure. Betel nut contains tannin. Tannin has ability to stabilize collagen by cross-linking it. With the progression of the disease type III collagen is almost completely replaced by type I.  Type I collagen is more resistant to degradation than type III. An important finding from these studies is the identification of excess alpha-1 chains relative to alpha-2, suggesting an alteration of collagen molecules during the progression of the disease. Although, the biological function of this trimer is not known, it is regarded as more resistant to degradation than the normal collagen molecule. 
Another component of betel nut that aids this cross-linking is copper. It is a constituent of enzyme lysyl oxidase. This enzyme also causes cross-linking and makes collagen resistant to degradation by collagenase. Due to action of tannin and copper, collagen that is produced in OSF is highly resistant to remodeling and phagocytosis [Figure 3]. 
It is fibroblast that brings about remodeling and phagocytosis of collagen. As in OSF, these firoblasts are affected and phenotypically changed, they cannot degrade collagen. Studies on the effects of arecoline on both normal and OSF fibroblasts in culture revealed an elevated rate of collagen synthesis by OSF fibroblasts as compared to normal fibroblasts. Although the reason for this elevation is not clear, some authors proposed that it could reflect the clonal selection of a highly fibrogenic cell population in the altered tissue under the influence of local factors such as interleukin-1 from inflammatory cells. This leads to decrease in phagocytosis and accumulation of collagen in oral mucosa [Figure 3]. Glycogen consumption is physiologically related to cellular activity of muscle fibers. Overactivity of muscles results in excessive glycogen consumption; leading to its depletion. In betel nut chewers there is overactivity of muscles due to repeated, continuous chewing and use of heavy force to crush the hard nut. This increased muscle activity along with diminished blood supply, following connective tissue changes leads to muscle degeneration and fibrosis. 
Oral squamous cell carcinoma
There is historical evidence dating back nearly a century that suggests that the betel nut may be involved in the development of oral squamous cell carcinoma. ,, Although it is widely accepted that the presence of tobacco in BQ plays an important role in the pathogenesis of oral squamous cell carcinoma, the carcinogenic potential of betel in the absence of other ingredients is less clear.  There are epidemiological data from several studies that confirm that the habit of BQ chewing increases the relative risk of developing oral squamous cell carcinoma. ,,,,
| > Conclusion|| |
It is clear from the literature that betel nut use may have significant effects on dental hard and soft tissues. Thus, there is an urgent need to curb this ongoing epidemic of betel nut habit. Legislation against open sale and use of such products should be stricter and more states and countries should bring out such legislations sooner than later. Public health programs regarding the harmful effects of betel nuts, coupled with increased awareness by healthcare professionals of the signs and symptoms of this disease, can limit its prevalence significantly. In addition to educating consumers about the health risks of betel nut use, dental professionals need to educate paan shop vendors about the repercussions of betel nut consumption and persuade them not to sell betel nut products to minors.
| > References|| |
Lan TY, Chang WC, Tsai YJ, Chuang YL, Lin HS, Tai TY. Areca nut chewing and mortality in an elderly cohort study. Am J Epidemiol 2006;165:677-83.
Auluck A, Hislop G, Poh C, Zhang L, Rosin MP. Areca nut and betel quid chewing among South Asian immigrants to Western countries and its implications for oral cancer screening. Rural Remote Health 2009;9:1118.
Pindborg JJ, Sirsat SM. Oral submucous fibrosis. Oral Surg Oral Med Oral Pathol 1966;22:764-79.
Aziz SR. Coming to America. Betel nut and oral submucous fibrosis. J Am Dent Assoc 2010;141:423-8.
Trivedy C, Warnakulasuriya S, Peters TJ. Areca nuts can have deleterious effects. Br Med J 1999;318:1287.
Pankaj C. Areca nut or Betel Nut Control is Mandatory if India wants to reduce the burden of Cancer especially Cancer of the Oral Cavity. Int J Head Neck Surg 2010;1:17-20.
