Year : 2003 | Volume
: 7 | Issue : 1 | Page : 1--4
Oral submucous fibrosis
Dept of Oral Pathology, Dental Wing, Medical College, Trivandrum, India
Dept of Oral Pathology, Dental Wing, Medical College, Trivandrum
Oral submucous fibrosis (OSF) is a chronic, progressive, scarring disease, that predominantly affects people of South-East Asian origin. This review article discusses the etiology, clinical features, epidemiology, pathology and management of oral submucous fibrosis in detail.
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Rajendran R. Oral submucous fibrosis.J Oral Maxillofac Pathol 2003;7:1-4
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Rajendran R. Oral submucous fibrosis. J Oral Maxillofac Pathol [serial online] 2003 [cited 2022 Jul 1 ];7:1-4
Available from: https://www.jomfp.in/text.asp?2003/7/1/1/40996
Oral submucous fibrosis (OSF) is a chronic, progressive, scarring disease, that predominantly affects the people of South-East Asian origin. This condition was described first by Schwartz (1952) while examining five Indian women from Kenya, to which he ascribed the descriptive term "atrophia idiopathica (tropica) mucosae oris". Later in 1953, Joshi from Bombay (Mumbai) redesignated the condition as oral submucous fibrosis, implying predominantly its histological nature. The WHO definition for an oral precancerous condition - "a generalized pathological state of the oral mucosa associated with a significantly increased risk of' cancer," accords well with the characteristics of OSF.
The onset is insidious over a 2-5 year period.
The Prodromal Symptoms (early OSF)
This includes a burning sensation in the mouth when consuming spicy food, appearance of blisters especially on the palate, ulcerations or recurrent generalized inflammation of the oral mucosa, excessive salivation, defective gustatory sensation and dryness of' the mouth. There are periods of exacerbation manifested by the appearance of small vesicles in the check and palate. The intervals between such exacerbations vary from three months to one year. Focal vascular dilatations manifest clinically as petechiae in the early stages of the disease. This may be part of a vascular response due to hypersensitivity of the oral mucosa towards some external irritant like arena nut products. Petechiae are observed in about 22% of OSF cases  , mostly on the tongue followed by the labial and buccal mucosa with no sign of blood dyscrasias or systemic disorders. Pain in areas where submucosal fibrotic bands are developing when palpated, is a useful clinical test.
Histologically, they revealed a slightly hyperplastic epithelium, sometimes atrophic with numerous dilated and blood-filled capillaries juxta-epithelially. The inflammatory cells seen are mainly lymphocytes, plasma cells and occasional eosinophils. The presence together of large numbers of lymphocytes and fibroblasts as well as plasma cells in moderate numbers, suggests the importance of' a sustained lymphocytic infiltration in the maintenance of the tissue reaction in OSF,
The advanced OSF
As the disease progresses, the oral mucosa becomes blanched and slightly opaque and white fibrous bands appear. The buccal mucosa and lips may be affected at an early stage although it was thought that the palate and the facial pillars are the areas involved first. The oral mucosa is involved symmetrically (with possible exception) and the fibrous hands in the buccal mucosa run in a vertical direction. The density of the fibrous deposit varies from a slight whitish area on the soft palate causing no symptoms to a dense fibrosis causing fixation and shortening or even deviation of the uvula and soft palate. The fibrous tissue in the facial pillars varies from a slight submucosal accumulation in both pillars to a dense fibrosis extending deep into the pillars with strangulation of the tonsils. It is this dense fibrosis involving the tissue around the pterygomandibular raphae that causes varying degrees of difficulty in mouth opening.
A factor, which seems to be overlooked by many investigators while recording the extent of mouth opening, is the acuteness of oral symptoms (persistent recurrent glossitis and stomatitis) at the time of recording. Sometimes the fibrosis spreads to the pharynx and down to the pyriform fossae. Upon palpation, a circular band can be felt around the entire rima oris (mouth orifice), and these changes are quite marked in the lower lip. All observers have noted impairment of tongue movement in patients with advanced OSF with significant atrophy of the tongue papillae. With progressing fibrosis stiffening of certain areas of the mucosa occurs leading to difficulty in opening the mouth, inability to whistle or blow and difficulty in swallowing. When the fibrosis involves the nasopharynx, the patient may experience referred pain to the ear and a nasal voice as one of the later signs in some patients.
An epidemiological assessment of the prevalence of OSF among Indian villagers based on baseline data recorded a prevalence of 0.2% (n - 10071) in Gujarat, 0.4% (n=1027) in Kerala, 0.04% (n=10169) in Andhra Pradesh, and = 0.07% (n - 20388) in Bihar. The prevalence among 101761 villagers in the state of Maharashtra (central India) was 0.03%. In a 10-year follow up study of oral precancer, Gupta et al 1980 calculated the incidence rate of OSF in Ernakulam, Kerala was 8 for men and 19 for women per 100,000. Variations in the prevalence figures are common between different studies, probably because of differences in the clinical criteria for diagnosis. Prevalence by sex varies widely in the different published studies. The general female preponderance may be related to factors like oral habits, deficiency states of iron and vitamin 13 complex among many others prevalent in Indian women.
