J Oral Pathol Med 1995: 24: 145-52 Printed in Denmark . All rights reserved Copyright © Munksgaard 1995 JOURNAL OF Oral Pathology&Meciidiie ISSN 0904-2512 Review article Etiology of oral submucous fibrosis with special reference to the role of areca nut chewing ^P. R. Murti, ^R. B. Bhonsle, ip. C. Gupta, ^D. K. Daftary, ^J. J. Pindborg and ^Fali S. Mehta ^ Basic Dental Research Unit and WHO Collaborating Centre for Oral Cancer Prevention, Tata Institute of Fundamental Research, Bombay, India, ^School of Dentistry, Faculty of Health Sciences, University of Copenhagen, Denmark Murti PR, Bhonsle RB, Gupta PC, Daftary DK, Pindborg JJ, Mehta FS: Etiology of oral submucous fibrosis with special reference to the role of areca nut chewing. J Oral Pathol Med 1995; 24: 145-52. © Munksgaard, 1995. Oral submucous fibrosis (OSF) is a high risk precancerous condition, predominantly affecting Indians. Consumption of chilli was hypothesized as an etiologic factor on the basis of ecological observations and a solitary animal experimental study. Subsequent epidemiologic studies that included case-series reports, large cross-sectional surveys, case-control studies, cohort and intervention studies have identified areca nut as the major etiologic agent. Tissue-culture studies involving human fibroblasts, areca nut extracts and areca nut alkaloids supported this etiologic hypothesis by showing fibroblastic proliferation and increased collagen formation. Currently, the role of genetic susceptibility and that of autoimmunity are receiving attention. The influence of nutritional factors, if any, remains unclear. Oral submucous fibrosis (OSF) is a chronic condition characterized by mucosal rigidity of varying intensity due to fibro-elastic transformation of the juxta-epithelial layer. This leads to restricted oral opening; when the tongue is involved, its protrusion may be impaired. Most affected individuals report a burning sensation of the oral mucosa aggravated by spicy food. The presence of palpable fibrous bands is a requisite diagnostic criterion for this condition, as otherwise other mucosal conditions such as anemic states are likely to be diagnosed as OSF, especially in field studies. Unfortunately, all investigators have not strictly adhered to this criterion in the past. OSF has been predominantly reported among Indians living in India as well as outside, to a lesser extent among other Asiatics and, sporadically, among Europeans. With a reported prevalence ranging up to 0.4% in Indian rural populations (1), several million individuals are estimated to suffer from this malady. OSF is a precancerous condition (2) with mahgnant transformation rates as high as 7.6% (3-5) and a relative risk of 397.3 for oral cancer development compared to individuals with tobacco habits but without any precancerous lesion or condition (5). Several factors such as chilli consumption, nutritional deficiency states, areca nut chewing, genetic susceptibility, autoimmunity and collagen disorders have been suggested to be involved in the pathogenesis of this condition. Some of these suggestions were based on ecological observations, others were more or less speculative. It is the purpose of this paper to summarize and critically analyze the considerable body of evidence which implicates areca nut in the etiology of this condition. Brief reference will be made to other suggested etiologic factors for which less satisfactory evidence exists. Finally, a short description on the pathogenic mechanism in OSF is included, as this aspect has been inadequately investigated so far. Key words: areca nut: epidemiology, oral: etiology: mouth, diseases: precancer: submucous fibrosis, oral R R. Murti, Basic Dental Research Unit, Tata Institute of Fundamental Research, Homi Bhabha Road, Colaba, Bombay 400 005, India. Accepted for publication October 15, 1994. Historical aspects OSF was first described by SCHWARTZ (6) in 1952 among five East African women of Indian origin. This was followed by the first description of this condition in India in 1953 in quick succession by LAL (7) and JOSHI (8). The first report among non-Indians was from Taiwan by Su (9) in 1954. Most of the large studies have been reported from India (1, 7, 8, 10-21), Pakistan (22), Indians in South Africa (23-25), and from Taiwan (26); people from India, Kenya, Uganda, Malawi and Pakistan living in the UK are also affected (27) (Table 1). The disease has been reported from Sri Lanka (28), Myanmar (formerly Burma) (29) and Bangladesh (30) as well as from Nepal, Malaysia, Singapore, Thailand, China, South Vietnam and Fiji (31), Papua New Guinea (32), Saudi Arabia (33), Asians in Kuwait (34), the USA (35), Canada (36) and sporadically among Europeans (37-39). The characteristic occurrence 146 MURTI et al. periments. Nevertheless, the results of the earlier experimental study (40) have been cited widely in the literature in favor of the etiologic role of chillies. From the observation of blood eosinophiha (10, 15), tissue eosinophils in the Etiology biopsy specimens (31, 41, 42), subepithChilli elial vesicles (41) among patients with The suspicion that chilh is an etiologic OSF, and considering the experimental agent arose on the basis of ecological findings reported earlier (40), PINDobservations and was strengthened by BORG & SINGH (41) suggested an allergic the clinical and histologic characteris- nature of this disease possibly due to tics of this condition. OSF is found chilli intake. Some epidemiologic studies have admostly among Indians and other population groups who use chillies {Capsi- dressed the etiologic role of chillies. In cum annum and Capsicum frutescence) a study of 104 cases and controls in Into spice their