Oral submucous fibrosis (OSMF) was first described by Schwartz in 1952. He termed the lesion “atrophia idiopathica (tropica) mucosa oris” which was later designated as OSMF by Joshi in 1953. It has been known under various other terminologies such as ‘idopathic scleroderma of the oral cavity’, ‘sclerosing stomatitis’ and ‘juxta epithelial fibrosis’ to name a few. There has been strange relation between India and OSMF as a literature search reveals that in 600 B.C a condition similar to OSMF was reported by Sushruta who termed it as ‘VIDARI’ [1] [2]. Another important relation between India and OSMF is its prevalence rate. It has been found that this disease is most common among people living in Southeast Asia, especially in the Indian subcontinent. It is seen in other parts of the world too, but it is assumed that this statistics is due to migrating people from Southeast Asia. The reason that has been stated for the occurrence of OSMF among people in this part of the world is mainly due to the extensive use of areca nut in various forms [3]. Apart from this various other factors have also been stated such as ingestion of chillies, genetic and immunologic processes, nutritional deficiencies, and other factors [4]. Although a lot about this disease in recent times, the definition given by Pindborg in 1966 still stands the apt description for OSMF clinically and histologically. He stated OSMF to be “an insidious, chronic disease affecting any part of the oral cavity and sometimes the pharynx. Although occasionally preceded by and/or associated with vesicle formation, it is always associated with juxtaepithelial inflammatory reaction followed by fibroelastic changes in the lamina propria, with epithelial atrophy leading to stiffness of the oral mucosa causing trismus and inability to eat.” [5] The prevalence rate of OSMF in India is between 0.2-0.5%. There is a slight disparity between the genders affected in India. The prevalence rate is about 0.2% to 2.3% in males and 1.2% to 4.57% in females. The age most commonly affected is between 20 and 40 years [6]. As far as the oral cavity is concerned the most affected areas is the buccal mucosa followed by palate, retromolar region, faucial pillars and pharynx [7]. OSMF is an important disease in consideration for dentists because of its potentially malignant nature. Numerous studies have indicated varying results as far as the percentage of OSMF turning malignant. A study published by Murty et al., in 1985 which was done over a time of 17 yrs showed alarmingly 7.6% malignancy rate of OSMF [8]. The exact reason behind OSMF turning malignancy is not known. Though it is considered to be a disorder of collagen the malignant potential of OSMF is probably due to micro trauma due to usage of areca nut and tobacco that is inflicted onto the epithelium which makes it susceptible to oral cancer [9] [10].

OSMF is considered to be a disease with altered collagen metabolism. The alteration in the metabolism is brought about by the contents in the areca nut. Arecoline which is an alkaloid plays a major and direct role in the pathogenesis of OSMF by producing an abnormal increase in collagen production. Similarly flavanoids present in the areca nut alter the collagen metabolism. Also a decreased degeneration of collagen fibres is seen due to increased cross linking of collagen fibers and reduced collagenase activity [11] [12] [13]. Thus, OSMF is a disease in which there is abnormal increase in collagen synthesis and reduced collagen degradation.

One of the major growth factors that plays a role in collagen production is TGF-β. In OSMF constant irritation results in chronic inflammation which in turn activates the T cells and macrophages in that site. These inflammatory cells release TGF-β which increases the collagen production in three ways [14]. First is by activation of procollagen genes such as COL1A2, COL3A1, COL6A1, COL6A3 and COL7A1 which are considered to be early induced genes in fibroblasts [15]. Secondly they increase the levels procollagen proteinases such as PCP and PNP. These enzymes play a vital role processing of procollagen to collagen fibrils [16]. Thirdly, TGF- β plays an important role in up-regulation of lysyl oxidase (LOX) activity. LOX plays a crucial role in final processing of collagen fibrils and in cross linking in the presence of copper. It has been found that areca nuts contain a high level of copper and thus play an important role in the pathogenesis of OSMF [17] [18].

The collagen degradation pathway is also affected in OSMF. The collagen degradation is also mediated by TGF-β and brings about decreased degradation. This is carried out by this growth factor by two mechanisms. One is that it increases the levels of tissue inhibitor of matrix metalloproteinase gene (TIMPs). TIMPs inhibit the activity of matrix metalloproteinases (MMPs) which play an important role breakdown of extracellular matrix and collagen [19]. TGF-β also activates of plasminogen activator inhibitor (PAI) gene. This results in failure of conversion of plasminogen to plasmin which is important for activation of collagenase. Thus degradation of collagen by collagenase is also decreased in OSMF due to the flavanoids present in the areca nut which increase the levels of TGF-β [20] [21].

There are various classification systems of OSMF both clinically and histopathologically.

