|Year : 2013 | Volume
| Issue : 3 | Page : 471-476
Oral submucous fibrosis: Comparing clinical grading with duration and frequency of habit among areca nut and its products chewers
Fareedi Mukram Ali1, Vinit Aher1, MC Prasant1, Priyanka Bhushan2, Anupama Mudhol1, Harshal Suryavanshi3
1 Department of Oral and Maxillofacial Surgery, SMBT Dental College and Hospital, Ahmednagar, Maharashtra, India
2 Department of Public Health Dentistry, SMBT Dental College and Hospital, Ahmednagar, Maharashtra, India
3 Department of Oral and Maxillofacial Surgery, YMT Dental College and Hospital, Khargar, Navi Mumbai, Maharashtra, India
|Date of Web Publication||8-Oct-2013|
Fareedi Mukram Ali
Department of Oral and Maxillofacial Surgery, SMBT Dental College and Hospital, Amrutnagar, Gulewadi Post, Sangamner Taluqa, Ahmednagar, Maharashtra
Source of Support: None, Conflict of Interest: None
Aims and objectives: To evaluate the effect of frequency, duration and type of areca nut products on the incidence and severity of oral submucous fibrosis (OSMF).
Materials and methods: Patients with the limited mouth opening and associated blanched oral mucosa with palpable fibrous bands were included in this study. Biopsies were done and the informed consent was taken from each patient included in this study. The tissues were taken from the affected areas and then studied histopathologically. The data was analysed statistically using X 2 -test.
Results: In this present prospective study done in 197 subjects (189 males and 8 females) who were screened and diagnosed clinically having OSMF with age ranging from 22 to 61 years with mean 38.8 years. Gutkha-chewing habit alone was identified in 58 subjects and those associated with gutkha and tobacco were 33 with mean age of 28.2 years and 32.3 years, respectively. The number of people getting affected with OSMF is more associated with gutkha and areca nut with the P-value of the analysis ranging from 0.05 to 0.01.
Conclusion: The occurrence of OSMF is related to areca nut and its products. The duration and frequency of its use and type of areca nut product has effect on the incidence and severity of OSMF. Gutkha and pan masala have more deleterious and faster effects on oral mucosa. The gutkha-chewing habit along with the other habits does not have any significant effect on the rate of occurrence and incidence and severity of the OSMF.
Keywords: Areca nut, gutkha, oral submucous fibrosis, precancerous condition
|How to cite this article:|
Ali FM, Aher V, Prasant M C, Bhushan P, Mudhol A, Suryavanshi H. Oral submucous fibrosis: Comparing clinical grading with duration and frequency of habit among areca nut and its products chewers. J Can Res Ther 2013;9:471-6
|How to cite this URL:|
Ali FM, Aher V, Prasant M C, Bhushan P, Mudhol A, Suryavanshi H. Oral submucous fibrosis: Comparing clinical grading with duration and frequency of habit among areca nut and its products chewers. J Can Res Ther [serial online] 2013 [cited 2020 May 26];9:471-6. Available from: http://www.cancerjournal.net/text.asp?2013/9/3/471/119353
| > Introduction|| |
Last century has seen the fast growth of industrialization and urbanization, as a result of this growth and progress; human beings are subjected to physical and mental stress. Humans react to this stress by taking stress-relieving habits such as smoking, alcohol, betel nut chewing, pan chewing, etc. These habits do much more harm, than good to human being. There are many detrimental effects on human body apart from being addictive. Different habits and cultural practices time and again have been abusing the oral cavity. In day-to-day clinical practice Medical practitioners and Dental surgeons often encounter a wide spectrum of oral mucosal alterations.
One such pathological condition is Oral submucous fibrosis (OSMF). OSMF is a peculiar, chronic progressive, insidious, irreversible, crippling disease of the oral cavity characterized by fibrotic change and severe burning sensation with restricted opening of the mouth.  The disease affects most part of oral cavity as well as the upper-third of the esophagus.  The disease is characterized by blanching and stiffness of oral mucosa, trismus, and burning sensation in the mouth. It also produces hypomobilty of the soft palate and tongue, and loss of gustatory sensation. Occasionally there can be mild hearing impairment due to blockade of the Eustachian tube. ,, Malignant transformation rate of OSMF was found to be in the range of 7-13%.  According to long-term follow-up studies a transformation rate of 7.6% over a period of 17 years was reported. 
