Submucosal fibrosis

From Otolaryngology Online


Oral Submucosal fibrosis is a chronic debilitating potentially malignant condition of the oral cavity associated with betel nut chewing. It is characterized by fibrosis of the oral soft tissue, resulting in marked rigidity and inability to open the mouth. The inability to open the mouth is slowly progressive in nature.


The term Submucosal fibrosis was first coined by Joshi in 1952. Su termed it as idiopathic sclerosis of mouth. Goleria in 1970 coined the term subepithelial fibrosis.


Buccal mucosa was the most commonly involved site, but no part of the oral cavity is immune to this condition. Almost all the patients were pan chewers. Pathophysiology of this disease is not well established. A number of factors trigger the disease process by causing a juxtaepithelial inflammatory reaction in the oral mucosa. Factors such as areca nut chewing, ingestion of chilies, genetic and immunologic processes, nutritional deficiencies can lead to this condition.

Betel nut chewing:

The areca nut component used along with betel leaf has been implicated. A recent study has clearly demonstrated the dose and frequency relationship of areca nut chewing in the pathogenesis of this disorder. Arecoline the active ingredient of areca nut is known to stimulate fibroblasts to increase its production of collagen by 150%. Flavinoids, catechin and tannin present in betel nuts cause collagen to cross link making them less susceptible to collagenase enzyme degradation. The disease process of Submucosal fibrosis is active even after cessation of betel nut chewing suggesting that arecoline not only affects the fibroblasts it also affects gene expression in fibroblasts causing them to produce increased amount of collagen with intense cross linkages.

Studies have also shown that arecoline inhibits metalloproteinases (particularly metalloproteinase 2) thus decreasing the overall breakdown of tissue collagen. Studies have also shown that keratinocyte growth factor-1, insulin like growth factor-1, and interleukin 6 expression, which have all been implicated in tissue fibrogenesis, were also significantly up-regulated by arecoline. Areca nuts are also rich in copper content. Chewing areca nuts increases the amount of copper in the oral cavity fluids. Copper is known to stimulate fibrinogenesis by activating copper dependent lysyl oxidase activity (suggested by Trivedi).

Ingestion of chillies in the pathophysiology has been controversial. Capsaicin the active ingredient of chillies have been demonstrated to increase the level of fibrosis in rats.

Genetic factors have also been postulated as the predisposing factor in the pathogenesis. Patients with submucosal fibrosis have been found to have an increased frequency of human leukocyte antigen A10 (HLA-A10), human leukocyte antigen B7 (HLA-B7), and human leukocyte antigen DR3 (HLA-DR3).

Immunologic process: have also been implicated in the pathophysiology of submucosal fibrosis. Increased levels of CD4 components have been demonstrated in these patients. The number of langerhan giant cells in the site have shown an increase.

Nutritional deficiencies: Iron deficiency, vitamin B complex deficiency, and zinc deficiency have also been postulated as predisposing factors. Infact these nutritional elements are necessary for normal repair mechanism to repair the oral mucosa which is constantly traumatized.

The morbidity and mortality of this condition is due to the fact that the patient is unable to open the mouth and consume normal quantities of food.

In Indian subcontinent females out number males in the incidence of this disease. No age group is immune to this condition. In Indian conditions in addition to the irritant effects of arecoline the nutritional deficiencies also play an important role in the pathogenesis of this disorder.

Clinical features:

1. Progressive inability to open the mouth due to fibrosis and scarring

2. Oral pain and burning sensation when the patient consumes spicy food

3. Increased salivation

4. Change in taste

5. Secretary otitis media due to stenosis of the pharyngeal end of Eustachian tube

6. Dryness of mouth

7. Dysphagia when consuming solids if esophagus is involved

Various stages of submucosal fibrosis are:

Stage I: Stomatitis, erythematous mucosa, vesicles, melanotic pigmentation of the oral mucosa, and mucosal petechia.

Stage II: Fibrosis begin with rupture of vesicles and healing of oral ulcers. Early lesions show blanching of the involved oral mucosa. Older lesions include vertical and circular palpable fibrous bands in the buccal mucosa and around the mouth opening or lips, resulting in a mottled marble like appearance of the mucosa because of the vertical, thick, fibrous bands running in a blanching mucosa. There is reduction of mouth opening in this stage, the tongue is stiff and small, the floor of the mouth has a blanched leathery appearance. The gingiva appears fibrotic and depigmented, the soft palate is rubbery with decreased mobility. The anterior and posterior pillars of the tonsils are pale and the tonsils also show atrophy. The uvula appear shrunken.

StageIII: Lekoplakia (premalignant condition) is a feature of this stage. Speech and hearing defects are also common in this stage

Khanna grouped these patients according to the degree of trismus to facilitate decision making regarding the management issues involved.

First degree: is the earliest stage. These patients do not have mouth opening difficulties. The only feature being the blanching seen in the oral mucosa associated with burning sensation on consuming spicy food.

Second degree: These patients have a mouth opening of 26 - 35 mm

Third degree: These are moderately advanced cases with mouth opening of 15 - 25 mm. Fibrotic bands are seen in the soft palate, anterior pillars of tonsils, and pterygo mandibular raphe.

Fourth degree: Most advanced case with severe trismus, presence of leukoplakia. This is infact a premalignant condition.

No specific lab study is indicated.


Very early stage: is characterized by the presence of fine fibrillar collagen, marked oedema, large fibroblasts, large congested blood vessels with acute inflammatory reaction cells around it.

Early stage: is characterized by the thickening of the collagen bundles, increase in the number of fibroblasts and inflammatory cells.

Advanced stage: Collagen sheets form dense bundles, thick bands of subepithelial hyalinization occur in the submucosal tissue, there is decreased vascularity, and chronic inflammatory cells are seen. Chronic inflammation of minor salivary glands are also seen. This is the stage associated with severe trismus.


Medical: Weekly Submucosal intralesional injections of steroids may help in prevention of progression of the disease. Cessation of betel nut chewing is a must. Placental extracts can be injected intra lesionally to reduce the inflammatory effects of the disease. Use of topical hyaluronidase in doses of 150 units in association with steroids has proved beneficial.

Intralesional injection of IFN-gamma has a role due to the immuno regulatory effect of the molecule.

Surgical management is reserved only for advanced cases with severe trismus. This include excision of fibrous bands, with split thickness skin grafting.