food. A frequent observa- dia in 1966, the role of chilh consumption is that OSF patients are unable to tion was assessed (15) but no significant tolerate spicy food containing chillies differences as to the amount of chilli which form a part of their normal diet consumption per month or the age of before they develop the disease. Sup- starting chilli consuriiption was found. port from histologic observations was In a Taiwanese study of 35 cases and 100 controls in 1979, SHIAU & KWAN provided in an evaluation of 85 palatal biopsies from OSF patients by SIRSAT & (26) found no association between chilli consumption and OSF. In South Africa, KHANOLKAR (40). They observed epithelial hyperplasia, presence of a chron- where the prevalence of OSF is high ic inflammatory cell exudate, and dense among people of Indian origin, SEEfibrogenesis with elastotic degeneration DAT & VAN WYK (25) did not observe of collagen; these changes were thought any significant difference in the type to indicate a simultaneous defense and and the amount of chillies consumed repair mechanism, similar to the chron- between 71 OSF patients and 103 betel ic productive response. This response is chewers without this condition. Indirect present where the agent responsible for observations from a 10-yr prospective exciting an inflammatory reaction is study in Ernakulam district, Kerala, Inmild and continues to operate over a dia, also did not substantiate the etioprolonged period of time. The hypo- logic role of chillies. For example, GUPthesis of chilli as an etiological agent TA et al. (43) observed 30,962 personyears of nonusers of areca nut (betel fitted with these observations. An animal experimental study using quid) and other forms of tobacco, capsaicin, an active principle of chillies, 20,222 person-years of smokers, 23,111 as a test substance has been conducted person-years of chewers and 8456 peron Wistar rats (40). The investigators son-years of smokers and chewers, of observed elastotic degeneration of pala- both genders, to obtain incidence rates tal collagen, and ultrastructurally par- of this condition. Although there were tial or complete degeneration of the col- substantial person-years of observalagen into elastin-hke filaments, sheets, tions in different groups, and their food or dense amorphous material. It was in- habits in general were similar, all cases ferred that capsaicin was capable of of OSF were observed only in those evoking a limited connective tissue re- who chewed areca nut (in betel quid). sponse in an unimpaired animal system There are some ecological arguments and the reaction was enhanced in against the chilli hypothesis. For examprotein- or vitamin-deficient animal ple, from Mexico or other South Amersystems. The authors, however, cau- ican countries where chilli consumption tioned that although the optical and is widespread, we are not aware of any submicroscopic changes of collagen in report on this condition. The overall astheir studies were comparable to human sessment is that there is no evidence OSF of the palate, it did not necessarily substantiating the etiologic role of chillimplicate chilh as the sole causative ies in OSF. agent because the alterations seen were Interestingly, however, in recent years nonspecific and indicated only a reac- short term experimental tests have tion to irritant. In contrast to the re- shown chilli extract to be mutagenic sponse observed by these investigators (44) and it has also been found to enHAMNER et al. (35) failed to reproduce hance the tumorigenicity of tobacco in the results in hamster cheek pouch ex- experimental animals (45). Furtherof OSF among Indians and other Asiatics has prompted many investigators to search for etiologic factors that may be a part of their diet or environment. more, epidemiologic studies have shown that chilh consumption increases the risk of cancers in the upper aerodigestive tract in a dose-dependent manner (46). Nutritional deficiencies Several investigators have reported anemia, vitamin, iron and protein deficiencies among OSF patients (6, 10, 1315, 23). Because of the presence of iron deficiency anemia in 10 of 13 OSF patients in Malaysia, RAMANATHAN (47) hypothesized that this condition was an Asian version of sideropenic dysphagia wherein the chronic deficiency leads to mucosal susceptibility to irritants such as chilli and areca nut use. Some of these observations were supported by case-control studies. For example, a higher frequency of clinical manifestations of deficiency of vitamins A,B and C, and lower serum vitamin levels were found in cases as compared to controls by WAHI et al. (15); no significant difference in the frequency of anemia between the cases and controls was observed. In a South African study, there was no difference in the prevalence of iron deficiency anemia between that observed in the cases and the general population (24). Serum folate and B12 levels were also within normal limits in this study. The above observations did not estabhsh an etiologic or contributory role for nutritional deficiencies in OSF. It is probable that the deficiency of these factors observed among OSF patients may be secondary; most OSF patients cannot tolerate spicy food, which is a normal family and community diet, and the opening of the mouth in OSF patients becomes progressively smaller. This functional impairment may affect normal food intake and lead to nutritional deficiencies. Areca nut use Currently, areca nut use is considered to be the most important etiologic factor for OSF Areca-nut chewing habits Areca nut (often erroneously referred to as betel nut) is the endosperm of the fruit of the Areca catechu tree. The fruit is orange-yellow in color