ORAL SUBMUCOUS FIBROSIS: PATHOGENESIS, CLINICAL FEATURES, HISTOPATHOLOGY AND TREATMENT
Author: Sanketh DS, MDS
Oral submucous fibrosis (OSF), first described by Schwartz in 1952, is a chronic, progressive, scarring disease due to an altered collagen metabolism that is classified as a potentially malignant disorder. It is characterised by dense fibrosis of the submucosal tissues of the oral cavity making it difficult to swallow and open the mouth. It predominantly affects people of the Indian sub-continent, China and other countries in South East Asia.
ETIOLOGY AND PATHOGENESIS
The main factor contributing to causing OSF is betel quid chewing. Betel quid consists of a betel leaf that wraps a mixture of arecanut, slaked lime, tobacco and other spices. Recent research has found arecoline, an arecanut alkaloid, to be the principle causative factor for OSF.
The pathogenesis of OSF revolves around numerous studies that hypothesize the following:
1. Arecoline causes fibroblastic proliferation, increased collagen synthesis and decreased collagen degradation.
2. In the oral mucosa there is an equilibrium maintained between Matrix Metalloproteinases (MMP) that degrade collagen and Tissue Inhibitors of Matrix Metalloproteinases (TIMP) that inhibit the action of MMPs. However, this balance is upset by arecoline which causes an increase in TIMPs, thereby causing decreased degradation and accumulation of collagen.
3. Arecoline causes an upregulation of numerous growth factors like FGF, PDGF & TGF β and cytokines like TNF α which could induce an increase in collagen synthesis.
4. Phagocytosis of fibroblasts, leading to collagen degradation is a significant pathway in physiological remodelling of the extra cellular matrix(ECM). Arecoline is reported to cause a decrease in phagocytic cells leading to accumulation of excess collagen.
5. Tannin and other polyphenols and copper present in arecanut cause crosslinking of collagen fibres making them less susceptible to degradation.
Nutritional deficiencies like iron and vitamin B complex deficiency, as well as malnutrition could be promoting factors of the disease. Genetic and molecular alterations have also been reported to contribute to pathogenesis of the disease.
OSF occurs in the Indian subcontinent and south-east Asian countries with a female predominance. OSF occurs in patients with ages ranging from 11- 60 years, with the disease occurring mostly in patients aged 45-54 years.
Initially OSF manifests with burning sensation of the mouth when consuming spicy foods. Blisters, ulcerations, excessive salivation and altered gustatory sensations are other symptoms. Also, 22% of patients with OSF may show petechiae on the tongue, labial and buccal mucosa in the initial stages of the disease.
The oral mucosa becomes blanched and opaque as the disease progresses and fibrous bands begin to appear in the palate, faucial pillars, buccal mucosa and lips. Fibrosis was thought to begin posteriorly from the faucial pillars and proceed to the buccal mucosa and lips. But it is now, known that buccal mucosa or the lips could be affected early. With fibrosis extending from the faucial pillars to the tissues around the pterygomandibular raphae, mouth opening becomes difficult. Dense fibrosis could also involve the soft palate and cause deviation of the uvula. Mouth opening could reduce to as much as <15mm in the later stages of the disease and tongue movements are impaired. This may result in difficulty in eating, whistling, blowing and swallowing. Fibrosis may spread to the pharynx and there may be referred pain in the ears when the naso-pharynx is involved.
OSF is usually divided into different stages depending on its progression:
The initial stages of OSF are characterised by flattening of rete ridges and a juxta-epithelial hyalinization, meaning there is glassy homogenous eosinophilic material deposited just under the epithelium. The collagen begins to thicken and there is a mild inflammatory infiltrate composed of neutrophils and occasional plasma cells.
Moderately advanced stage
In this stage, the rete ridges are lost and epithelium is markedly atrophic. The collagen bundles in the stroma become thicker and blood vessels are constricted. The inflammatory infiltrate consists mainly of lymphocytes and muscle fibres show signs of degeneration.
Epithelium is atrophic, the stroma becomes densely fibrosed and hyalinised, obliterating blood vessels and there is extensive degeneration of muscle fibres.
OSF is a potentially malignant disorder which has a 7-13% rate of malignant transformation. It has been hypothesized that dense fibrosis and decreased vascularity could create a hypoxic environment. This together with altered cytokine activity and arecoline induced DNA damage and oxidative stress could cause dysplastic and malignant changes to the epithelium leading to transformation to squamous cell carcinoma.
The degree of clinical involvement dictates the treatment protocol for the disease. Detection at a very early stage could be managed by cessation of the habit. However, progression to moderate to advanced stage makes the disease irreversible and could be treated only symptomatically.
1. Intralesional injections or topical application of corticosteroids and submucosal administration of placental extracts are known to improve the condition.
2. Hyaluronidase either topically or in combination with steroid injections are shown to improve symptoms faster and have better long term results.
3. Nutritional supplements like multivitamins and antioxidants improve symptoms.
4. Surgical excision of the fibrotic bands and laser fibrotomy could be useful in managing oral submucous fibrosis.
Shafer’s Textbook of Oral Pathology. Rajendran and Sivapathasundaram.6th Edition.
Oral and Maxillofacial Pathology.Neville,Damm,Allen,Chi. South Asian Edition.
Oral Pathology: Clinicopathologic correlations.Regezzi,Sciubba,Jorda.5th Edition.
Lountzis NI, Ferringer T, Macaron N, Howard A. Oral Submucous Fibrosis. 2016. Available at http://emedicine.medscape.com/article/1077241-overview
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