Oral submucous fibrosis: A clinicopathological study of 674 cases in China

Background Oral submucous fibrosis (OSF) has been reported frequently in India and other countries in South Asia. There are few reports on the clinicopathological features of OSF in China, where OSF is an epidemic. This study analyses the clinicopathological features of OSF in Hunan Province, China. Methods A total of 674 cases of OSF were collected from July 2013 to August 2018 in Xiangya Stomatological Hospital, Central South University, and gender, age, site, pathological stage, habits, symptoms and associated lesions were recorded. Results The male to female ratio was 32.7:1. The average age was 35.23 ± 10.08. The buccal mucosa was the most common site. A total of 99.85% of OSF cases chewed areca nut. Pale mucosa, restricted mouth opening, burning and fibrous bands were common clinical manifestations. Oral leukoplakia (OLK) was the most common associated lesion. The extended duration of chewing areca nut increased the risk of associated lesions (P < 0.05). The risk of OSF associated with OLK decreased with increasing OSF stage (P < 0.05). Conclusion The prevalence of OSF in males was higher than that in females, the buccal mucosa was most affected, and chewing areca nut is the most common habit of OSF patients.


| MATERIAL S AND ME THODS
A total of 674 cases of OSF were diagnosed by two experienced pathologists at the Department of Oral Pathology, Xiangya Stomatological Hospital, Central South University, from July 2013 to August 2018 (5-year period). Criteria for the clinical diagnosis of OSF were the presence of pale mucosa, fibrous bands, burning sensation or restricted mouth opening. Histopathological changes of OSF observed were fibrous degeneration of connective tissue, mild hyalinization of collagen fibrous tissue beneath the epithelium (early stage), moderate hyalinization of collagen fibrous tissue beneath the epithelium with mild oedema (middle stage), and hyalinization of total collagen fibrous beneath the epithelium with stenosis or occlusion of vessels (advanced stage). 8 All cases were diagnosed by incisional biopsy. All cases included a complete history, such as gender, age, site, pathological stage, chewing habits, symptoms and associated lesions. This study was approved by the medical ethics committee of Xiangya Stomatological Hospital, Central South University.

| Statistical analysis
Gender, age, site, pathological stage, habits, symptoms and associated lesions of OSF were collected. All statistical analyses were performed using SPSS 24.0 software. Chi-square tests were performed for comparing percentages of two independent samples and the differences between China and India (Table 1). A one-way ANOVA test was performed on the ages at different pathological stages. P < 0.05 was considered statistically significant.
One hundred and sixty patients who chewed areca nut with smoking tobacco did not have an increased risk of pathologic stage of OSF compared to patients chewing areca nut only (P > 0.05). No significant difference in the duration of chewing areca nut and OSF stage was observed (P > 0.05). With increasing OSF stage, OSF associated with OLK significantly decreased (P < 0.05).

| D ISCUSS I ON
Oral submucous fibrosis was first proposed as a precancerous condition by Pindborg, who found a malignancy rate of 7.6%. 9,10 OSF was mainly reported in Asia, especially in India and southern China, with other reports from Pakistan, Sri Lanka, Bangladesh, Malaysia, Singapore, Thailand and Saudi Arabia. OSF was also observed in the Asian populations of Britain and America and is considered a worldwide health problem. 11 The differences in the clinicopathological features of OSF in this study compared to those in another detailed study are listed in betel nut, and the proportion of male was significantly higher than female, which was similar to this study. 16  OSF. 20 Ara et al identified that chewing gutkha was the major risk factor for OSF, especially in young age groups. As the duration and frequency increased, the severity of OSF increased, but the clinical stage was not related to pathological grade. 21 The youngest OSF patient was 16 in this study. Agrawal et al reported a case of OSF in a 9-year-old Indian girl with a history of F I G U R E 2 OSF associated with OLK (×200). Fibrous degeneration of connective tissue, mild epithelial dysplasia, disappearance of basal cell polarity, epithelial rete peg hypertrophy chewing areca nut. 22 Dhariwal et al demonstrated 2 cases of Indian OSF in children, specifically, a 10-year-old boy with a history of chewing gutkha and a 12-year-old girl with a history of chewing pan masala. 23 Shah et al reported an 11-year-old Bangladeshi girl with OSF who had a history of chewing areca nut and supari. 24 Chaturvedi et al found that patients with oral cancer caused by OSF were younger than non-OSF patients, 25 suggesting that children chewing areca nut could suffer from OSF. Parents and children were not aware of the harm of areca nut. The mean ages of OSF in the early (81 cases), middle (513 cases) and advanced (80 cases) stages were 39.69 ± 9.66, 35.16 ± 10.12 and 31.18 ± 8.14, respectively, which decreased with increasing stage (P < 0.05), suggesting that young patients chewing areca nut might lead to an advanced stage of OSF. This may be related to the high susceptibility in a small population. More studies need to be performed to illustrate the specific mechanism. To prevent OSF, it is important to strengthen the management of youth to stop them from chewing areca nut.
The lesion most associated with OSF was OLK (14.99%), which was higher than the 4.8% found in India. 12 28 The risk of OSF associated with OLK decreased with the increase in pathological stage (P < 0.05).
Early-stage OSF with a low degree of atrophied epithelium, fibrosis tissue and collagen fibre glassiness was more likely to cause epithelial hyperplasia and dysplasia associated with OLK. OSF might be caused by the epithelial-mesenchymal transition. 29 The transition of epithelial cells to a mesenchymal phenotype might affect epithelial hyperplasia and decrease the occurrence of OLK.
In addition, the fibrosis of sub-epithelial connective tissue was expected to affect the epithelial components. 30 The incidence of OLK decreases with the severity of fibrosis. The specific mechanism still needs more research in the future. The malignant transformation cannot be identified from the current cases of OSF.
There was no information about nutritional status. The case of malignant transformation from OSF and nutritional status should be collected and analysed in the future.

| CON CLUS ION
This study was performed to analyse the clinicopathological features of OSF in China. Males were preponderant, and the buccal mucosa was most affected. Almost all patients chewed areca nut.
Interesting findings were the increased risk of OSF-associated lesions with extended duration of chewing betel nut. A minority of F I G U R E 3 OSF associated with well-differentiated OSCC (×200). Fibrous degeneration of connective tissue; proliferating epithelium invades the connective tissue, forming the keratin pearl F I G U R E 4 OSF associated with OLP (×200). Fibrous degeneration of connective tissue, liquefaction degeneration of the basal layer, lymphocyte infiltration at mucosal lamina propria individual appeared to experience an advances stage of disease at a younger mean age suggesting high susceptibility in a small population. Education regarding the risks of the use of betel quid and the development of OSF should include younger individuals and parents.