when ripe. The fibrous pericarp is removed from the seed or endosperm, which is then used fresh, after sun drying or in a cured Etiology of submucous fibrosis 147 form. Areca nut contains tannins (11.426.0%), of which gallotannic acid (18.03%) and D-Catechol (0.4%) are important (48, 49). It contains several alkaloids (0.15-0.67%) of which arecoline is the most abundant; arecaidine, guvacine, isoguvacine, arecolidine and guvacoline are also present in small quantities. Other substances comprise fats, carbohydrates, proteins, and mineral matter. In India areca nut is chewed by itself, in the form of various areca nut preparations such as scented supari, mawa, mainpuri tobacco, pan masala, and in betel quid, either with or without tobacco (50). Areca nut chewing is also practiced in various forms in several countries in South East Asia, Oceania, and the Pacific Islands and by Indian emigrants living abroad (24, 49, 51). Epidemiologic studies The studies that have led to the identification of areca nut chewing as an etiologic factor for OSF include ecological observations, case reports, case-series studies, case-control studies, cross-sectional studies, prospective studies, and intervention studies. The concept has been strengthened by the demonstration of a dose-response relationship and by the regional variation in clinical features of the disease that are Hnked with the type of areca nut use. Ecological observations - The occurrence of OSF in an area or population in which areca nut chewing is popular, compared to its rarity in populations or areas where areca nut chewing is unknown or less common, constitute the ecological observation. In South Africa OSF is common among women of Indian origin and rare among blacks (24). This corresponds with the fact that areca nut chewing is often practiced by the Indian women but rarely by South African blacks. In Bhavnagar town, Gujarat, India, there was a sudden upsurge of this condition (52) with 275 cases being recorded in a recent 5-yr period as compared to very few cases observed earher. This trend corresponded with the increase in an areca nut {mawa) chewing habit in that area. Ecological observations can point towards a possible hypothesis, but are weak for inferring any causal relationship. Case reports - These comprise reports on OSF cases indicating the presence of an areca nut chewing habit among the patients involved. For example, Su (9) reported that all 3 cases he observed chewed areca nut and he hy- pothesized that OSF may have been caused by the tannic acid, slaked lime powder and the continued action of arecoline affecting the "vascular nerves" of the oral mucosa and causing "neurotropic disorder". Case reports also include anecdotal observations such as the occurrence of this condition in a 4yr old Indian immigrant girl in Canada who had been chewing areca nut since the age of 2 (36)! Case-series studies - These comprise a large number of reports by various investigators over a 27-yr period from which the frequency of areca nut chewing could be extracted. Table 1 shows that areca nut chewing was practiced by 31-100% of the cases. Despite lacking controls, these studies indicated that the frequency of areca nut chewing was probably far higher than was expected or known in the unaffected group or in the general population. These data have limitations as the studies were conducted at various points over a long time span and with differing concepts of the diagnostic criteria and the etiology of the disease. Case-control studies - These studies provide the relative risk estimates. A case-control study from Agra, India, in- eluded three categories of OSF patients (15). Considering only 13 cases with definite palpable fibrous bands (group III), the relative risk of this condition among areca nut chewers was computed to be 43.8 (/'<0.01) (21). In a Taiwanese study of 35 cases and 100 controls, SHIAU & KWAN (26) observed a high correlation between this condition and areca nut chewing. In an Indian study of 60 cases and 60 controls, SINOR et al. (21) reported a relative risk of 109.6 for all forms of areca nut chewing, 106.4 for chewing mawa and 780.0 for the combined use of mawa and betel quid. In a recent study of 157 cases and 157 controls from Pakistan, MAHER et al. (22) observed that those who chewed areca nut in some form had a substantially higher relative risk (RR 94) compared to those who did not chew areca nut. Areca nut chewing alone showed the highest relative risk of 154, pan chewing with tobacco the next highest (RR 64), and the RR for chewing without tobacco was 32. The attributable risk for chewing areca nut products as compared to no chewing in the population was 98%. Dose-response relationship - The relationship between the degree of exposure Table 1. Distribution of large series of OSF cases according to gender ratio and frequency of areca nut chewing n M:F % with areca nut chewing habit 20 41 64 21 85 46 25 104 40 63 33 65 30 NA 0.9:1 0.9:1 NA NA 0.6:1 1.5:1 2.1:1 1.6:1 0.3:1 0.1:1 NA 1.5:1 100% NA 31% NA NA NA 84% 34% 80% 67% 55% 71% 80% 0.4:1 1.2:1 29.0:1 100% 100% 21 64 24 60 22 157 23 18 115 Ref. no. Author(s) India LAL (1953) 7 8 JOSHI(1953) DESA (1954) SHARAN (1959) SHIRAT & KHANOLKAR (1962) RAO (1962) PINDBORG et al. (1964) WAHI et al (1968) MANI & SINGH (1968) PINDBORG et al (1968)+ MEHTA et al (1972) ABROL (1975) AKBAR (1976) BRONSLE et al. (1986) ERNAKULAM PUNE SINOR et al (1990) 10 11 12 13 14 15 16 1 17 18 19 20 98% Pakistan MAHER et al. (1994) 1.0:2.3 99% South Africa RANDERIA (1977) SEEDAT (1985)+ + SEEDAT & VAN WYK (1988) 24 25 71 18.0:0 0.1:1 0.01:1 100% 100% 100% 44 0.2:1 100% UK CANNIFF et al (1986) NA, Not available +From five areas of India ++Only