'There is compelling evidence to implicate the habitual chewing of areca nut with the development of OSF. It occurs predominantly in the Indian subcontinent where the habit is more prevalent. The frequency of this habit in population affected by OSF ranged from 35% to 100% (Bhonsle RB et al 1987). This has been reported to be higher among OSF patients than in the general population. In a study of 100,000 villagers in Maharashtra (India), 4.2% of females who chewed areca nut and did not use tobacco, suffered from OSF. Thus chewing areca nut may be an important factor in the aetiology of OSF. Previous studies on the pathogenesis of OSF have suggested that the occurrence may be due to:
(a) Clonal selection of fibroblasts with a high amount of collagen production during the long-term exposure to areca quid ingredients (Meghji Set al 1987).
(b) Stimulation of fibroblast proliferation and collagen synthesis by areca nut alkaloids (Harvey Wet al 1986).
(c) By fibrogenic cytokines secreted by activated macrophages and T lymphocytes in the OSF tissue (Haque MF et al 2000).
(d) By decreased secretion of collagenase (Shieh TY et al 1992).
(e) Deficiency in collagen phagocytosis by OSF fibroblasts (Tsai CC et al 1999).
(f) By production of collagen with a more stable structure (collagen type I trimer) by OSF fibroblasts (Kuo MYP et al 1995)
(g) By stabilization of collagen structure by (+) catechin and tannins from the areca nut (ScuttAetal 1987)
(h) And by an increase in collagen crosslinkage as caused by upregulation of lysyl oxidase by OSF fibroblasts (Ma RH et al 1995).
Genetic susceptibility may be associated with OSF because raised frequencies of HLA-A10, -B7 and DR3 are found in OSF patients compared to normal subjects. Further HLA typing done by use of' the polymerase chain reaction (PCR) also demonstrates significantly increased frequencies of HLA A24, DDRB I-I I and DRB3 0202/3 antigens in 21 OSF patients when compared with the English controls (Saeed B et al 1997).
Structural and microstructural changes
The epithelial changes in the different stages of OSF are predominantly hyperplasia (early) and atrophy (advanced), associated with an increased tendency for keratinizing metaplasia. The epithelial atrophy reported by Pindborg et al (1966) is the marked epithelial change in advanced OSF, which contrasts with the predominantly hyperplastic epithelium of early OSF. Lesions involving the palate showed predominantly orthokeratosis and those of the buccal mucosa, parakeratosis. The high mitotic count in parakeratotic epithelium, which is more common with OSF and the association with parakeratotic leukoplakia and atrophic epithelial changes predisposes OSF to malignancy.
On the basis of' the histopathological appearance of stained (H&E) sections, OSF can be grouped into four clearly definable stages: very early, early, moderatey advanced and advanced. These stages are based not only on the amount and nature of the subepithelial collagen, but also on the following criteria taken together.
(a) Presence or absence of oedema
(b) Physical state of the mucosal collagen
(c) Overall fibroblastic response (number of cells and age of individual cells)
(d) State of the blood vessels and
(e) Predominant cell type in the inflammatory exudates
A vascular response due to inflammation, apart from the connective tissue repair process, has been very commonly found in OSF. Normal, dilated and constricted blood vessels have been seen often in combination, in the same section. Apparent narrowing of the smaller vessels appears first in the upper mucosa and spreads gradually to the larger, deeper vessels. Persistent dilation has also been seen in many moderately advanced and advanced biopsies. A rise in mast cells occurs in the earlier stages of the tissue reaction but in advanced stages, the counts are less in number. The inflammatory cells seen are mainly lymphocytes and plasma cells. The connective tissue in advanced stages is characterized by submucosal deposition of extremely dense and avascular collagenous tissues with variable numbers of chronic inflammatory cells. Epithelial dysplasia without carcinoma is found in l 0 to 15 % of cases submitted for biopsy and carcinoma is found in at least 5 percent of sampled cases. The excessive fibrosis in the mucosa seems to be the primary pathology in OSF and the atrophic changes in the epithelium secondary.
Biological studies on individuals and tissues from OSF
(a) Blood chemistry and haematological variations
Deficiency of Vitamin B 12, folate and iron can affect the integrity of the oral mucosa. Significant haematological abnormalities have been reported in OSF, including an increased blood sedimentation rate (ESR), anemia and eosinophilia, increased gamma globulin, a decrease in serum iron and an increase in total iron binding capacity (TIBC). The percentage saturation of transferrin also decreased and a significant reduction in total serum iron and in albumin was found. It is doubtful regarding the role of iron deficiency anaemia as the cause or the effect of the disorder. A rise in serum mucoproteins. mucopolysaccharides and antistreptolysin titre '0' (measured in Todd's unit) has also been reported. A significant depression of the lactate dehydrogenase isoenzyme ratio (LDH IV / LUH 11) is reported at the tissue level in OSF. A significant alteration in the serum copper and zinc ratio is also reported with a reduction in zinc content.