Verma S. Areca nut (betel nut) chewing: A popular Indian cultural practice and its mucosal implications. Int J Dermatol 2011;50:229-32.
Trivedy CR, Craig G, Warnakulasuriya S. The oral health consequences of chewing areca nut. Addict Biol 2002;7:115-25.
Review of Areca (Betel) Nut and Tobacco Use in the Pacific- A Technical Report. World Health Organization; 2012.
Yeh CJ. Fatigue root fracture: a spontaneous root fracture in non-endodontically treated teeth. Br Dent J 1997;182:261-6.
Norton SA. Betel: Consumption and consequences. J Am Acad Dermatol 1998;38:81-8.
Schamschula RG, Adkins BR, Barmes DR, Charlton G. Betel chewing and caries experience in New Guinea. Community Dent Oral Epidemiol 1977;5:284-6.
Nigam P, Srivastava AB. Betel chewing and dental decay. Fed Oper Dent 1990;1:36-8.
Howden GF. The cariostatic effects of betel chewing. P
N G Med J 1984;27:123-31.
de Miranda CM, van Wyk CW, van der Biji P, Basson NJ. The effect of areca nut on salivary and selected organisms. Int Dent J 1996;46:350-6.
Williams SA, Summers RM, Ahmed IH, Prendergast MJ. Caries experience, tooth loss and oral health related behaviours among Bangladeshi women resident in West Yorkshire, UK. Community Dent Health 1996;13:150-6.
Jeng JH, Hahn LJ, Lin BR, Hsieh CC, Chan CP, Chang MC. Effects of areca nut, inflorescence piper betle extracts and arecoline on cytotoxicity, total and unscheduled DNA synthesis in cultured gingival keratinocytes. J Oral Pathol Med 1999;28:64-71.
Chang MC, Kuo MY, Hahn LJ, Hsieh CC, Lin SK, Jeng JH. Areca nut extract inhibits the growth, attachment, and matrix protein synthesis of cultured human gingival fibroblasts. J Periodontol 1998;69:1092-7.
Anerud A, Loe H, Boysen H. The natural history and clinical course of calculus formation in man. J Clin Periodontol 1991;18:160-70.
Parmar G, Sangwan P, Vashi P, Kulkarni P, Kumar S. Effect of chewing a mixture of Areca nut and tobacco on periodontal tissues and oral hygiene status. J Oral Sci 2008;50:57-62.
Zain RB, Ikeda N, Gupta PC, Warnakulasuriya S, van Wyk CW, Shrestha P, et al
. Oral mucosal lesions associated with betel quid, areca nut and tobacco chewing habits: Consensus from a workshop held in Kuala Lumpur, Malaysia, November 25-27, 1996. J Oral Pathol Med 1999;28:1-4.
Avon SL. Oral mucosal lesions associated with use of quid. J Can Dent Assoc 2004;70:244-8.
Bhonsle RB, Murti PR, Daftary DK, Mehta FS. An oral lesion in tobacco-lime users in Maharashtra, India. J Oral Pathol 1979;8:47-52.
Gupta PC, Mehta FS, Daftary DK, Pindborg JJ, Bhonsle RB, Jalnawalla PN, et al
. Incidence of oral cancer and natural history of oral precancerous lesions in a 10-year follow-up study of Indian villagers. Community Dent Oral Epidemiol 1980;8:283-333.
Reichart PA, Schmidtberg W, Scheifele CH. Betel chewer′s mucosa in elderly Cambodian women. J Oral Pathol Med 1996;25:367-70.
Zain R, Ikeda N, Yaacob MB. Oral mucosal lesions survey of adults in Malaysia. Kuala Lampur: Ministry of Health; 1995.
Ikeda N, Handa Y, Khim SP, Durward C, Axéll T, Mizuno T, et al.
