A case-control study of oral submucous fibrosis with special reference to the etiologic role of areca nut

A case-control study to elucidate the etiology of oral submucous fibrosis was conducted in Bhavnagar, Gujarat. Sixty consecutively arriving oral submucous fibrosis patients at a dental clinic were selected as cases. An equal number of controls matched for age, sex, religion and socioeconomic status were selected from individuals who did not exhibit any oral mucosal lesion or condition. Among cases, 98% chewed areca nut regularly in one form or the other whereas among controls 35% chewed areca nut, giving an overall relative risk of 109.6. Areca nut chewing was practiced most commonly in the form of mawa: a mixture containing mainly areca nut (over 90% by weight), some tobacco, and a few drops of lime. Mawa chewers and those who chewed mawa along with other chewing habits showed very high relative risks. The relative risks increased with increase in the frequency as well as the duration of chewing habits. In a bivariate analysis the effect of frequency and duration of chewing appeared to be multiplicative. The present findings confirm areca nut as the most important etiologic factor in oral submucous fibrosis.     

Etiology of oral submucous fibrosis with special reference to the role of areca nut chewing

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.     

Malignant transformation rate in oral submucous fibrosis over a 17-year period

Sixty-six patients with oral submucous fibrosis were followed-up for a period of 17 yr (median observation 10 yr) in Ernakulam District, Kerala, India. Oral cancer developed in five (7.6%) patients. The malignant transformation rate in the same sample was 4.5% over a 15-yr observation period (median 8 yr). These findings impart a high degree of malignant potential to this condition.     

Prevalence of oral submucous fibrosis among areca nut chewers: A systematic review and meta-analysis

Background: Worldwide millions peoples consume AN who are at risk of OSMF. Prevalence of OSMF is reported between 0.03% and 30% irrespective of AN habit. Further, these estimates are based on sample population comprised of OSMF patients or general population rather AN chewers (ANC). Therefore, available evidence does not reflect the true prevalence of OSMF among ANC. Method: The studies providing the prevalence of OSMF in ANC were identified in PubMed, Scopus, and Web of Science. Pooled prevalence and quality assessment using New-Ottawa Scale were performed. Results: Fifteen studies reported the prevalence of OSMF (929) in ANC (53,213). Most studies were from China (six studies) and India (four studies) correlating with regions having high ANC. The pooled prevalence of OSMF in ANC was 5% (0.05 [95% CI, 0.03, 0.08]). All studies' quality was satisfactory; however, the OSMF diagnosis method, age, gender, and habits need further scrutiny. Conclusion: Available evidence suggested a low prevalence of OSMF in ANC, although further large-scale studies are recommended to validate this finding. Understanding the prevalence and distribution patterns of OSMF might aid intervention healthcare programs and contribute to the reduction of the oral cancer burden related to OSMF.     

Effect on the incidence of oral submucous fibrosis of intervention in the areca nut chewing habit

Incidence of oral submucous fibrosis was calculated from a 10-yr prospective intervention study of 12,212 individuals with a strong component of health education on tobacco and area nut chewing. Based on 11 new cases among 6341 chewers, the annual incidence was 8.0 per 100,000 among men and 29.0 for women. An earlier 10-yr follow-up study, with no intervention component, served as control. Based on 11 new cases among 3,809 chewers, the annual incidence was 21.3 per 100,000 for men and 45.7 for women controls. Although the decrease in the incidence in the intervention cohort was not statistically significant due to small number of cases, the results underscored the causal role of areca nut chewing and indicated the potential for primary prevention of oral submucous fibrosis.     

Oral submucous fibrosis: a case-control study in Chennai, South India

BACKGROUND: Oral submucous fibrosis (OSF) is a pre-cancerous condition caused by the use of areca nut in various forms. There are very few published reports on areca nut use and OSF from Chennai, South India. METHODS: A hospital-based case-control study on habits and OSF was performed in Chennai over a 3-year period. A total of 185 consecutive patients with OSF were matched with age- and sex-matched controls. History was recorded in a pre-determined format by qualified dental surgeons. RESULTS: The male to female ratio of OSF cases was 9.9 : 1. All areca nut products were associated with OSF, with the risk being greatest for pan masala. The duration of the habit was more significant than the frequency of the chewing habit. CONCLUSION: The present study confirms the strong association between areca nut use and OSF and the increasing use of pan masala.     