referred cases included here 27 148 MURTI et al. and the risk of a disease is an important criterion for causal inference. In the case-control study from India referred to earlier (21), the relative risk increased with the duration as well as the frequency of the areca nut chewing habit. In a bivariate analysis of the duration and frequency of the habit, the risk of OSF showed a clear dose-response relationship (21). In the study from Pakistan (22), relative risks increased with the increase in the frequency and duration of the habit, although not consistently. The authors opined that the frequency of areca nut chewing was more important than the duration of the habit. While the Indian (21) and Pakistani (22) studies demonstrated a dose-response relationship, in a South African study (25) there was a significant difference between the median duration of areca nut chewing among those with the disease (16 years) and those without the disease (26 years). Although these findings are apparently opposed to the hypothesis of a dose-response relationship, the difference was not adjusted for age. Cross-sectional studies - These provide the prevalence of OSF among chewers and non-chewers of areca nut, and also compare the frequency of this habit between the affected individuals and the general population. The prevalence of this condition in Ernakulam district, Kerala, India was 894 per 100,000 among areca nut chewers as compared to 31 per 100,000 in non-users of areca nut (53). The two cases detected among non-chewers were really among past chewers, so essentially the prevalence among non-chewers of areca nut was zero. In four cross-sectional studies from India (17) and South Africa (25, 54, 55) there was an over-representation of the areca nut chewing habit in the affected subjects as compared to that in the general population (Table 2). Prospective studies - These are reported only from India where, over a 10-yr period, large cohorts of individ- uals with and without areca nut chewing habits have been foUowed-up annually to obtain the incidence rates of OSF (43). There were a substantial number of person-years of observation among non-users of areca nut, including smokers, but all new cases of this condition developed among areca nut chewers (43). Intervention studies - An intervention study has shown a decrease in the risk for OSF as a result of education against chewing habits (56, 57). MURTI et al. (56) demonstrated a fall in the incidence of OSF from 21.3 per 100,000 personyears among men in the control cohort to 8.3 in the intervention cohort, and from 45.7 to 29.0 among women in the control cohort (the cohort which was subjected to habit intervention). This reduction was not statistically significant because of the small number of incidence cases; nevertheless, it highlighted the decreased risk with the reduction in areca nut habit. Regional variations - The prevalence and the frequency of OSF vary considerably in different areas in India (1, 58-62). It has been suggested that the arecoline content of the areca nut varies from place to place in India and perhaps this may have some influence on the prevalence rate (63). Certain distinct clinical observations in India also support the etiologic role of areca nut in OSF. For example, BHONSLE et al. (20) demonstrated that in Pune district, Maharashtra, this condition affected the posterior one-third of the buccal mucosa, soft palate, the uvula, and retromolar areas significantly more often than in Ernakulam district, Kerala; on the other hand the tongue, floor of the mouth and the hard palate were not involved in Pune. The average age of patients in Pune was lower than in Ernakulam. In Pune 67% chewed only areca nut, while in Ernakulam 77% chewed areca nut as an ingredient of betel quid with tobacco and the remainder both chewed areca nut and smoked tobacco. A plausible explanation for these regional differences is Table 2. Distribution of areca nut chewing habits in cases and the general population Areca nut habit Author(s) SHEAR et al. (1967) DocKRAT & SHEAR (1969) MEHTA et al. (1972) SEEDAT & VAN WYK (1988) Ref. no. 54 55 17 25 Population 1000 1200 101761 2058 Cases Population % Cases % 5 7 33 63 12.3 22.0 2.1 9.0 100.0 100.0 52.1 100.0 that when individuals chew areca nut without tobacco, as in Pune, they generally swallow the juice, thus exposing the posterior part of the oral mucosa (such as the posterior one-third of the buccal mucosa, soft palate and uvula) to areca nut contents much more than the anterior parts. In Ernakulam, areca nut is chewed in betel quid with tobacco, therefore the quid and the juice are held for a longer time and are spat out when they become bland. This results in a more generalized contact of the quid with the oral mucosa, perhaps leading to its generalized involvement in OSF. Animal experiments and tissue-culture studies While epidemiologic studies have identified areca nut as the primary etiologic agent involved in this condition, animal experiments have investigated the effect of arecohne on submucosal collagen and tissue-culture studies have explored the action of areca nut extracts and specific alkaloids on human fibroblasts. As part of the attempt at induction of submucous fibrosis in animal models SIRSAT & KHANOLKAR (64) painted the palates of 27 Wistar rats with arecoline, an active principle of areca nut {Areca catechu). The submucosal collagen showed altered staining similar to that seen in human OSF only in two rats, and therefore the investigators opined it was improbable that arecoline per se played any part in the causation of human OSF. They pointed out, however, that tissue changes brought about in animal systems by a test substance cannot be