The disease is predominantly seen in India, Bangladesh, Sri Lanka, Pakistan, Taiwan, China, and among other Asiatics, with a reported prevalence ranging up to 0.4% in Indian rural population.  As a result of transmigration of populations, an increasing number of cases are being seen in other countries.  A study conducted in 2002 indicates that more than 5 million people in India have OSMF (0.5 % of Indian population),  the figure that must have increased sharply by now. It has been suggested that consumption of chillies, nutritional deficiency, chewing of areca nut, genetic susceptibility, altered salivary constituents, autoimmunity, and collagen disorders may be involved in the pathogenesis of this condition.  Teenagers and youths are getting more attracted to commercially available areca nut products like Gutkha and pan masala due to wide publicity, marketing and easy availability of such products. 
Currently areca nut/betel quid use is the single-most important etiological factor considered in OSMF. This observation has been made by a growing body of evidence over the last 40 years, mainly in the form of large-scale epidemiological and experimental studies, observational studies in case reports, case-control studies, cross-sectional studies and interventional studies, animal studies, tissue culture studies as well. ,,,,,,,,, Chewing tobacco alone and smoking are not considered to play a role in the development of this disease, ,,,, it has been conclusively proven that OSMF occurs because of areca nut consumption and is not associated with tobacco. ,,,,,,,,,,,,,,
Keeping the above points in view the present study was carried out with the aim to correlate the severity of OSMF with duration and frequency of areca nut and its product chewers.
| > Materials and Methods|| |
This prospective study has been conducted in the Department of Oral Medicine, Diagnosis and Radiology and Oral and Maxillofacial Surgery of a Dental College. Patients who reported with the limited mouth opening and associated blanched oral mucosa with palpable fibrous bands were screened and those patients who were diagnosed clinically having OSMF were included in this study. Proforma was given to the patient to fill up the information regarding type of Habit, type of placement of areca nut/product and the demographic characteristics such as age, sex, etc. Biopsies were taken with informed consent for each patients included in the study. The tissues were taken from the affected areas and then studied histopathologically. The data was analysed statistically using X 2 -test.
Criteria for OSMF were followed according to the workshop held in Kuala Lumpur, Malaysia in 1996. OSMF can be diagnosed on the basis of the presence of one or more of the following characteristics.
Patients were divided into four groups according to severity, following the criteria from a study done by Ranganathan et al. The criteria taken was mouth opening as follows.
- Palpable fibrous bands.
- The mucosal texture feels tough and leathery.
- Blanching of the mucosa together with the histopathological features characteristic of OSMF.
Grade I: Only symptoms, with no demonstrable restriction in mouth opening
Grade II: Limited mouth opening. 20 mm and above
Grade III: Mouth opening less than 20 mm.
Grade IV: OSMF advanced with limited mouth opening. Precancerous or cancerous changes seen throughout the mucosa.
| > Results|| |
In this present prospective study done from January 2011 to June 2012 there were 197 subjects (189 males and 8 females) who were identified and diagnosed clinically having OSMF. The age of subjects was ranging from 22 years minimum to 61 years maximum with mean of 38.8 years. Gutkha-chewing habit alone was identified in 58 subjects and those associated with gutkha and tobacco were 33 with mean age of 28.2 years and 32.3 years, respectively. The details of gutkha with tobacco and smoke (18 subjects with mean age 35.8 years), gutkha with tobacco, smoke and alcohol (12 subjects with mean age 36.2 years), Mawa (20 subjects with mean age 41.2 years), betel quid (14 subjects with mean age 43.5 years), areca nut alone (41 subjects with mean age 30.3 years) and areca nut with tobacco (31 subjects with mean age 32.7 years) are tabulated in the [Table 1]. The statistical analysis using the X 2 -test was done on the collected data. It was found that the number of people getting affected with OSMF at an early age is more associated with gutkha and areca nut with the P-value of the analysis ranging from 0.05 to 0.01 with the difference of freedom of 120 and X 2 value 121.382. The addition of tobacco and smoking habits along with the gutkha or areca nut does not show a statistical significant difference in the duration and frequency of habit to the occurrence of OSMF. Also there is no significant difference in the mean age groups with gutkha and those with gutkha and other associated habits.
[Table 2] - shows the association between OSMF with gutkha and arecanut. Study subjects who had gutkha only (58) were more as compared to arecanut + tobacco (28). The difference was found to be statistically significant (p=0.05).
