AN ANALYSIS OF RATE AND FACTORS AFFECTING MALIGNANT TRANSFORMATION OF ORAL SUBMUCOUS FIBROSIS IN PATIENTS ATTENDING THE ORAL MEDICINE CLINIC, DENTAL HOSPITAL PERADENIYA, SRI LANKA A RETROSPECTIVE STUDY

ruwanja@pdn.ac.lk _____________________________________________________________________________ Abstract Background : Oral submucous fibrosis (OSF) is a chronic, progressive, scarring and potentially malignant disease of the oral mucosa seen primarily in the Indian subcontinent and in South East Asia. OSF is a premalignant condition with a malignant transformation rate varying from 7-12%. Even though OSF and oral cancer are common in Sri Lanka, malignant transformation potential and rate have not been studied in our population. Objectives : To identify the relationship of malignant transformation with age, gender, habits, amount of mouth opening, duration of follow up, presence of other oral potentially malignant disorders and dysplasia in a group of patients with OSF attending the Oral


Introduction
Oral submucous fibrosis (OSF) is a chronic, progressive, scarring and potentially malignant disease of the oral mucosa seen primarily in the South and South East Asian regions of the world. OSF is characterized by

AN ANALYSIS OF RATE AND FACTORS AFFECTING MALIGNANT TRANSFORMATION OF ORAL SUBMUCOUS FIBROSIS IN PATIENTS ATTENDING THE ORAL MEDICINE CLINIC, DENTAL HOSPITAL PERADENIYA, SRI LANKA -A RETROSPECTIVE STUDY
fibrosis of the submucosa, atrophy of the epithelium and reduction of vasculature. Schwartz first described this condition in 1952 and named it 'atrophica idiopathica mucosa oris' and Joshi in 1953 renamed it 'oral submucous fibrosis'. Although various factors have been proposed as aetiological factors in the past, areca nut use is the only proven factor in the aetiology of OSF 1,2 .
Arecoline, an alkaloid found in areca nut stimulates fibroblastic proliferation and collagen synthesis leading to OSF. In addition to the local factors, various systemic factors have been suggested to play a role in the causation of the disease. These include anaemia, chronic iron and vitamin B complex deficiency and genetic predisposition 1,3,4 .

Materials and Methods
A hospital-based observational retrospective study was designed to identify the malignant transformational rate of OSF. All the clinical files of patients attending the Oral Medicine clinic, University Dental Hospital, Peradeniya, Sri Lanka were searched and cases diagnosed with OSF were selected for the study.
Exclusion criteria for the study were: 1. Cases of OSF where histopathological diagnosis was not available 2. Those patients who had developed oral cancer before the diagnosis of OSF. 3. Patients who were diagnosed as OSF but had previously received surgical therapy 4. Follow up period of less than 6 months.
All the files were examined and general data including the age, sex, history of complaint, medical problems and habits (especially in relation to tobacco and areca nut usage and alcohol consumption) at the time of presentation were retrieved using a preprepared data sheet. Records were searched to identify the existence of potentially malignant lesions other than OSF and development of cancer during the follow-ups. Functional staging and grading were done. The site in the mouth of any malignancy was also recorded. Patients who had not come to the clinic for a long period were recalled. Informed consent was taken from the patient and thorough clinical examination was carried out to identify the presence of potentially malignant lesions other than OSF or cancer. If a suspected lesion was present, a biopsy procedure was carried out to confirm the diagnosis.
This study was carried out using the retrospective details of patients and was in accordance with the Helsinki Declaration. Ethical clearance for the study was obtained from the Faculty Research and Ethics Review committee, Faculty of Dental Sciences, University of Peradeniya, Sri Lanka (Reference No-FDS-FRC/2014/01) Data were analysed using SPSS version 17 to identify any relationship of malignant transformation with other variables. Chisquare test was performed to identify the statistical significance between malignant transformation and other different parameters.