identically correlated to those in man. Areca nut alkaloids yield powerful carcinogenic nitrosamines (65). The carcinogenicity of areca nut has been investigated in many animal experiments, with conflicting results (49), but there was no mention of any changes suggestive of OSF in these studies. In contrast to the above observation from experimental studies, tissue-culture experiments using human fibroblasts suggested that areca nut is involved in the pathogenesis of OSF. CANNIFF & HARVEY (66) demonstrated that ethanohc extracts of three varieties of areca nut stimulated collagen synthesis to the extent of 170% over that in control cultures. HARVEY et al. (67) studied the interaction of arecoline and arecaidine with human fibroblasts. They found that although both alkaloids stimulated collagen synthesis, the influence of are- Etiology of submucous fibrosis 149 caidine was more pronounced and it was concentration-dependent. The synthesis of collagen stimulated by arecoline was time-dependent, peaking at 24 h. Both alkaloids stimulated proliferation of fibroblasts, although at the 100 g level arecoline was cytotoxic. Fibroblasts metabolized [^^]-arecoline to P"]-arecaidine and various esters of arecaidine. The metabolism of arecoline to arecaidine was considered important and necessary, as the latter was a more potent stimulator of fibroblast prohferation and collagen synthesis. Interestingly, it was suggested that the addition of slaked lime to areca nut in pan (betel quid) hydrolyses arecoline to arecaidine (67). This means that the hydrolysis of arecoline could occur in the saliva as well as in fibroblasts. It was suggested that the inflamed oral mucosa has enhanced permeability to arecoline and arecaidine. In-vitro comparison of human fibroblasts from the normal and OSF tissue did not reveal any intrinsic differences in their response to arecoline, although OSF fibroblasts did show a shghtly higher basal rate of collagen synthesis (68). The large quantities of tannins and the flavanoid catechin present in the areca nut do not appear to take part in collagen synthesis. However, they form cross-hnkages between the collagen peptide chain, inhibiting collagen degradation by collagenase (69) and resulting in the accumulation of collagen in OSF Genetic susceptibiiity The possibihty of genetic susceptibihty for this condition has been probed by CANNIFF et al. (27). They performed HLA tissue typing and observed that the frequencies of HLA AlO, DR3, and DR7 in their sample of 44 patients were significantly different from the ethnically-, regionally-, and age-matched control group. Further analysis of the haplotypic pairs A10/DR3, A10/B8 and B8/DR3 showed an increased frequency in the patients, although this was not statistically significant for the latter two pairs. These observations were interpreted to imply a possible genetic susceptibility to the action of extrageneous factors such as areca alkaloids and tannins. The famihal occurrence of this condition has also been reported from India (21) and South Africa (24). In the Indian study of 60 cases, seven individuals were siblings from three families. The occurrence of OSF among individuals without areca nut chewing habits (3739, 70-73) has also been thought to be due to genetic factors (73). Autoimmunity Suspicion of an autoimmune explanation for OSF stems from certain similarities of this condition with other collagen disorders, namely scleroderma, which is presumed to have an autoimmune pathogenesis (74, 75). Scleroderma is characterized by induration and fixation of the skin to the deeper subcutaneous tissues. Oral mucosal involvement, which occurs rarely, is marked by thinness of the lips, stiffening of the tongue, difficulty in eating and inability to open and close the mouth properly. Because of the similarities of clinical features between OSF and scleroderma, Su (9) felt that his cases represented oral scleroderma. A link between scleroderma and OSF has also been suspected on the basis of the similarity of histologic characteristics. SIRSAT & KHANOLKAR (76) observed refractile eosinophilic material and a marked increase in PAS-positive material with metachromasia in the ground substance in OSF. These characteristics were similar to the histochemical reaction indicative of the presence of fibrinoid in a number of connective tissue disorders involving dense collagen prohferation. The ultrastructural changes in this condition were also similar to those seen in rheumatoid arthritis and scleroderma. It became apparent that DR antigen, which indicates an autoimmune basis of a disease, was associated with scleroderma (74, 75). Interestingly, CANNIFF et al. {11) reported an increase in DR3 antigen in OSF and also the presence of serum immunoglobulins and autoantibodies. In view of the female bias, the age of onset of this condition, and other immunologic and genetic findings, the authors felt that OSF, like scleroderma, could have an autoimmune basis. In a South African study the possible influence of autoimmunity was investigated among 105 patients by examining their sera for the presence of antibodies to parietal cells and nuclear proteins (24). About 18% of the patients exhibited serum parietal cell antibodies, which was higher than in the general population (5-8%). The author postulated that betel nut alkaloids may act as haptens which may produce antibodies to parietal cells. Furthermore, because of the similarities between the betel nut protein and parietal cell protein, antibodies produced to betel nut antigens may cross-react with parietal cell protein. There was, however, no evidence of gastric mucosal involvement in this disease. Comments There are some inherent difficulties in