The results have been represented in both tables as well as in graphs. [Figure 1] shows type of habit and the various grades of OSMF.
|Figure 1: The correlation between type of areca nut habits and grades of OSMF|
Click here to view
| > Discussion|| |
The practice of chewing areca nut in a betel quid has a long history which is deeply ingrained in many socio-cultural and religious activities, especially offered at the social and wedding gatherings. References to betel nut appear in ancient Sanskrit literature as early as the 1 st century BC. The practice of chewing betel leaves after meals had become common (75 A.D. to 300 A.D.) as mentioned in Charaka and Sushruta Samhitas.  Areca nut with ancient history of chewing in Indian subcontinent, oral sub mucous fibrosis is not a new disease. This must be the reason, Sushruta - a renowned Indian physician, in his book "mouth and throat diseases" mentioned about a condition "Vidari", the features of which simulate OSMF.  There has been no change in these symptoms till today.  A treatise on Indian surgery written in Sanskrit around 600 B.C. though tobacco was introduced around the sixteenth century. 
Areca nut (usually incorporated in betel quid) is the fourth most common psychoactive substance in the world (after caffeine, alcohol and nicotine), its use extending to several hundred million people. It has been estimated that betel quid is used by about 10-20% of the world's population and that globally up to 600 million users chew areca nut. 
In this present prospective study there were 197 subjects (189 males and 8 females) who were identified and diagnosed clinically for having OSMF. Although OSMF affects both sexes, male predominance for this condition has been noted in many studies. In our present study males 189 (95.93%) were dominating. The male to female ratio was 23.6:1, which was quite high when compared to earlier studies. Ahmed et al., in their studies at Patna dental college, Patna, Bihar, reported a male to female ratio of 2.7:1.  However, a male predominance for this condition has been noted in several studies.  Even studies from China showed higher prevalence among males.  The reason for male predominance is because of easy availability of gutkha and other related products among youngsters. Moreover males are the working gender and money earner among Indian subcontinent. Areca nut/betel quid, gutkha is chewed for variety of reasons such as stress reliever, mouth freshener, improving concentration and digestion after food.  Whereas, females are more conscious about their esthetic values and it is considered socially unacceptable for a female to get gutkha from gutkha vendors. All the female patients in our present study with OSMF were addicted to areca nut or betel quid, none showed addiction to gutkha.
In contrast female predominance also has been noted in many studies. As these studies were done in 70s and 80s, it was common few decades earlier for females to chew areca nut for digestion after having food. ,
In our present study the age of subjects was ranging from 22 years minimum to 61 years maximum with mean of 38.8 years. Gutkha-chewing habit alone was identified in 58 subjects and those associated with gutkha and tobacco were 33 with mean age of 28.2 years and 32.3 years respectively. It is similar to another hospital based study by Ahmed where they reported majority of the OSMF cases belonged to 21-40 years of age group. Similarly Sirsat reported OSMF cases from 20 to 40 years of age. , According to a population-based relation studies in India conducted by Bhosle et al. (1987) the mean age of the 27 patients was 37 years which was significantly lower compared to the mean age of 64 patients in Ernakulum which was 52 years.  Increasing availability and marketing through advertisement of gutkha in 1980s was less as compared to present condition.
In our study, gutkha chewers showed more predominance of grade III, grade IV stages of OSMF and mean duration was much less when compared to those having betel quid and mawa only. , Similar findings were seen in the study of Reicharts and Gupta for the severity of OSMF in relation to gutkha and other areca nut products with more cases of grade III and IV stages associated with gutkha. The effect of other concurrent habits like alcohol, smoking along with gutkha or areca nut products in the same person has been shown in various studies that it does not affect the incidence and severity of OSMF. Subjects having habits along with gutkha chewing like smoking beetle quid and alcohol consumption does not have a statistically significant difference in the occurrence and severity of OSMF in the present study as shown in the [Table 1]. Similar findings of no effect of simultaneous alcohol and smoking on the occurrence of OSMF in gutkha chewing. ,,
The mean age and duration of gutkha chewers with and without associated other habits is less as observed in our study as compared with those having areca nut consumption in other form. This shows that people having the areca nut in the form of gutkha are having higher severity and faster occurrence of OSMF. In our study the mean duration of gutkha chewers to develop OSMF was 8.2 years which was low when compared to betel quid, mawa, areca nut (21.8, 11.5, 10.9 years, respectively). The abrasive nature of areca nut, which is the main constituent of gutkha and pan masala causes continuous local trauma and irritation to the oral mucosa leading to morphological changes in the oral mucosa.  The other reason for increased severity and risk of developing OSMF in gutkha chewers is due to more dry weight of areca nut releasing high amount of arecoline. The dry weight of areca nut in gutkha sachets is 3.26 g, whereas that in betel quid is 1.14 g.  The betel quid chewers show less amount of severity, as the betel leaf contains beta-carotene, which has the capacity to neutralize the free radicals that are released from the areca nut. 