Results
There were 135 patients. The majority (75.6%) were males. Age range of the sample was between 21 years to 81 years. Average age of a patient at the initial diagnosis was 49.3 years. Most of them were between 40 to 59 years (54.8%) but there were 24.4% (n=33) young patients who were less than 40 years. The follow up period of the cases studied ranged from 6 months to 23.0 years and average follow up period was 5.26 years. Almost 20% of patients were followed up for more than 10 years ( Table 1).
The majority of the patients in the study used betel quid with all ingredients whereas 5 patients were using only areaca nut ( Table  1). Among the patients who used betel quid, a substantial numbers of patients were either smoking or/and using alcohol together with betel quid. Burning sensation was the main complaint (42.2%) in these patients with OSF. Eighty percent of the participants in this study had fibrous bands, 50.8% had restricted tongue movements, 70.4% had depapillation of the tongue whereas depigmentation in lips/ buccal mucosa was found in 45.9% of them. Average mouth opening at the initial presentation in the present study was 31.6mm and the majority of the participants (57%) had 20mm-40mm mouth opening. Twenty three patients had leukoplakia whereas only one patient had erythroplakia in addition to the OSF ( Table 1). Eight patients developed malignancy during the follow up period giving a malignant transformation rate of 5.9% ( Table 1). Five of them (62.5%) were males. Average age at the diagnosis of malignancy was 55.4 years with the range of 44 to 68 years. Malignant transformation was observed after 0.9 years to 11.3 years of follow up with an average of 6.49 years ( Table 2).
A statistically significant association was observed with the malignant transformation and duration of betel chewing (p=0.018). Presence of other potentially malignant disorders (p=0.006) and presence of dysplasia at the initial biopsy (p<0.001) were also significant. However the observed differences of the malignant transformation were not statistically significant with reference to the sex, age, type of habit, frequency of betel chewing, extent of mouth opening at the day of presentation or duration of follow up (p>0.05) ( Table 3). *System missing n=3 **Some patients had more than one symptoms of OSF

Discussion
Oral submucous fibrosis (OSF) is a chronic progressive potentially malignant disorder predominantly seen in India, Bangladesh, Sri Lanka, Pakistan, Taiwan, Southern China, Polynesia and Micronesia. Clinical presentation of OSF depends on the stage of the disease. The majority of patients present with burning sensation to spicy food, blanching and stiffening of the oral mucosa and oropharynx, loss of stretchability of buccal mucosa, lip and tongue leading to limitation of mouth opening and tongue movement 1,7 . Even though OSF is common among adults, it has been reported among children as well 8 .
OSF has been identified as a potentially malignant disorder for a long time. Paymaster in 1956 first reported the precancerous nature of OSF and it was confirmed later by many other investigators 6,9 . Several findings including high occurrence of OSF in patients with oral cancer, higher incidence of oral cancer in patients with OSF, histological diagnosis of cancer without any clinical suspicion in OSF, high frequency of epithelial dysplasia in cases of OSF and higher prevalence of other potentially malignant disorders specially leukoplakia among OSF cases are considered to be some evidence to suggest the precancerous nature of OSF 1 .
Malignant transformation rate of OSF has been reported to be in the range of 7-13% 1,6 . Malignant transformation rate in the present study was 5.9% which is almost within the range reported. But a much lower value of 3.3% has been reported by Hazarey  The main complaint in most of the patients in the present study was burning sensation of the mouth particularly for spicy food but Hazarey et al., 2007 10 reported it to be difficulty in mouth opening. Average mouth opening at the initial presentation in the present study was 31.6mm. This difference may be due to the duration of the disease prior to the presentation to the clinic. Progression of the disease with time leads to restricted mouth opening whereas at the early part of the disease process, burning sensation is more problematic for the patients.  Malignant transformation was observed after 0.9 years to 11.3 years with an average of 6.49 years. Four out of 8 patients who developed cancer in the current series were either smokers or consumers of alcohol or used both other than betel quid. Similar results had been demonstrated by many others 10,11 . Malignant transformation in OSF would be enhanced due to smoking having a modifying effect. One of the most important predictors of malignant transformation of OSF is the presence of epithelial dysplasia at the initial biopsy. This fact was confirmed by the present study as well as the study done by Shue-Sang Hsue et al., in 2007 12 .

Conclusions
This study shows that the malignant transformation rate of OSF was 5.9% after a mean follow up period of 6.5 years. The most important factor associated with malignant transformation was the presence of dysplasia in the initial biopsy followed by the presence of other potentially malignant disorder and duration of betel quid chewing.