• Stage I: Stomatitis includes erythematosus mucosa, vesicles, mucosal ulcers, melanotic mucosal pigmentation and mucosal petechiae.
• Stage II: Fibrosis occurs in healing vesicles and ulcers, which is the hallmark of this stage.
  • i. Early lesions show blanching of the oral mucosa.
  • ii. Older lesions include vertical and circular palpable fibrous bands in the buccal mucosa and around the mouth opening or lips.
  • iii. This results in a mottled marble like appearance of the mucosa because of the vertical thick, fibrous bands in association with a blanched mucosa.
  • iv. Specific findings include reduction of mouth opening, stiff and small tongue, blanched and leathery floor of the mouth, fibrotic and de-pigmented gingiva, rubbery soft palate with decreased mobility, blanched and atrophic tonsils, shrunken bud like uvula and sunken cheeks, not commensurate with age or nutritional status.
• Stage III: Sequelae of OSMF are as follows:
  • v. Leukoplakia is found in more than 25% of individuals with OSMF.
  • vi. Speech and hearing deficit may occur because of involvement of tongue and the Eustachian tube.

• a. Group A: >35 mm
• b. Group B: Between 30 and 35 mm
• c. Group C: Between 20 and 30 mm
• d. Group D: <20 mm

• a. Early OSF: Burning sensation in the mouth. Blisters especially on the palate, ulceration or recurrent generalized inflammation of oral mucosa, excessive salivation, defective gustatory sensation and dryness of mouth.
• b. Advanced OSF: Blanched and slightly opaque mucosa, fibrous bands in buccal mucosa running in vertical direction. Palate and faucial pillars are the areas first involved. Gradual impairment of tongue movement and difficulty in mouth opening [22].

• a. Clinical Staging
  • i. Stage 1 (S1): Stomatitis and/or blanching of oral mucosa.
  • ii. Stage 2 (S2): Presence of palpable fibrous bands in buccal mucosa and/or oropharynx, with /without stomatitis.
  • iii. Stage 3 (S3): Presence of palpable fibrous bands in buccal mucosa and/or oropharynx, and in any other parts of oral cavity, with/ without stomatitis.
  • iv. Stage 4 (S4) as follows:
    • 1. Any one of the above stage along with other potentially malignant disorders, e.g. oral leukoplakia, oral erythroplakia, etc.
    • 2. Any one of the above stage along with oral carcinoma.
• b. Functional staging:
  • i. M1: Interincisal mouth opening up to or greater than 35 mm.
  • ii. M2: Interincisal mouth opening between 25 and 35 mm.
  • iii. M3: Interincisal mouth opening between 15 and 25 mm.
  • iv. M4: Interincisal mouth opening less than 15 mm [23].

• a. Very early stage: Finely fibrillar collagen dispersed with marked edema. Plump young fibroblast containing abundant cytoplasm. Blood vessels are dilated and congested. Inflammatory cells, mainly polymorphonuclear leukocytes with occasional eosinophils are found.
• b. Early stage: Juxta-epithelial area shows early hyalinization. Collagen still in separate thick bundles. Moderate number of plump young fibroblasts is present. Dilated and congested blood vessels. Inflammatory cells are primarily lymphocytes, eosinophils and occasional plasma cells.
• c. Moderately advanced stage: Collagen is moderately hyalinized. Thickened collagen bundles are separated by slight residual edema. Fibroblastic response is less marked. Blood vessels are either normal or compressed. Inflammatory exudate consists of lymphocytes and plasma cells.
• d. Advanced stage: Collagen is completely hyalinized. Smooth sheets with no separate bundles of collagen are seen. Edema is absent. Hyalinized area is devoid of fibroblasts. Blood vessels are completely obliterated or narrowed. Inflammatory cells are lymphocytes and plasma cells.

• a. Early stage: Large number of lymphocytes in subepithelial, connective tissue, zone along with myxedematous changes.
• b. Intermediate stage: Granulation changes close to the muscle layer and hyalinization appears in subepithelial zone where blood vessels are compressed by fibrous bundles. Reduced inflammatory cells in subepithelial layer.
• c. Advanced stage: Inflammatory cell infiltrate hardly seen. Number of blood vessels dramatically small in subepithelial zone. Marked fibrous areas with hyaline changes extending from subepithelial to superficial muscle layers. Atrophic, degenerative changes start in muscle fibers.22

The most common initial symptoms of submucous fibrosis are burning sensation of the oral mucosa aggravated by spicy food, followed by either hypersalivation or dryness of the mouth. The most common and initial clinical sign as well as a regular feature of this disease is blanching, i.e., marble-like appearance of the oral mucosa. Blanching is caused by the impairment of the local vascularity. The disease often starts as a blanched area and palpable fibrous bands develop over time.