assessing data reported over a long time period, from 1953-94, by many workers with varied concepts concerning the etiology and clinical criteria for OSF. For example, not all investigations have included the presence of palpable fibrous bands among the diagnostic criteria, nor have the criteria for completeness of recording areca nut chewing always been clear. The importance of having palpable fibrous bands as a diagnostic criterion for submucous fibrosis can be better appreciated from re-analysis of the data on 104 cases of OSF reported by WAHI et al. (15). In this study, among 13 patients in group III, one of the inclusion criteria was palpable fibrous bands, while patients were included in groups I and II on the basis of other symptoms such as a burning sensation. The relative risk for areca-nut chewing, including tobacco chewing, for group III was 43.8, but the similar relative risk for the remaining two groups combined was 1.0. Although chilli consumption, nutritional deficiencies and autoimmune background have been thought to be involved in the pathogenesis of OSF, the evidence is too circumstantial to be of any relevance. Concerning genetic susceptibility, there is only one study so far indicating that it renders the mucosa more prone for irritants like areca nut chewing (27). This study used now out-dated serological methods. Further studies utilizing more recent immunochemical techniques are desirable for understanding this aspect of the disease. Similarly, the occurrence of OSF among those without an areca nut habit has been suspected to be due to spontaneous genetic susceptibihty (73); this viewpoint also needs further elucidation. In contrast to other suspected factors, considerable data has accrued over the years in support of the etiologic role of areca nut in this condi- 150 MuRTi et al. tion. They derive from a variety of epickmiologic studies providing consistency, strength, and a dose-response relationship as well as from tissue-culture studies (66, 67). Tissue-culture studies involving cell lines from human fibroblasts have reproduced connective tissue disorders, as the fibroblasts retain their phenotypes in culture and possess many of their properties seen in vivo (67). Collectively, these two approaches have demonstrated that areca nut is the most likely factor in the etiopathogenesis of OSF. In the light of this information, the pathogenesis of OSF can be suggested to consist of stimulation of fibroblasts by the areca nut constituents, notably the alkaloids, which results in their phenotype alteration as well as increased coUagenogenesis. The large quantities of tannins and the flavanoid catechin in the areca nut inhibit collagen degradation by collagenase (69), resulting in the accumulation of collagen; genetic susceptibility perhaps accentuates the pathogenesis. The chronic inflammatory cell infiltrate often present in the submucosal layer is also believed to stimulate fibroblast proliferation and collagen synthesis through release of factors like IL 1 (interleukin 1) (68). In recent times the role of cytokines of inflammatory cell origin in stimulating fibroblast proliferation is receiving attention. In that context it would be of interest to investigate whether the inflammatory cells in submucous fibrosis play a role in its pathogenesis. Some investigators have studied the ultrastructural changes of collagen in submucous fibrosis (76-78). BINNIE & CAWSON (77) reported fine (immature) fibrils in the solitary sample they studied and felt that these probably represented embryonic collagen and that the pathogenesis involves defects in the polymerization and maturation of collagen. In contrast, more recently VAN WYK et al. (78) studied 11 tissue samples from submucous fibrosis and 15 controls and reported that while there was excessive deposition of collagen, especially Type I, the fibrils were morphologically normal. the use of areca nut products, including those without tobacco, through public education. This is essential because of the increasing and widespread use of areca-nut preparations like pan masala (betel quid mixtures) by all classes of people (50). These products are now commercially manufactured and marketed in attractive foil packs and tins. Carrying a pan masala tin has become a status symbol and offering pan masala is accepted as implying hospitality and equality. There are no data on the prevalence of its use, but its popularity can be gauged by the fact that the Indian market for pan masala is worth Rs. 2000 million (US$ 116 million). These products are also exported to many countries and OSF is reported among those who use them (27). There are already indications in India of an increased occurrence of OSF due to this product and it is likely to reach an alarming proportion in the near future. Its implication is that oral cancer occurrence would also increase correspondingly. Encouragingly, primary prevention has been demonstrated to be practicable (56, 57) and useful in reducing the incidence of OSF (56) and therefore efforts must be initiated in that direction. Acknowledgements - This study was supported by funds from the Indo-US Fund Research agreement No. N-406-645. References 1. PiNDBORG JJ, MEHTA F S , GUPTA PC, Prevalence of oral submucous fibrosis among 50,915 Indian villagers. Br J Cancer 1968; 22: 646-54. 2. PiNDBORG JJ. Oral cancer and precancer. Bristol: John Wright & Sons, 1980. DAFTARY D K . 3. PiNDBORG JJ, MURTI PR, BHONSLE R B , GUPTA PC, DAFTARY DK, MEHTA FS. Oral submucous fibrosis as a precancerous condition. Scand J Dent Res 1984: 89: 270-4. 4. 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 Epidemiol 1985: 13: 340-1. 