In our study the subjects consuming gutkha only or areca nut only showed high occurrence of Grade III and Grade IV cases in short duration (mean duration 8.2 and 10.9 years, respectively) than in other types of areca nut-containing products. In a similar hospital-based study by Canniff, as the mean duration of the areca nut consumption increased above 10 yrs, the probability of getting Grade II and Grade III OSMF increased severely. 
Duration and frequency of chewing gutkha has a definite role in increased severity of developing OSMF, subjects who chewed for more than 10 packets per day and kept in mouth for more than 10 minutes each packet showed the highest rate of occurrence for grades II, III, IV cases as shown in [Table 3]. On the contrary, Rajendran et al., were of opinion that severity of OSMF depends only on frequency of gutkha and other areca nut products rather than duration of chewing each packet of gutkha or areca nut product. 
The occurrence of OSMF was seen significantly in those having one or the other forms of areca nut. This occurrence has shown that the products which leaches out from areca nut would be responsible for the development of OSMF.  People having tobacco alone have never been seen to have OSMF. This was also observed in our study that there was no synergistic effect on development of OSMF in those consuming tobacco along with gutkha or in those consuming alcohol, tobacco, and gutkha simultaneously. If tobacco would have been a causative factor for OSMF then other forms of tobacco like cigarette, bidi, pipe smoking should have manifested OSMF as one of the clinical feature. In the areca nut chewers the lysyl oxidase activity is upregulated to alter fibroblast metabolism producing more collagen. This may add to the conclusion of the occurrence of OSMF due to the products leaching out from areca nut causes OSMF and not from those leaching out from tobacco. 
The pathogenesis of OSMF involves the mechanical as well as chemical trauma to the oral mucosa. The dry areca nut pieces present in gutkha and pan masala causes microtrauma to the oral mucosa. The traumatized mucosa undergoes chronic inflammation due to repeated microtrauma and irritation. This causes the oxidative stress and cytokines production due to chronic inflammation. The hypothesis that dense fibrosis and less vascularity of the corium, in the presence of an altered cytokine activity creates a unique environment for carcinogens from both tobacco and areca nut to act on the epithelium is widely being accepted. The alkaloid like arecoline, arrecadine guaccine, tannins, catechins, leaches out in saliva from areca nut and acts on the chronically inflamed mucosa. Increased amount of cytokines produced in oral mucosa like fibroblast growth factor, transforming growth factor and platelet-derived growth factor increases the production of collagen in the submucosal region. Also the inhibitory cytokine in collagen-production interferon-alpha is decreased in oral mucosa which leads to decreased degradation of collagen. Alkaloid leached out from areca nut acts on the fibroblast and induces the phenotypic changes, which leads to the decreased capacity of fibroblasts to degrade and remodel the collagen fibers in the submucosal region. This leads to the increased amount of collagen fibers in the submucosal region of oral cavity leading to OSMF. 
OSMF is considered as a premalignant condition of oral cavity. Pindborg et al., 1966, has given five criteria for relation of malignancy and OSMF like high occurrence of OSMF in oral cancer patients, incidence of squamous cell carcinoma (SCC) in OSMF cases, high occurrence of dysplasia of epithelium of oral cavity in OSMF cases, high frequency of leukoplakia along with the OSMF.  Pay Master 1956 was the first person to introduce the malignant potential of OSMF by showing the atypia in oral mucosal epithelium and also the presence of dysplastic changes in the oral mucosa of OSMF. Jeng has shown the carcinogenicity of areca nut without tobacco.  Also IARC has declared areca nut as 'Group 1 carcinogen'.  Many studies have shown the malignant transformations of OSMF, like in the range of 7-13% of cases of OSMF (Tilakaratne 2006) and that in another study it was 7.6% (Murti 1985). ,
Although OSMF is a progressive disease and it spreads even after stopping the habit. Treatment of OSMF includes various modalities but the main step to avoid progression of OSMF is to stop the habit completely.  There are medical and surgical modalities of treatment. Medical treatment modalities of OSMF include the antioxidants, local applications of corticosteroids and local injections of collagenolytics and placenteral extracts to increase the flaccidity of the submucosal tissues. Surgical treatment modalities are excision of mucosa and submucosal collagenous fibrous bands along with placement of various flaps and free grafts like buccal pad of fat, tongue flap, nasolabial flap, skin graft and collagen sheets, etc.