Chromosomal instability has long been associated with the neoplastic process and the quantitative assay of sister chromatid exchange (SCE) provides an easy, rapid and sensitive method for studying chromosome / DNA instability and its subsequent repair processes. This increase may be attributed to the genotoxic effect of the constituents of betel quid. The role of areca nut alkaloids in this regard may be significant.
Silver-binding nucleolar organizer region proteins (Ag NORs) comprise a simple and reproducible cytological test indicative of the proliferative status of cells particularly of epithelial and haematopoitic origin. It was found that the pooled mean Ag NOR count in clinically advanced OSF was higher than in moderately advanced Cases. Counting of Ag NORs may be useful as a predictor of the biological behaviour of OSF.
Because of a possible immunological connection, the fact that the disease has been reported in subjects who do no practice the betel habit and the inability to prove a dose and effect relationship in all cases, the question arose whether there is a predisposition for the disease. In this respect the finding by Canniff et al (1981) that the human leukocyte antigens (HLA) A10, B7 and DR3 occurred significantly more frequently in OSF, is important. Later van Wyk et al (1994), investigated the frequency of HLA in areca nut chewers with and without OSF and comparing them to control comprising people with a similar background (South African Indians) was unable to detect specific frequencies as was found by Canniff and co-workers. Thus the problem of a possible predilection remains unanswered. In addition studies on the relationship between systemic disease and OSF was also proved negative.
Cell Kinetic studies
Investigations carried out in UK and South Africa found that the growth of OSF fibroblasts is normal. However when fibroblasts are exposed to the alkaloids of areca nut their proliferation rate according to certain workers increases; a finding in contrast to the results of others. The second group found a dose-dependent inhibition of growth by alkaloids (van Wyk ct al 1995). These studies prompt one to propose that the connective tissue changes in OSF is probably not due to increased tibroblast proliferation. On the other hand, OSF fibroblasts can play a role in over-production of collagen. The UK group (Scutt A et al 1987) found that collagen formation by fibroblasts increases when exposed to nut extracts and alkaloids, a finding which has been questioned recently by Jeng et al (1996), who found the opposite. Thus it would seem that OSF fibroblasts have the capability to produce collagen in excess, but what triggers it, is controversial. Ma et al 1995 discovered increased lysyl oxidase activity in fibroblasts cultured from OSF patients. Lysyl oxidase, an extra-cellular metallo-enzyme of copper, is secreted by fibroblasts and initiates cross-linking of collagen which makes it relatively resistant to digestion by mammalian collagenase. Therefore, increased lysyl oxidase activity can result in collagen accumulation. Recently Trivedy et al (1997), demonstrated the copper content in areca nut to be relatively high and that it is released in the mouth with chewing. Other reasons proposed for excessive accumulation of' collagen arc decreased collagenase activity in OSF mucosa and reduced phagocytosis by OSF researchers. In both instances accumulation of collagen is enhanced. To conclude, the effect of the areca nut on cells is the trigger resulting initially among others in excessive accumulation of collagen, which is followed by a permanent change possibly in the fibroblast population, characterized by a continued abnormal accumulation of collagen. The mechanism of this permanent change is not known at present.
Reduction or even elimination of the habit of areca nut chewing is an important preventive measure. Atleast in the early stages of OSF, it could probably slow the progress of the disease. To improve current treatment regimens of OSF, the following strategies have been proposed.
(a) Nutritional support
Mainly for high proteins and calories and for vitamin B complex and other vitamins and minerals.
(b) Immuno modulatory drugs
Local and systemic applications of glucocorticoids and placental extracts are commonly used. These also prevent or suppress inflammatory reaction, thereby preventing fibrosis by decreasing fibroblastic proliferation and deposition of collagen.
This includes measures such as forceful mouth opening and heat therapy. Heat has been commonly used and the results have been described as satisfactory.
(d) Local drug delivery
Local injection of corticosteroids and placental extract have been tried, in addition to hyaIuronidase, collagenase and like substances which break down intercellular cement substances and also decreases collagen formation.
(e) Combined therapy
With peripheral vasodilators (nylidrin hydrochloride), Vitamin D, E and 'B' complex, iodine, placental extract, local and systemic corticosteriods and physiotherapy claim a high success rate in OSF management. Evaluation of the merits and disadvantages of individual items in treatment is not possible owing to the use of combined treatment protocols; which is unavoidable at present because of the empirical nature of each approach.
(f) Surgical management
Measures such as forcing the mouth open and cutting the fibrotic bands have resulted in more fibrosis and disability. Submucosal resection of fibrotic bands and replacement with a partial thickness skin or mucosal graft have also been attempted along with procedures such as bilateral temporalis myotomy. At a retrospective glance surgery seems to be a poor option in the overall management of the disease. Controlled studies of different regimens in the management of OSF are needed. They will not be easy to organize because of the number of items in current management protocols, but they should greatly increase our understanding of OSF.
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