Prevalence study of oral mucosal lesions in a selected Cambodian population. Community Dent Oral Epidemiol 1995;23:49-54.
Reichart PA, Mohr U, Srisuwan S, Gerlings H, Theetranont C, Kangwanpong T. Precancerous and other oral mucosal lesions related to chewing, smoking and drinking habits in Thailand. Community Dent Oral Epidemiol 1987;15:152-60.
International Agency for Research on Cancer. IARC monograph on the evaluation of Carcinogenic risks to humans. Betel-quid and Areca-nut chewing and some Areca-nut derived Nitrosamines. Vol 85. Lyon: IARC; 2004.
Reichart P, Böning W, Srisuwan S, Theetranont C, Mohr U. Ultrastructural findings in the oral mucosa of betel chewers. J Oral Pathol 1984;13:166-77.
Hjorting-Hansen E, Holst E. An analysis of oral mucosal changes due to biting and sucking habits. Scand J Dent Res 1970;78:492-9.
Van Wyk CW, Staz J, Farman AG. The chewing lesion of the cheeks and lips: Its features and prevalence among a selected group of adolescents. J Dent 1977;5:193-9.
Mehrotra S, Yadav S. Oral squamous cell carcinoma: Etiology, pathogenesis and prognostic value of genomic alterations. Indian J Cancer 2006;43:60-6.
Reichart PA, Phillipsen HP. Betel chewer′s mucosa-a review. J Oral Pathol Med 1998;27:239-42.
Andersson G, Axéll T, Larsson A. Clinical classification of Swedish snuff dipper′s lesions supported by histology. J Oral Pathol Med 1991;20:253-7.
Seedat HA. Oral submucous fibrosis in Durban, Natal: A study of its epidemiology, aetiology and morphological features. PhD Thesis. University of Stellenbosch; 1985.
Daftary DK, Bhonsle RB, Murti RB, Pindborg JJ, Mehta FS. An oral lichen planus-like lesion in Indian betel-tobacco chewers. Scand J Dent Res 1980;88:244-9.
Axell T, Holmstrup P, Kramer IR, Pindborg JJ, Shear M. International seminar on oral leukoplakia and associated lesions related to tobacco habits. Community Dent Oral Epidemiol 1984;12:145-54.
Shiu MN, Chen TH, Chang SH, Hahn LJ. Risk factors for leukoplakia and malignant transformation to oral carcinoma: A leukoplakia cohort in Taiwan. Br J Cancer 2000;82:1871-4.
Thomas SJ, Harris R, Ness AR, Taulo J, Maclennan R, Howes N, Bain CJ. Betel quid not containing tobacco and oral leukoplakia: A report on a cross-sectional study in Papua New Guinea and a meta-analysis of current evidence. Int J Cancer 2008;123:1871-6.
Lee CH, Ko YC, Huang HL, Chao YY, Tsai CC, Shieh TY, et al
. The precancer risk of betel quid chewing, tobacco use and alcohol consumption in oral leukoplakia and oral submucous fibrosis in southern Taiwan. Br J Cancer 2003;88:366-72.
Yang YH, Lee HY, Tung S, Shieh TY. Epidemiological survey of oral submucous fibrosis and leukoplakia in aborigines of Taiwan. J Oral Pathol Med 2001;30:213-9.
Chung CH, Yang YH, Wang TY, Shieh TY, Warnakulasuriya S. Oral precancerous disorders associated with areca quid chewing, smoking, and alcohol drinking in southern Taiwan. J Oral Pathol Med 2005;34:460-6.
Pindborg JJ, Murti PR, Bhonsle RB, Gupta PC, Daftary DK, Mehta FS. Oral submucous fibrosis as a precancerous condition. Scand J Dent Res 1984;92:224-9.
Pillai R, Balaram P, Reddiar KS. Pathogenesis of oral submucous fibrosis. Relationship to risk factors associated with oral cancer. Cancer 1992;69:2011-20.