Pilot survey of oral mucosa in areca (betel) nut chewers on Hainan Island of the People''s Republic of China

100 people on Hainan Island were studied for their smoking and chewing habits and the condition of their oral mucosa. Ninety-five percent of the study population chewed areca (betel) nut. In men this habit was supplemented with either smoking cigarettes or water pipe. In two men a small commissural leukoplakia was found. In three women clinical and histologic changes pointed towards oral submucous fibrosis.     

湖南地区口腔黏膜下纤维性变流行趋势变化(附278例回顾性研究)

目的 :观察湖南地区口腔黏膜下纤维性变 (OSF)流行趋势。方法 :对 2 78例OSF患者的年龄、性别、职业、地区来源、咀嚼槟榔时间、频率、主要症状、病变部位、张口度等临床资料进行分析。结果 :OSF患者平均年龄3 4.5岁 ,男女性别比为 94.6∶5 .4,OSF发病以司机、公务员、商人、警察等职业为多 ,湖南各地区都发现OSF患者。OSF患者典型临床表现为黏膜刺激痛、黏膜苍白、张口受限、纤维条索。其它症状有舌功能障碍 ,黏膜水疱、溃疡、烧灼痛等 ,病变部位以口腔后份为主 ,病变部位越靠前 ,范围越广 ,张口度越小 ,病变程度越严重 ( p <0 .0 0 5 ) .结论 :湖南地区OSF流行趋于年轻化 ,以男性为主 ,OSF发病覆盖全省各地区 ,OSF在某些职业中发病率较高 ,OSF患者到医院就诊大多为中晚期 ,临床症状、体征明显 ,病变部位与疾病严重程度 (即张口度 )有明显关系     

Predictors of the severity of oral submucous fibrosis among gutka consumers: a regression analysis

Oral submucous fibrosis (OSMF) is an insidious chronic disease of the oral mucosa that is characterised by severely limited mouth opening, blanching of the oral mucosa, and a burning sensation in the oral cavity. Consumption of betel nut and/or gutka are the known risk factors. We undertook this study to correlate the frequency and duration of gutka intake with the severity of OSMF and to determine the predictors of severe OSMF (mouth opening <20mm). A cross sectional study was conducted on 300 participants (who were known gutka chewers) selected at the Baqai Dental College and Fatima Hospital, Karachi, Pakistan. Participants’ medical and dental histories were recorded. Informed consent was obtained, and clinical oral examination was done. Information regarding the extent of mouth opening, chewing habits, frequency and duration of gutka intake, the site of placing gutka, duration of chewing, and whether they swallowed or spat out the gutka were collected. A standardised questionnaire was used to document the findings. Binary logistic regression was applied using the severity of OSMF (mouth opening <20mm) as an outcome variable. Out of 300 participants, 172 (57.3%) were males; mean (SD) age of the sample was 38.2 (12.3) years. A total of 156 (52%) participants had the habit of chewing gutka, of which 213 (71%) had clinical stage I OSMF, 75 (25%) had stage II, and 12 (4%) had stage III. As per functional staging, 18 (6%) subjects had mouth opening <20mm. Nearly 144 (48%) participants were consuming other forms of tobacco in addition to the gutka. Patients with palpable bands = 232 (77.3%), ulcerative lesions = 212 (70.7%), altered taste sensation = 210 (70%) and altered hunger = 252 (85.7%) were common findings. The duration of gutka intake was found to be positively correlated with the severity of OSMF; however; its frequency was not. Among intraoral findings, the presence of red and white lesions inside the mouth was the most significant predictor of the severity of OSMF.     

The fibroblast population in oral submucous fibrosis

The purpose of the investigation was to compare the morphology of fibroblasts cultured from healthy oral mucosa and mucosa of patients with oral submucous fibrosis (OSF) and to collate the occurrence of cell types of similar morphology. Cells cultured from biopsy specimens from the buccal mucosa of six subjects who did not chew the areca nut and six patients with OSF who chewed areca nut were grown according to standard techniques. Ninety cells per cell line were recorded daily for 8 days, classified into types F1, F2 and F3 according to their morphology, and the results statistically analyzed. We found that there was a relative increase of F3 cells in relation to Fl cells in OSF resulting in the ratio of F3 to F1 cells being significantly larger in OSF than the ratio in the controls. As it has been reported that F3 cells m rat connective tissues produce significantly more collagen types I and III than F1 cells, we concluded that a change of fibroblast population has occurred in OSF and that this relative increase of F3 cells in humans, which could be committed to the production of large quantities of collagen, can be an explanation for the excessive collagen formation in OSF.     