5. GUPTA PC, BHONSLE RB, MURTI PR, DAFTARY DK, MEHTA FS, PINDBORG JJ. Control of OSF So far, there does not seem to be any satisfactory treatment for OSF (31, 72). As areca nut has been identified as an etiologic agent, it is amenable to primary prevention. The preventive measures should be in the form of curbing An epidemiologic assessment of cancer risk in oral precancerous lesions in India with special reference to nodular leukoplakia. Cancer 1989: 63: 2247-52. 6. SCHWARTZ J. Atrophia idiopathica (tropica) mucosae oris. Demonstrated at the 11th International Dental Congress, London, July 1952. 1. LAL D. Diffuse oral submucous fibrosis. J All-India Dent Assoc 1953: 26: 1-3. 8. JosHi SG. Submucous fibrosis of the palate and the pillars. Indian J Otolaryngol 1953: 4: 1-4. 9. Su I-PiN. Idiopathic scleroderma of the mouth. Arch Otolaryngol 1954: 59: 3302. 10. DESA J V Submucous fibrosis of the palate and cheek. Ann Otol Rhinol Laryngol 1957:66: 1143-59. 11. SHARAN J. Histopathological observations on cases of submucous fibrosis of the oral cavity. Indian J Pathol Bacteriol 1959: 2: 150-2. 12. SiRSAT SM, KHANOLKAR V R . Submucous fibrosis of the palate and pillars of the fauces. Indian J Med Sci 1962: 16: 189-97. 13. RAO A B N . Idiopathic palatal fibrosis. Br J Surg 1962: 50: 23-5. 14. PINDBORG JJ, CHAWLA T N , SRIVASTAVA AN, GUPTA D, MEHROTRA M N . Clinical aspects of oral submucous fibrosis. Acta Odontol Scand 1964: 22: 679-91. 15. WAHI P N , KAPUR V L , LUTHRA UK, SRIVASTAVA MC. Submucous fibrosis of the oral cavity. 2. Studies on epidemiology. Bull WHO 1966: 35: 793-9. 16. MANI N J , SINGH B. Studies on oral submucous fibrosis. 1. Clinical aspects. / Indian Acad Dent 1968: 9: 27-36. 17. MEHTA FS, GUPTA PC, DAFTARY DK, PINDBORG JJ, CHOKSI S K . An epidemio- logic study of oral cancer and precancerous conditions among 101,761 villagers in Maharashtra, India. Int J Cancer 1972: 10: 134^1. 18. ABROL B M . Clinicopathological, biochemical and immunological studies in syndrome of idiopathic oral fibrosis (submucous fibrosis). Bombay Hosp J 1975: 19: 50-61. 19. AKBAR M . Oral submucous fibrosis - a clinical study. J Indian Dent Assoc 1976: 48: 365-73. 20. BHONSLE RB, MURTI PR, DAFTARY DK, et al. Regional variations in oral submucous fibrosis in India. Community Dent Oral Epidemiol 1987: 15: 225-9. 21. SiNOR PN, GUPTA PC, MURTI PR, et al. A case-control study of oral submucous fibrosis with special reference to the etiologic role of areca nut. / Oral Pathol Med 1990: 19: 94-8. 22. MAHER R, LEE AJ, WARNAKULASURIYA KAAS, LEWIS J A , JOHNSON N W . 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. 23. RANDERIA J D . Oral submucous fibrosis as a precancerous lesion. J Dent Assoc S Afr 1982: 37: 521-6. 24. SEEDAT H A . Oral submucous fibrosis in Durban, Natal: a study of its epidemiology, aetiology and morphological features. Thesis. Stellenbosch, South Africa. University of Stellenbosch, 1985. 25. SEEDAT HA, VAN WYK CW. Betel chew- Etiology of submucous fibrosis 151 ing and dietary habits of chewers without and with submucous fibrosis and with concomitant oral cancer. South Afr MedJl98H:14: 572-5. 26. SHIAU YY, KWAN HW. Submucous fibrosis in Taiwan. Oral Surg Oral Med Oral Pathol 1979: 47: 453-7. 27. CANNIFF JP, HARVEY W, HARRIS M . Oral submucous fibrosis: its pathogenesis and management. Br Dent J 1986: 160: 42934. 28. WARNAKULASURIYA S. Semi-quantitative clinical description of oral submucous fibrosis. Ann Dent 1987: 46: 18-21. 29. LAY KM, SEIN K , MYINT A, Ko SK, PINDBORG JJ. Epidemiologic study of 6000 villagers of oral precancerous lesions in Bilugyun: preliminary report. Community Dent Oral Epidemiol 1982: 10: 152-5. 30. CHOUDHRY CR, 31. 32. 33. 34. BHUIYAN M , MOHIDU- ZAMMAN M. Submucous fibrosis in Bangladesh. PINDBORG JJ, SIRSAT SM. Oral submucous fibrosis. Oral Surg Oral Med Oral Pathol 1966: 22: 764-79. BARMES D, DUKE P. Submucous fibrosis. Papua New Guinea Med J 1975: 18: 6670. MANI NJ, KIM HW, SASTRY KARH. Oral submucous fibrosis in a Saudi female. Ann Dent 1985: 44: 12-3. FAHMY MS. Submucous fibrosis. A premahgnant oral disease. Case report. J Kuwait Med Assoc 1972: 6: 23-8. 35. HAMNER JE, III, LOONEY PD, CHUSED TM. Submucous fibrosis. Oral Surg Oral Med Oral Pathol 1974: 37: 412-21. 36. HAYES PA. Oral submucous fibrosis in a 4-year old girl. Oral Surg Oral Med Oral Pathol 1985: 59: 475-8. 37. LEMMER J, SHEAR M . Oral submucous fibrosis: a possible case in a person of Caucasian descent. Br Dent J 1967: 122: 343-6. 38. SIMPSON W. Submucous fibrosis. Br J Oral Surg 1969: 6: 196-200. 39. LASKARIS G, BOVOPOULOU O, NICOLIS G, Oral submucous fibrosis in a Greek female. Br J Oral Surg 1981: 19: 197-201. 40. SIRSAT SM, KHANOLKAR VR. Submucous fibrosis ofthe palate in diet-preconditioned Wistar rat. Arch Pathol 1960: 70: 171-9. 41. PINDBORG JJ, SINGH B. Formation of vesicles in oral submucous fibrosis. Acta Pathol Microbiol Scand 1964: 62: 562-6. 42. SIRSAT SM, PINDBORG JJ. Subepithelial changes in oral submucous fibrosis. Acta Pathol Microbiol Scand 1967: 70: 16173. 43. GUPTA PC, MEHTA FS, DAFTARY DK, et al. Incidence rates of oral cancer and natural history of oral precancerous lesions in a 10-yr follow-up study of Indian villagers. Community Dent Oral Epidemiol 1980: 8: 287-333, 44. NAGABHUSHAN M , BHIDE SV Mutagenicity of chillie extract and capsaicin in short term tests. Environ Mutagen 1985: 7: 881-8. 45. SV. Carcinogenic potential of some Indian tobacco products. In: GUP- BHIDE TA PC, HAMNER JE, III, MURTI PR, eds. Control of tobacco-related cancers and other diseases. Bombay. Oxford University Press, 1992. pp. 217-22. 46. NOTANI PN. Role of diet and alcohol in tobacco-related cancer at sites in the upper aerodigestive tract in an Indian population. In: GUPTA PC, HAMNER JE, III, MURTI PR, eds. Control of tobaccorelated cancers and other diseases. Bombay. Oxford University Press, 1992. pp. 149-55. 