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Oral submucous fibrosis (OSF)  

Oral submucous fibrosis (OSF) is a well-recognized oral precancerous condition, observed predominantly in populations of South Asian ethnic origin. Thuse, it predominantly occurs in the Indian subcontinent and people of South Asian ethnicity living in other countries such as the UK, Singapore and Malaysia, among others. It is characterized by a unique generalized fibrosis of the submucosal oral soft tissues, resulting in marked rigidity of the oral mucosa leading to progressive inability to open the mouth, rigidity of lips and difficulty in protruding the tongue. The prevalence of OSF ranges from 0.2-1.2% in India .

Etiopathogenesis:

A number of risk factors seem to contribute to the juxtaepithelial inflammatory disease process in the oral mucosa leading to OSF. A strong association has been observed with areca nut chewing with or without tobacco and OSF .The other factors that are considered to be responsible are capsaicin in chilies and micronutrient deficiencies of iron, zinc and essential vitamins . An increase in the frequency of this disease, especially among the young, has been reported in India due to the increase in the use of commercially prepared areca nut preparations without betel leaf (pan masala ) . A genetic predisposition for the development of this disease has also been reported .
The areca nut, which contains alkaloids, such as arecoline, and other chemicals, such as catechin and tannin, plays a major role by stimulating production of collagen fibres and making them less susceptible to the action of collagenase . It is suggested that components of the areca nut also affect gene expression in the fibroblasts leading to the production of greater amounts of normal collagen . Areca nut has been shown to have a high copper content, and chewing areca nuts for 5–30 minutes significantly increases soluble copper levels in oral fluids. This increased level of soluble copper supports the hypothesis that copper acts as an initiating factor in OSF by stimulating fibrogenesis through up-regulation of lysyl oxidase activity

It is not clear if a hypersensitivity reaction to chilies plays any role in the development of OSF . Iron deficiency anemia, vitamin B complex deficiency, and malnutrition are implicated in the pathogenesis of OSF leading to deranged repair processes of the inflamed oral mucosa, contributing to defective healing and scarring . The resulting atrophic oral mucosa is more susceptible to the effects of areca nut and alcohol. An immunologic process and a genetic component are assumed to be involved because of reported cases in non–areca nut chewers . Increased levels of pro-inflammatory cytokines and reduced antifibrotic interferon have also been demonstrated in patients with OSF .

Natural history:

Oral submucous fibrosis is considered to be an irreversible oral precancerous condition that does not regress, either spontaneously or with cessation of betel quid chewing and elimination of other presumed risk factors. Patients with OSF experience a burning sensation of the oral mucosa, which is often aggravated by spicy food. Initially, increased salivation is observed, but as the disease progresses, salivary flow is diminished and dryness of the mouth and intolerance to spicy food, especially chili, becomes a prominent symptom. Surprisingly, most of these patients tolerate pepper. As the disease progresses the mucosa becomes non-elastic and stiff, considerably restricting the patient's ability to open the mouth. If the tongue is involved, patients may experience altered taste to food, difficulty in speech, eating, blowing, whistling and sucking. Swallowing difficulty may be observed if the pharynx and oesophagus are involved in the disease process. Some patients may even complain of some partial hearing loss, due to stenosis of eustachian tubes. The disease process remains active even after cessation of the chewing habit. However, the Trivandrum Oral Cancer Screening Study (TOCS ) observed good symptomatic improvement following cessation of habits, multivitamin supplementation and diet modification (diet rich in green vegetables and fruits) in many patients. Regeneration of papillae was observed (figure 16, figure 17, figure 18 and figure 19), and mouth opening improves with regular exercises to increase the mouth opening, especially before the onset of dense fibrosis. These patients were able to tolerate spicy food as well.

The frequency of malignant transformation in OSF has been reported to be in the range of 7–13% . A high frequency of mutations in the APC gene and low expression of wild-type TP53 tumour suppressor gene product was observed in patients with OSF having malignant transformation. Whether the malignant transformation is more common in leukoplakic areas than nonleukoplakic areas in patients with OSF is not clear.

Diagnosis:

Clinically, patients present with a lustreless, marble-like blanching of the oral mucosa. In the early stages, features of stomatitis such as erythematous mucosa, vesicles, mucosal ulcers, blotchy melanotic mucosal pigmentation, and mucosal petechiae may be observed. As the disease advances, vertical and circular fibrous bands may be palpated in the buccal mucosa and around the pericommissural area. A mottled, marble-like appearance may be evident due to the bands running in the blanched mucosa. In advanced disease, we can observe difficulty in mouth opening (trismus), sinking of the cheeks out of proportion to age, stiff and small depapillated tongue, blanched floor of mouth, fibrotic gingival tissues, stiff soft palate with reduced mobility and shrunken bud-like uvula, and blanched and atrophic tonsils. More than one fourth of affected persons may have coexisting leukoplakia. The buccal mucosa is the most commonly involved site, followed by the lip and tongue, but OSF can occur in any intraoral site.

A clinical diagnosis of OSF is made based on the symptoms and clinical feautures described above. A biopsy should be taken to confirm the diagnosis and to rule out dysplasia and malignancy.