HLA-antigens in oral submucous fibrosis

HLA–typing was carried out on 122 areca nut chewers who attended hospitals for complaints unrelated to the habit. The subjects were South Africans of Indian extraction. The study did not include haplotypes. Palpable fibrous bands in the mouth indicated oral submucous fibrosis. The subjects were divided into 4 groups based on specific oral symptoms and signs. Groups A and B were without fibrous bands. Group A (47 subjects) included those with one or no symptoms while group B (28 subjects) suffered from 2 to 7 oral symptoms. Group C (17 subjects) had oral symptoms and represented early or mild oral submucous fibrosis and exhibited at least one discrete palpable fibrous hand. Group D (30 subjects) were classic oral submucous fibrosis cases with multiple bands. The high occurrence of oral submucous fibrosis in this study group (39%) is similar to the occurrence in comparable age groups reported earlier–n South Africa and is conceivably due to the higher age range of the subjects and their relatively long exposure to the area nut. We were unable to demonstrate a specific pattern of HLA–antigen frequencies in chewers with or without the disease. Furthermore, there were no differences between the study population and the controls. It is concluded that there is not necessarily a HLA–associated susceptibility in oral submucous fibrosis.     

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口腔黏膜下纤维性变(oral submucous fibrosis,OSF)是一种慢性、隐匿性且具有癌变倾向的疾病,主要发生于印度、巴基斯坦等东南亚国家以及我国湖南、台湾两省。OSF病因不明,咀嚼槟榔是其最主要的致病因素,且咀嚼槟榔的频率越高、年限越长,越易患OSF。所有OSF患者都有咀嚼槟榔史,咀嚼槟榔还与口腔白斑、口腔癌发病高度相关。此外,OSF的发生还与遗传因素、免疫反应、胶原相关性基因,营养缺乏等有关。本文就OSF致病因素做一简单介绍。     

Evaluation of myofibroblasts in oral submucous fibrosis: correlation with disease severity

J Oral Pathol Med (2011) 40 : 208–213 Background: Oral submucous fibrosis (OSMF) is a chronic debilitating disease and a premalignant condition of the oral cavity characterized by generalized submucosal fibrosis. Myofibroblasts are contractile cells expressing α‐smooth muscle actin (α‐SMA) and are considered primary producers of extracellular matrix after injury. Their accumulation has been established as a marker of progressive fibrosis in organs like lungs, liver, kidney and skin. This study aims to evaluate the presence of myofibroblasts in various histological stages of OSMF. Materials and Method: Seventy cases of OSMF, which were further categorized histologically into early (35 cases) and advanced (35 cases), were subjected to immunohistochemistry using α‐SMA antibody for detection of myofibroblasts. Fifteen normal oral mucosa specimens were also stained as controls. Results: The number of α‐SMA‐stained myofibroblasts in OSMF was significantly increased when compared to that of the normal controls (P < 0.001). Additionally, a statistically significant increase in the myofibroblasts population between early and advanced stages was observed (P = 0.000). Conclusions: Our results corroborate the possibility that OSMF actually represents an abnormal healing process in response to chronic mechanical and chemical irritation because of areca nut chewing as demonstrated by the increased incidence of myofibroblasts in this disease. Furthermore, the progressive increase in myofibroblasts from early to advanced stages suggests their potential use as markers for evaluating the severity of OSMF.     

Association between lysyl oxidase polymorphisms and oral submucous fibrosis in older male areca chewers

Objective:  Areca use is the major cause for oral squamous cell carcinoma and oral submucous fibrosis (OSF) in South Asians. Lysyl oxidase (LOX) is a copper-activated enzyme critical for collagen cross-linking and organization of extracellular matrix. The presence of a G to A polymorphism at nucleotide 473 caused a non-conservative Arg158Gln change in the LOX amino acid sequence. OSF is a precancerous lesions characterized by the accumulation of collagen in oral submocousa. The aim of this study was to investigate the relationship between LOX Arg158Gln polymorphism and the risk of OSF.
Method:  PCR-restriction fragment length polymorphisms and direct sequencing was utilized to compare LOX polymorphic allelotype in male areca-chewing controls ( n  = 216) and OSF ( n  = 83) patients.
Results:  There was a borderline of statistically significant difference in Arg158Gln genotype lying between control and OSF patients. However, the G/A+A/A of LOX Arg158Gln in OSF patients older than 50 year was statistically significantly higher than controls older than 50 year (odd's ratio: 4.48; 95% CI = 1.58–12.67).
Conclusion:  The elder OSF patients were increased in LOX Arg158Gln. Our findings may suggest a potential application in risk population selection using LOX polymorphism for preventive intervention of OSF genesis in a subset of areca chewers.     