| > Conclusions|| |
OSMF is a commonly occurring and widely spread premalignant condition increasingly affecting the youth. The occurrence of OSMF in gutkha chewers is far more faster and more severe as compared in other forms of areca nut products chewers. The easy availability and promotions of these areca nut products specially gutkha and pan masala outside the schools colleges and social places has impacted younger population in India which has led to the increased occurrence of OSMF a premalignant condition and malignancies like SCC. Now it is a times call to have a control on use of areca nut and its products in various forms specially gutkha and pan masala. Recently a good step has been taken by the Indian government in some of the major states by applying the policies to control the cultivation and production of areca nut by having a complete ban over sale and advertisement of the areca nut products like gutkha and pan masala to control its social impact in the society.
| > References|| |
|1.||Rao PK. Efficacy of alpha lipoic acid in adjunct with intralesional steroids and hyaluronidase in the management of oral submucous fibrosis. J Cancer Res Ther 2010;6:508-10. |
|2.||Misra SP, Misra V, Dwivedi M, Gupta SC. Oesophageal subepithelial fibrosis: An extension of oral submucosal fibrosis. Postgrad Med J 1998;74:733-6. |
|3.||Thakur N, Keluskar V, Bagewadi A, Shetti A. Effectiveness of micronutrients and physiotherapy in the management of oral submucous fibrosis. Int J Contemp Dent 2011;2:101-5. |
|4.||Aziz SR. Lack of reliable evidence for oral submucous fibrosis treatments. Evid Based Dent 2009;10:8-9. |
|5.||Pindborg JJ. Oral submucous fibrosis: A review. Ann Acad Med Singapore 1989;18:603-7. |
|6.||Tilakaratne WM, Klinikowski MF, Saku T, Peters TJ, Warnakulasuriya S. Oral submucous fibrosis: Review on etiology and pathogenesis. Oral Oncol 2006;42:561-8. |
|7.||Murti PR, Bhonsle RB, Pindborg JJ, Daftary DK, Gupta PC, Mehta FS. Malignant transformation rates in oral submucous fibrosis over a 17 year period. Community Dent Oral Epidemiol 1985. 13:340-1. |
|8.||Murti PR, Bhonsle RB, Gupta PC, Daftary DK, Pindborg JJ. Etiology of oral submucous fibrosis with special reference to the role of areca nut chewing. J Oral Pathol Med 1995;24:145-52. |
|9.||Reichart PA, Philipsen HP. Oral submucous fibrosis in a 31-year-old Indian women: First case report from Germany. Mund Kiefer Gesichtschir 2006;10:192-6. |
|10.||Hayes PA. Oral submucous fibrosis in a 4-year-old girl. Oral Surg Oral Med Oral Pathol 1985;59:475-8. |
|11.||Sudarshan R, Annigeri RG, Vijayabala GS. Pathogenesis of oral submucous fibrosis: The past and current concepts. Int J Oral Maxillofac Pathol 2012;3:27-36. |
|12.|| Seedat HA, Van Wyk CW. Betel nut chewing and oral submucous fibrosis in Durban. S Afr Med J 1988;74:572-5. |
|13.|| Pindborg JJ, Murti PR, Bhonsle RB, Gupta PC, Daftary DK, Metha FS. Oral submucous fibrosis as a precancerous condition. Scand J Dent Res 1984;92:224-9. |
|14.|| Sinor PN, Gupta PC, Murti PR, Bhonsle RB, Daftary DK, Mehta FS, et al. A case-control study of oral submucous fibrosis with special reference to the aetiologic role of areca nut. J Oral Pathol Med 1990;19:94-8. |
|15.|| Maher R, Lee AJ, Warnakulasuriya KA, Lewis JA, Johnson NW. Role of areca nut in the causation of oral submucous fibrosis: A case control study in Pakistan. J Oral Pathol Med 1994;23:65-9. |
|16.||Merchant AT, Haider SM, Fikree FF. Increased severity of oral submucous fibrosis in young Pakistani men. Br J Oral Maxillofac Surg 1997;35:284-7. |