Histopathology:

Submucous fibrosis is characterized by atrophic oral epithelium that may show atypia and dysplasia, and diffuse hyalinization of the subepithelial stroma with pigment incontinence from the overlying epithelial melanin. Other histological findings include intercellular edema, with or without hyperkeratosis, parakeratosis, or orthokeratosis. Early cases of OSF demonstrate epithelial hyperplasia, marked oedema, thickened collagen bundles, moderate numbers of large fibroblasts, dilated and congested blood vessels and inflammatory cell infiltration containing a number of polymorphonuclear leukocytes. In advanced stages, epithelial atrophy, dense bundles and sheets of collagen, thick bands of subepithelial hyalinization extending into the submucosal tissues (replacing fat or fibrovascular tissue), decreased vascularity, no edema, and decreased inflammatory cells (lymphocytes and plasma cells) are found. Minor salivary glands in the area of habitual quid placement often demonstrate a chronic inflammatory infiltration and replacement of acinar structures by the hyalinized fibrosis.

Various grades of epithelial dysplasia may be found in approximately one quarter of patients with OSF .

Management:

• Cessation of habits
• Correction of nutritional deficiency
• Mouth opening exercise
• Oral lycopene
• Submucosal injections of steroids, hyaluronidase, collagenase and placentral extract
• Surgical removal of fibrous tissues and use of tissue graft

The treatment of patients with OSF depends on the degree of clinical involvement. If the disease is detected at a very early stage, cessation of the habit is effective. However, it is often irreversible in OSF patients who present with severe disease. The focus of treatment should be on reducing exposure to the risk factors, especially the use of betel quid, and correcting any nutritional deficiencies, such as iron and vitamin B complex and on regular exercise aiming at improving mouth opening. Muscle stretching exercises for the mouth may be helpful to prevent further limitation of the mouth opening. Submucosal injections of agents such as dexamethasone, hyaluronidase, placentral extracts and collagenase have been tried with some benefit in symptomatic improvement . Lycopene has been shown to be of some benefit . In general, there is no effective treatment for oral submucous fibrosis, and the condition is irreversible once fibrosis sets in. Excision of the fibrous tissues, with correction of the defect using various grafts especially with buccal fat pad graft, has been tried in patients with severe OSF . Even though several treatment regimens have been tried with varying success, so far no effective treatment is available for OSF.

Image	Caption
	Figure 1: Early oral submucous fibrosis. Hyperkeratotic minimally hyperplastic epithelium with inflammatory cells and congested capillaries in an edematous sub epithelial connective tissue.
	Figure 2: Advanced oral submucous fibrosis. Atrophic squamous epithelium with collagenisation of the sub epithelial tissue with scanty inflammatory cells.
	Figure 3: Advanced oral submucous fibrosis. Atrophic squamous epithelium with collaginisation of the sub epithelial tissue with scanty inflammatory cells.
	Figure 4: Advanced oral submucous fibrosis with dysplastic changes. Atrophic squamous epithelium with collagenisation of the sub epithelial tissue with scanty inflammatory cells.
	Figure 5: Restricted mouth opening in a patient with oral submucous fibrosis (OSF). Note the blanching and extensive depapillation of the tongue.
	Figure 6: Oral submucous fibrosis. Note the diffuse blanching on the right buccal mucosa, with severe blanching in the retromolar area. Note tobacco stains on the tongue and teeth.
	Figure 7: Oral submucous fibrosis of the tongue. Note the coexisting verrucous leukoplakia.
	Figure 8: Oral submucous fibrosis. Note the coexisting homogeneous leukoplakia on the left side of dorsum tongue.
	Figure 9: Oral submucous fibrosis. Note the extensive depapillation and difficulty in protruding the tongue. Note the associated angular cheilitis (yellow arrows).
	Figure 10: Oral submucous fibrosis with coexisting homogeneous leukoplakia dorsum tongue. Note the discrete white patch and total depapillation of the dorsum of tongue and the limitation in its protrusion.The tongue has a smooth and shining appearance.
	Figure 11: Oral submucous fibrosis. Note the blanching on the lower labial mucosa.
	Figure 12: Note the diffuse blanching (marble-like appearance) on the right buccal mucosa of a habitual betel quid chewer. The betel quid stains can be appreciated on the lingual aspect of maxillary teeth, which have undergone attrition.
	Figure 13: Oral submucous fibrosis. Note the multiple pinpoint petechiae and generalised depapillation of the tongue.
	Figure 14: Localized oral submucous fibrosis. Note the restricted mouth opening and the normal tongue in this 58–year-old habitual areca nut chewer with oral submucous fibrosis.
	Figure 15: Oral submucous fibrosis. Photograph of the same patient showing the hard and soft palate, and the left buccal mucosa. Note the intermingling of the hypo- and hyperpigmented areas which are seen typically in areca nut chewers.
	Figure 16: Regeneration of the papillae in a 65–year-old lady who started chewing at the age of 7 and stopped the habit when she was 47 years.
	Figure 17: Tongue in an oral submucous fibrosis patient. Note the regeneration of papillae in the central part and tip of tongue in this 76–year-old female patient who chewed betel quid from age 18 to 56.
	Figure 18: Oral submucous fibrosis. Note the regeneration of papillae in the anterior part of the tongue (red arrows), three and half years after cessation of habits. Note also the hyperpigmentation (yellow arrows) in the mid part of dorsum tongue.
	Figure 19: Oral submucous fibrosis. Note the regeneration of papillae on the tip and mid-part of dorsum tongue 6 years after cessation of habits.