Yang YH, Lien YC, Ho PS, Chen CH, Chang JS, Cheng TC, et al
. The effects of chewing areca/betel quid with and without cigarette smoking on oral submucous fibrosis and oral mucosal lesions. Oral Dis 2005;11:88-94.
Arakeri G, Brennan PA. Oral submucous fibrosis: An overview of the aetiology, pathogenesis, classification, and principles of management. Br J Oral Maxillofac Surg 2013;51:587-93.
Muttagi SS, Chaturvedi P, Gaikwad R, Singh B, Pawar P. Head and neck squamous cell carcinoma in chronic areca nut chewing Indian women: Case series and review of literature. Indian J Med Paediatr Oncol 2012;33:32-5.
Haider SM, Merchant AT, Fikree FF, Rahbar MH. Clinical and functional staging of oral submucous fibrosis. Br J Oral Maxillofac Surg 2000;38:12-5.
Murti PR, Bhonsle RB, Pindborg JJ, Daftary DK, Gupta PC, Mehta FS. Malignant transformation rate in oral submucous fibrosis over a 17-year period. Community Dent Oral Epdemiol 1985;13:340-1.
Pindborg JJ. Oral submucous fibrosis: A review. Ann Acad Med Singapore 1989;18:603-7.
Gupta MK, Mhaske S, Ragavendra R, Imtiyaz. Oral submucous fibrosis-Current concepts in etiopathogenesis. People′s J Sci Res 2008;1:39-44.
Kuo MY, Chen HM, Hahn LJ, Hsieh CC, Chiang CP. Collagen biosynthesis in human oral submucous fibrosis fibroblast cultures. J Dent Res 1995;74:1783-8.
Haque MF, Harris M, Meghji S, Barrett AW. Immunolocalization of cytokines and growth factors in oral submucous fibrosis. Cytokine 1998;10:713-9.
Utsunomiya H, Tilakaratne WM, Oshiro K, Maruyama S, Suzuki M, Ida-Yonemochi H, et al.
Extracellular matrix remodeling in oral submucous fibrosis: Its stage-specific modes revealed by immunohistochemistry and in situ
hybridization. J Oral Pathol Med 2005;34:498-507.
Tsai CC, Ma RH, Shieh TY. Deficiency in collagen and fibronectin phagocytosis by human buccal mucosa fibroblasts in vitro
as a possible mechanism for oral submucous fibrosis. J Oral Pathol Med 1999;28:59-63.
Orr IM. Oral cancer in betel chewer′s in Travancore, its aetiology, pathology and treatment. Lancet 1933;2:575-80.
Fells A. Cancer of the mouth in Southern India. A summary of 1700 cases. Br Med J 1908;2:1428-31.
Balaram AP. The use of betel nut: a cause of cancer in Malabar. Indian Med Gaz 1902;37:414.
Tobacco habits other than smoking; betel-quid and areca-nut chewing; and some related nitrosamines. IARC Working Group. Lyon, 23-30 October 1984. IARC Monogr Eval Carcinog Risk Chem Hum 1985;37:1-268.
Gupta B, Ariyawardana A, Johnson NW. Oral cancer in India continues in epidemic proportions: Evidence base and policy initiatives. Int Dent J 2013;63:12-25.
Merchant A, Husain SS, Hosain M, Fikree FF, Pitiphat W, Siddiqui AR, et al
. Paan without tobacco: An independent risk factor for oral cancer. Int J Cancer 2000;86:128-31.
Sharan R, Mehrotra R, Choudhury Y, Asotra K. Association of betel nut with carcinogenesis: Revisit with a clinical perspective. PLoS One 2012;7:e42759.
Jeng JH, Chang MC, Hahn LJ. Role of areca nut in betel quid associated chemical carcinogenesis: current awareness and future perspectives. Oral Oncol 2001;37:477-92.
[Figure 1], [Figure 2], [Figure 3]