47. RAMANATHAN K . Oral submucous fibrosis - an alternative hypothesis as to its causes. Med J Malaysia 1981: 36: 243-5. 48. ARJUNGI KN. Areca nut. A review. Arzneimittelforschung 1976: 26: 951-6. 49. INTERNATIONAL AGENCY FOR RESEARCH ON CANCER. IARC monographs on the evaluation of the carcinogenic risk of chemicals to humans. Vol. 37. Tobacco habits other than smoking: betel-quid and areca nut chewing; and some related nitrosamines. Lyon: International Agency for Research on Cancer, 1985. 50. BHONSLE RB, MURTI PR, GUPTA PC. In: GUPTA PC, Tobacco habits in India. HAMNER JE, III, MURTI PR, eds. Control of tobacco-related cancers and other diseases. Bombay. Oxford University Press, 1992. pp. 25-46. 51. PINDBORG JJ, MURTI PR, BHONSLE RB, GUPTA PC. Global aspects of tobacco use and its implications for oral health. In: GUPTA PC, HAMNER JE, III, MURTI PR, eds. Control of tobacco-related cancers and other diseases. Bombay. Oxford University Press, 1992. pp. 13-9. 52. SiNOR PN, MURTI PR, BHONSLE RB, GUPTA PC. Mawa chewing and oral submucous fibrosis in Bhavnagar, Gujarat, India. In: GUPTA PC, HAMNER JE, III, MURTI PR, eds. Control of tobacco-related cancers and other diseases. Bombay. Oxford University Press, 1992. pp. 10712. 53. MEHTA FS, PINDBORG JJ, HAMNER JE, III, et al. Oral cancer and precancerous conditions in Indian rural populations, 1966-69, Copenhagen, Munksgaard, 1971, 54. SHEAR M , LEMMER J, DOCKRAT I. Oral submucous fibrosis in South African Indians. An epidemiologicai study. South Afr J Med Sei 1967: 32: 41-6. 55. DOCKRAT 1, SHEAR M . Oral submucous fibrosis in Natal. In: CAHN L, ed. 4th Proceedings of the International Academy of Oral Pathology. New York, Gordon & Breach, 1969. pp. 57-63. 56. MURTI PR, GUPTA PC, BHONSLE RB, DAETARY DK, MEHTA FS, PINDBORG JJ. Effect on the incidence of oral submucous fibrosis of intervention in the areca nut chewing habit. J Oral Pathol Med 1990: 19: 99-100. 57. GUPTA PC, MEHTA FS, PINDBORG JJ, et al. Primary prevention trial of oral cancer in India: a 10-year follow-up study. J Oral Pathol Med 1992: 21: 4339. 58. PINDBORG JJ. Frequency of oral submucous fibrosis in North India. Bull WHO 1965: 32: 748-50. 59. PINDBORG JJ, CHAWLA TN, MISRA RK, NAGPAUL RK, GUPTA VK. Frequency of oral carcinoma, leukoplakia, leukokeratosis, leukoedema, submucous fibrosis, and lichen pianus in 10,000 Indians in Lucknow, Uttar Pradesh, India: preliminary report. J Dent Res 1965: 44: 615 (only). 60. PINDBORG JJ, KALAPESI HK, KALE SA, SINGH B, TALEYARKHAN BN. Frequency of oral leukoplakia and related conditions among 10,000 Bombayites: preliminary report. J All-India Dent Assoc 1965: 37: 228-9. 61. PINDBORG JJ, BHAT M , DEVANATH KR, NARAYANA HR, RAMACHANDRA S. Fre- quency of oral white lesions among 10,000 individuals in Bangalore, South India: preliminary report. Indian J Med Sei 1966: 20: 349-52. 62. ZACHARIAH J, MATHEW B, VARMA NAR, IQBAL AM, PINDBORG JJ. Frequency of oral mucosal lesions among 5000 individuals in Trivandrum, South India: preliminary report. / All-India Dent Assoc 1966: 38: 290-4. 63. AwANG MN. Estimation of arecoline contents in commercial areca (betel) nuts and its relation to oral precancerous lesions. Singapore Med J 1986: 27: 31720. 64. SIRSAT SM, KHANOLKAR VR. The effect of arecoline on the palatal and buccal mucosa of the wistar rat. An optical and electron microscopic study. Indian J Med Sei 1962: 16: 198-202. 65. HOFFMANN D, RIVENSON A, PROKOPCZYK B, BRUNNEMANN KD, CARMELLA SG, HOFFMANN I. Advances in tobacco carcinogenesis. I. Smokeless tobacco and betel quid. In: GUPTA PC, HAMNER JE, III, MURTI PR, eds. Control of tobaccorelated cancers and other diseases. Bombay. Oxford University Press, 1992. pp. 193-204. 66. CANNIFF JP, HARVEY W The aetiology of oral submucous fibrosis: the stimulation of collagen synthesis by extracts of areca nut. Int J Oral Surg 1981; 10 (Suppl): 163-7. 67. HARVEY W, SCUTT A, MEGHJI S, CANNIFF JP. Stimulation of human buccal mucosa fibroblasts in vitro by betel-nut alkaloids. Arch Oral Biol 1986: 31: 459. 68. MEGHJI S, SCUTT A, HARVEY W, CANNIFF JP. An in-vitro comparison of human fibroblasts from normal and oral submucous fibrosis. Arch Oral Biol 1987: 32: 213-5. 69. KuTTAN R, DoNNELY PV, Di FERRANTE N. Collagen treated with (+) catechin becomes resistant to the action of mammalian collagenase. Experientia 1981: 37: 221-3. 152 MURTI et al. 70. PAISAT DK. Oral submucous fibrosis. Int J Oral Surg 1981: 10: 307-12. 71. McGuRK M, CRAIG GT. Oral submucous fibrosis: two cases of malignant transformation in Asian immigrants to the United Kingdom. Br J Maxillo-fac Surg 1984: 22: 56-64. 72. PINDBORG JJ. Oral submucous fibrosis: a review. Ann Acad Med 1989: 18: 603-7. 73. SEEDAT HA, VAN WYK CW. Submucous fibrosis in non-betel nut chewing subjects. J Biol Buccale 1988: 16: 3-6. 74. KALLENBBERG CGM, VAN DER VOORTBEELEN JM, D'AMARO J. THE TH. Sclroderma: increased frequency of B8/ DR3 in scleroderma and association of the haplotype with impaired cellular immune response. Clin Exp Immunol 1981: 43: 478-85. 75. WHITESIDE TL, MEDSGER TA, JR, ROD- NAN GP. HLA DR antigens in progressive systemic sclerosis (scleroderma). J Rheumatol 1983: 10: 163-7. 76. SIRSAT SM, KHANOLKAR VR. A histo- chemical and electron microscopic study of submucous fibrosis of the palate. / Pathol Bacteriol 1957: 73: 439-42. 77. BiNNiE WH, CAWSON RA. A new ultrastructural finding in oral submucous fibrosis. Br J Dermatol 1972: 86: 28690. 78. VAN WYK CW, SEEDAT HA, PHILLIPS VM. Collagen in submucous fibrosis: an electron microscopic study. / Oral Pathol Med 1990: 19: 182-7.
© Copyright 2024