|17.||Shah N, Sharma PP. Role of chewing and smoking habits in the aetiology of oral submucous fibrosis (OSF): A case control study. J Oral Pathol Med 1998;27:475-9. |
|18.||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. |
|19.||Farrand P, Rowe RM, Johnston A, Murdoch H. Prevalence, age of onset and demographic relationships of different Areca nut habits amongst children in Tower Hamlets, London. Br Dent J 2001;190:150-4. |
|20.||IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Betel-quid and areca-nut chewing and some areca-nut derived nitrosamines. IARC Monogr Eval Carcinog Risks Hum 2004;85:1-334. |
|21.||Jacob BJ, Straif K, Thomas G, Ramadas K, Mathew B, Zhang ZF, et al. Betel quid without tobacco as a risk factor for oral precancers. Oral Oncol 2004;40:697-704. |
|22.||Porter S. Strong association between areca nut use and oral submucous fibrosis. Evid Based Dent 2006;7:79-80. |
|23.||Ahmad MS, Ali SA, Ali AS, Chaubey KK. Epidemiological and etiological study of Oral Submucous fibrosis among Gutkha chewers of Patna, Bihar, India. J Indian Soc Pedod Prev Dent 2006;24:84-9. |
|24.||Afroz N, Hassan SA, Naseem S. Oral Submucous fibrosis. A distressing disease with malignant potential. Indian J Community Med 2006;31:270-1. |
|25.||Jayanthi V, Probert CS, Sher KS, Mayberry JF. Oral submucous fibrosis: A preventable disease. Gut 1992;33:4-6. |
|26.||Sirsat SM, Khanolkar VR. Submucous fibrosis of palate in diet pre- conditioned wistar rats: Induction by local painting of capsaicin-optical electron microscope study. Arch Pathol 1960;70:171-9. |
|27.||Shiaw YY, Kwan HW. Submucous fibrosis in Taiwan. Oral Surg 1979;47:453-7. |
|28.||Sumeth Perera MW, Gunasinghe D, Perera PA, Ranasinghe A, Amaratunga P, Warnakulasuriya S, et al. Development of an in vivo mouse model to study oral submucous fibrosis. J Oral Pathol Med 2007;36:273-80. |
|29.||Prabhu VD, Brave VR, Prabhu R, Chandrashekar P, Jose M, Brave D, et al. Oral submucous fibrosis- A study of prevalence and etiology among adults of Bagalkot District. Int J Prev Dent Oral Epidemiol 2012;1:1-7. |
|30.||Murthi PR, Gupta PC, Bhosle RB, Daftary DK, Mehta FS, Pindborg JJ. Effect on incidence of oral submucous fibrosis of intervention of areca nut chewing habit. J Oral Pathol Med 1990;19:99-100. |
|31.||Ranganathan K, Devi U, Elizabeth J, Arun B, Rooban T, Viswanathan R. Mouth opening, cheek flexibility and tongue protrusion parameters of 800 normal patients in Chennai, South India. A base line study to enable assessment of alterations in oral submucous fibrosis. JIDA 2001;72:78-80. |
|32.||Raina C, Raizada RN, Chaturvedi VN, Harinath BC, Puttewar MP, Kennedy AK. Clinical Profile and serum beta carotene levels in oral submucous fibrosis. Indian J Otolaryngol Head Neck Surg 2005;57:191-5. |
|33.||Ahuja SC, Ahuja U. Betel leaf and betel nut in India: History and uses. Asian Agrihist 2011;15:13-35. |
|34.||Chiba I. Prevention of betel quid chewers oral cancer in the Asian-Pacific Area. Asian Pac J Cancer Prev 2001;2:263-9. |
|35.||Gupta PC, Warnakulasuriya S. Global epidemiology of areca nut usage. Addict Biol 2002;7:77-83. |
|36.||Ahmad MS, Ali SA, Ali AS, Chaubey KK. Epidemiological and etiological study of oral submucous fibrosis among Gutkha chewers of Patna, Bihar, India. J Indian Soc Pedod Prev Dent 2006;24:84-9. |
|37.||Wahi PN, Kapoor VL, Luthra UK, Srivastava MC. Submucous fibrosis of the oral cavity: 2. Studies on epidemiology. Bull World Health Organ 1966;35:793-9. |