Initially, an increased salivation is observed, but as the disease progresses, salivary flow is diminished and dryness of the mouth and intolerance to spicy food, especially chilli, becomes a prominent symptom. 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.

Clinically, patients present with a marble-like blanching of the oral mucosa. In the early stages, features of stomatitis such as erythematous mucosa, vesicles, mucosal ulcers, 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 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, and stiff soft palate with reduced mobility and shrunken bud-like uvula, blanched and atrophic tonsils. Buccal mucosa is the most commonly involved site, followed by the lip and tongue but can occur in any intraoral site. The clinical diagnosis of OSF is made based on the symptoms and clinical features described above. An incisional biopsy should be done to confirm the diagnosis and to rule out dysplasia and malignancy.

Treatment is based on severity of disease. Typically, if the disease is noted prior to development of trismus, cessation of the betel nut chewing habit will often resolve the disease. Once trismus has developed the goal of medical and surgical therapy is to maintain oral function and limit progression of disease. Treatment at this stage is focused on restoring mandibular range of motion, oral cancer surveillance, and cessation of betel nut habit. Physical therapy combined with medical treatment is often utilized.

The treatment of patients with oral submucous fibrosis depends on the degree of clinical involvement. If the disease is detected at a very early stage, cessation of the habit is sufficient. Most patients with oral submucous fibrosis present with moderate-to-severe disease. Medical treatment is symptomatic and predominantly aimed at improving mouth opening [24]. Treatment strategies include the following

• • Steroids: In patients with moderate oral submucous fibrosis, weekly submucosal intralesional injections or topical application of steroids may help to prevent further damage.
• • Placental extracts: The rationale for using placental extract in patients with oral submucous fibrosis derives from its proposed anti-inflammatory effect, hence, preventing or inhibiting mucosal damage. Cessation of areca nut chewing and submucosal administration of aqueous extract of healthy human placental extract (Placentrex) has shown marked improvement of the condition.
• • Hyaluronidase: The use of topical hyaluronidase has been shown to improve symptoms more quickly than steroids alone. Hyaluronidase can also be added to intralesional steroid preparations. The combination of steroids and topical hyaluronidase shows better long-term results than either agent used alone.
• • IFN-gamma: This plays a role in the treatment of patients with oral submucous fibrosis because of its immunoregulatory effect. IFN-gamma is a known antifibrotic cytokine. IFN-gamma, through its effect of altering collagen synthesis, appears to be a key factor to the treatment of patients with oral submucous fibrosis, and intralesional injections of the cytokine may have a significant therapeutic effect on oral submucous fibrosis.
• • Lycopene: Newer studies highlight the benefit of this oral nutritional supplement. It mainly acts as an anti-oxidant and inhibits the free radical formation, thus halts the malignant transformation.
• • Pentoxifylline: This drug is a methylxanthine derivative that has vasodilating properties and was envisaged to increase mucosal vascularity, the biologic activities of which are numerous. This includes increasing red cell deformability, leukocyte chemotaxis, antithrombin and anti- plasmin activities, and more importantly to the present context, its fibrinolytic activity. Pentoxifylline decreases red cell and platelet aggregation, granulocyte adhesion, fibrinogen levels, and whole blood viscosity. Recent work has delineated pentoxifylline's ability to decrease production of tumor necrosis factor alpha and reduce some of the systemic toxicities mediated by interleukin. These two cytokines are important mediators of the inflammatory response. In addition, pentoxifylline has been shown to increase the production of PGE2 and PGI2 by vascular epithelium, important in maintaining cellular integrity and homeostasis after acute injury

Surgical treatment is indicated in patients with severe trismus and/or biopsy results revealing dysplastic or neoplastic changes. Surgical modalities that have been used include the following:

• • Simple excision of the fibrous bands: Excision can result in contracture of the tissue and exacerbation of the condition.
• • Split-thickness skin grafting following bilateral temporalis myotomy or coronoidectomy: Trismus associated with oral submucous fibrosis may be due to changes in the temporalis tendon secondary to oral submucous fibrosis; therefore, skin grafts may relieve symptoms.
• • Nasolabial flaps and lingual pedicle flaps: Surgery to create flaps is performed only in patients with oral submucous fibrosis in whom the tongue is not involved.

OSF is associated with significant morbidity, with restricted mouth opening causing eating difficulties so a range of surgical modalities have been attempted, from moderately to significantly invasive. Aggressive physical therapy post surgery is essential: without physical therapy compliance, the risk of recurrent trismus is possible. Patients should be aware that, although the trismus has resolved post surgery, their OSF has not been cured. As such, continued physical therapy for the rest of their life is the best way to prevent recurrence of trismus. In addition, cessation of betel nut use is essential to minimize disease progression. Finally, oral cancer surveillance is necessary for the rest of the patient’s life.