Growth of oral and skin fibroblasts from patients with oral submucous fibrosis

The purpose of the investigation was to evaluate and compare the proliferation (growth) of mouth fibroblasts and skin fibroblasts from patients with oral submucous fibrosis (OSF). Material comprised fibroblasts from fibrous bands situated in the buccal mucosa and from the inner aspect of the forearm of 8 patients with classic features of OSF as well as fibroblasts from 6 buccal mucosa and 8 skin biopsy specimens from healthy non-areca nut chewing individuals. Cells were cultured for 8 days according to standard techniques. Their growth was monitored daily, under optimal conditions as well as exposure to concentrations of arecoline. The data were analyzed using regression analysis, analysis of variance and the Kruskal-Wallis test. We found no statistically significant differences between the proliferation patterns of oral and skin fibroblasts from patients or between those from patients and controls. The reaction of the cells exposed to concentrations of arecoline was similar; at low concentrations (0.1–10 μg/ml) normal growth was maintained, while 100 μg/ml inhibited growth. It is concluded that fibroblasts from mouths affected by OSF have proliferation patterns which fall within normal parameters, that the excessive collagen formation in established OSF is not due to increased fibroblast proliferation and that arecoline does not stimulate fibroblast proliferation.     

An immunohistochemical study of oral submucous fibrosis

Oral submucous fibrosis (OSF) is a chronic disease of the oral cavity characterized by inflammation and progressive mucosal fibrosis. These reactions may be the result of either direct stimulation from exogenous antigens like areca alkaloids or by changes in tissue antigenicity that may lead to an autoimmune response. This study investigated the presence and distribution of inflammatory cells and MHC class II antigen expression by epithelial and immunocompetent cells using a three-stage immunoperoxidase method on frozen sections. Thirty OSF tissue specimens and ten normal buccal mucosae were studied and compared. All tissues were investigated using antibodies to T cells (CD3), T helper/inducer cells (CD4), T suppressor/cytotoxic cells (CD8), B cells (CD20), naive T cells and monocytes (CD45RA), macrophages. Langerhans' cells (CD68) and HLA-DR-positive cells (HLA-DR alpha). The predominant cell populations detected in normal tissues were CD3, CD4 and HLA-DR-positive cells. The distribution of CD4-positive cells was similar to that of CD3-positive cells, which were scattered, often uniformly distributed, both in the epithelium and connective tissue. CD8-positive cells were occasionally seen in the normal epithelium and lamina propria. Few scattered B cells (CD20) and macrophages (CD681) were observed in normal mucosa. Naive T cells (CD45RA) were seen in all normal tissues focally concentrated around the connective tissue papillae with a similar distribution to that of CD3-positive cells. All normal sections showed HLA-DR-positive cells scattered both in the epithelium and in the lamina propria. Epithelial cells did not show any positive reaction to this antibody and many intraepithelial positive cells showed a dendritic morphology. The cell populations detected in OSF showed higher numbers of CD3 and HLA-DR-positive cells compared with those of the normal tissues. The pattern of staining for CD4-positive cells in OSF tissues was similar to that of CD3-positive cells both in the epithelium and connective tissue and was higher than that in normal tissues. A few scattered CD8-positive cells and only occasional CD20- and CD68-positive cells were seen in OSF sections. Few CD45RA-positive cells were found in the epithelium and lamina propria of OSF sections. However, OSF specimens showed high numbers of HLA-DR-positive cells in the basal layer of the epithelium, juxtaepithelium and in the lamina propria in a similar distribution to that of CD3 cells compared with the normal tissues. Most HLA-DR-positive cells in the epithelium showed dendrites directed vertically towards the surface. The increased evidence of CD4 and HLA-DR-positive cells in OSF tissues suggests that most lymphocytes were activated and shows an increased presence of Langerhans' cells. The presence of these immunocompetent cells and high ratio of CD4 to CD8 in OSF tissues suggest an ongoing cellular immune response leading to a possible imbalance of immunoregulation and alteration in local tissue architecture.