|38.||Tang JG, Jian XF, Gao ML, Ling TY, Zhang KH. An epidemiological survey of oral submucous fibrosis in Xiangtin city, Hunan province, China. Community Dent Oral Epidemiol 1997;25:177-80. |
|39.||Rajan G, Ramesh S, Sankaralingam S. Areca nut use in rural Tamil Nadu: A growing threat. Indian J Med Sci 2007;61:332-7. |
|40.||Pindborg JJ, Daftary DK, Mehta FS. A follow up study of 61 dysplastic precancerous lesions in Indian villagers". Oral Surg 1977;43:383-90. |
|41.||Gupta PC, Mehta FS, Daftary DK, Pindborg JJ, Bhonsle RB, Jalnawalla PN, et al. Incidence rates of oral cancer and natural history of oral precancerous lesions in a 10 year follow up study of Indian villages. Community Dent Oral Epidemiol 1980;8:287-333. |
|42.||Ahmad MS, Ali SA, Ali AS, Chaubey KK. Epidemiological and etiological study of oral submucous fibrosis among gutkha chewers of Patna, Bihar, India. J Indian Soc Pedod Prev Dent 2006;24:84-9. |
|43.||Khanolkar VR. Sub mucous fibrosis of the palate in diet. Pre conditioned Wister rats: Induction by local painting of capsaicin-an optical and electron microscopic study. Arch Pathol 1960;70:171-9. |
|44.||Bhonsle RB, Murti PR, Daftary DK, Gupta PC, Mehta FS, Sinor PN. Regional variations in oral submucous fibrosis in India. Community Dent Oral Epidemiol 1987;15:225-9. |
|45.||Reichart P, Boning W, Srisuwan S, Theetranout C, Mohr U. Ultrastructural finding in the oral mucosa of betel chewers. J Oral Pathol 1984;13:166-77. |
|46.||Gupta PC, Ray CS. Smokeless tobacco and health in Indian and South Asia. Respirology 2003;8:419-31. |
|47.||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. |
|48.||Maher R, Lee AJ, Warnakulasuriya KA, Lewis JA, Johnson NW. Role of areca nut in the causation of oral submucous fibrosis: A case control study in Pakistan. J Oral Pathol Med 1994;23:65-9. |
|49.||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. |
|50.||Nair U, Bartsch H, Nair J. Alert for an epidemic of oral cancer due to use of the betel quid substitutes gutkha and pan masala: A review of agents and causative mechanisms. Mutagenesis 2004;19:251-62. |
|51.||Macfarlane GJ, Zheng T, Marshall JR, Boffetta P, Niu S, Brasure J. Alcohol, tobacco, diet and the risk of oral cancer: A pooled analysis of three case-control studies. Eur J Cancer 1995;31:181-7. |
|52.||Stich H, Mathew B, Sankaranarayanan R, Nair MK. Remission of oral precancerous lesions of tobacco/areca nut chewers following administration ob beta-carotene or vitamin A, and maintenance of the protective effect. Cancer Detect Prev 1991;15:93-8. |
|53.||Canniff J, Harvey W, Harris M. Oral submucous fibrosis: Its pathogenesis and management. Br Dent J 1986;160:429-34. |
|54.||Rajendran R, Karunakaran A. Further on the causation of oral submucous fibrosis. Indian J Dent Res 2002;13:74-82. |
|55.||Smita, Afjal M, Siddiqui YH. Genotoxic effects of Panmasala and Gutkha: A review. World J Zool 2011;6:301-6. |
|56.||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. |
|57.||Sirsat S, Khanolkar V. The effect of arecoline on the palatal and buccal mucosa of the Wistar rat. An optical and electron microscope study. Indian J Med Sci 1962;16:198-202. |
|58.||Pindborg JJ, Sirsat SM. Oral submucous fibrosis. Oral Surg Oral Med Oral Pathol 1966;22:764-79. |
|59.||Jeng JH, Kuo ML, Hahn LJ, Kuo MY. Genotoxic and non genotoxic effects of betel quid ingredients on oral mucosal fibroblasts in vitro. J Dent Res 1994;73:1043-9. |
|60.||Boffetta P, Islami F. The contribution of molecular epidemiology to the identification of human carcinogens: Current status and future perspectives. Ann Oncol 2013;24:901-8. |
[Table 1], [Table 2], [Table 3]