Oral submucous fibrosis

• Per Jens J. Pindborg and Satyavati Sirsat (1966, pathological definition): '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 a juxta-epithelial inflammatory reaction followed by a fibro-elastic change of the lamina propria, with epithelial atrophy leading to stiffness.'[5]

• Per Mohit Sharma and Raghu Radhakrishnan (2019): 'An insidious, chronic potentially malignant fibrotic disorder affecting the entire oral cavity and sometimes the pharynx and oesophagus. Although occasionally preceded by and/or associated with vesicle formation, it is always associated with a juxta-epithelial inflammatory reaction followed by a fibroelastic change of the lamina propria with epithelial atrophy leading to stiffness of the oral mucosa, progressive decrement in mouth opening and inability to eat'[6]

• Per Chandramani More and Naman Rao (2019, clinical definition): 'A debilitating, progressive, irreversible collagen metabolic disorder induced by chronic chewing of areca nut and its commercial preparations; affecting the oral mucosa and occasionally the pharynx and esophagus; leading to mucosal stiffness and functional morbidity; and has a potential risk of malignant transformation.'[7]

The incidence of the disease is higher in people from certain parts of the world including South and South East Asian, South Africa and the Middle Eastern countries.[8]

In the initial phase of the disease, the mucosa feels leathery with palpable fibrotic bands. The oral mucosa loses resiliency in the advanced stage and becomes blanched and stiff. The condition is believed to begin in the posterior part of the oral cavity and gradually spread outward. The premise posterior to the anterior progression of oral submucous fibrosis has been recently rebutted based on several reports stating that the disease may be restricted to the anterior part of the oral cavity without involvement of posterior parts; the sites are dictated by the manner of use anterior areas of the oral cavity when spitting and posterior when swallowed.[9]

Other features of the disease include:

• Xerostomia
• Recurrent ulceration
• Pain in the ear or deafness
• Nasal intonation of voice
• Restriction of the movement of the soft palate
• A budlike shrunken uvula
• Thinning and stiffening of the lips
• Pigmentation of the oral mucosa
• Dryness of the mouth and burning sensation (stomatopyrosis)
• Decreased mouth opening and tongue protrusion

Dried products such as paan masala and gutkha have higher concentrations of areca nut and appear to cause the disease. Other causes include:

• Immunological diseases
• Extreme climatic conditions
• Prolonged deficiency to iron and vitamins in the diet

"Exposure to areca nut (Areca catechu) containing products with or without tobacco (ANCP/T) is currently believed to lead to OSF in individuals with genetic immunologic or nutritional predisposition to the disease."[10]. On the other hand, reduced CD1a+ Langerhans cells and CD207+ dendritic cells indicate evolving immunosuppression in OSF and its progression to OSCC.[11]

This hypersensitivity reaction results in a juxta-epithelial inflammation that leads to increased fibroblastic activity and decreased breakdown of fibers. The fibroblasts are phenotypically modified, and the fibers they form are more stable, produce thicker bundles that progressively become less elastic. once the original loosely arranged fibrous tissue is replaced by the ongoing fibrosis, the movability of the oral tissues is reduced, there is loss of flexibility and reduced opening of the mouth. These collagen fibers are non degradable and the phagocytic activity is minimized.The role of pure capsaicin in the etiology and pathogenesis of oral submucous fibrosis has been debunked, as its has been shown to have antifibrotic and anticancer effects.[12] It has been shown by computational biology, capsaicin hinders the collagen fibre formation.[12]

According to a 2015 cross-sectional study, the time taken for return of salivary pH to baseline levels after chewing areca-nut-containing mixtures is significantly longer in habitual users with OSF when compared to unaffected users.[10] Prolonged alkaline pH induces death of the fetal fibroblast type and replacement by a profibrotic fibroblast.[10] The patterns of intraoral fibrotic bands produced by alkaline chemical injury mimic those produced by areca nut chewing.[13] Sharma et al. have equated the pathogenesis of OSF to an over-healing wound, to explain its evolution as well as malignant transformation.[13][14] Increased mechanical stiffness through YAP/TAZ pathway accelerates the malignant transformation of OSF.[15] The atrophic epithelium in OSF has been attributed to the senescence of the basal stem cell layer and the development of hyperplastic epithelium through senescence escape.[14][16] The role of senescence in pathogenesis of oral submucous fibrosis has been supported by further research.[17][18][19]

Biopsy screening, although necessary, is not mandatory; most dentists can visually examine the area and proceed with the proper course of treatment.

Treatment includes:

• Abstention from chewing areca nut (also known as betel nut) and tobacco
• Minimizing consumption of spicy foods, including chiles
• Maintaining proper oral hygiene
• Supplementing the diet with foods rich in vitamins A, B complex, and C and iron
• Forgoing hot fluids like tea, coffee
• Forgoing alcohol
• Employing a dental surgeon to round off sharp teeth and extract third molars
• Interprofessional treatment approach[23]

Treatment also includes following:

• The prescription of chewable pellets of hydrocortisone (Efcorlin); one pellet to be chewed every three to four hours for three to four weeks
• 0.5 ml intralesional injection Hyaluronidase 1500 IU mixed in 1 ml of Lignocaine into each buccal mucosa once a week for 4 weeks or more as per condition
• 0.5 ml intralesional injection of Hyaluronidase 1500 IU and 0.5 ml of injection Hydrocortisone acetate 25 mg/ml in each buccal mucosa once a week alternatively for 4 weeks or more as per condition[24]
• Submucosal injections of hydrocortisone 100 mg once or twice daily depending upon the severity of the disease for two to three weeks
• Submucosal injections of human chorionic gonadotrophins (Placentrax) 2–3 ml per sitting twice or thrice in a week for three to four weeks
• Surgical treatment is recommended in cases of progressive fibrosis when interincisor distance becomes less than 2 centimetres (0.79 in). (Multiple release incisions deep to mucosa, submucosa and fibrotic tissue and suturing the gap or dehiscence so created by mucosal graft obtained from tongue and Z-plasty. In this procedure multiple deep z-shaped incisions are made into fibrotic tissue and then sutured in a straighter fashion.)
• Pentoxifylline (Trental), a methylxanthine derivative that has vasodilating properties and increases mucosal vascularity, is also recommended as an adjunct therapy in the routine management of oral submucous fibrosis.[25]
• IFN-gamma is an antifibrotic cytokine which alters collagen synthesis and helps in OSF.[26]
• Colchicine tablets 0.5 mg twice a day[27]
• Lycopene, 16 mg a day helps in improvement of OSF[28]

The treatment of patients with oral submucous fibrosis depends on the degree of clinical involvement.[29] 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. Severe oral submucous fibrosis is irreversible. Moderate oral submucous fibrosis is reversible with cessation of habit and mouth opening exercise. Current modern day medical treatments can make the mouth opening to normal minimum levels of 30 mm mouth opening with proper treatment.

Scientists have proven that intralesional injection of autologous bone marrow stem cells is a safe and effective treatment modality in oral submucosal fibrosis. It has been shown autologous bone marrow stem cell injections induces angiogenesis in the lesion area, which in turn decreases the extent of fibrosis, thereby leading to significant increase in mouth opening.[30][31]

In 1952, T. Sheikh coined the term distrophica idiopathica mucosa oris to describe an oral fibrosing disease he discovered in five Indian women from Kenya.[32] S. G. Joshi subsequently coined the termed oral submucous fibrosis (OSF) for the condition in 1953.[33]

• Cutaneous condition