Oral Submucous Fibrosis - A Review
Falguni Patel1, Shreyas N. Shah2, Christina James3
1, 2, 3 Department of Oral and Maxillofacial Pathology and Microbiology, K.M. Shah Dental College and Hospital, Sumandeep Vidyapeeth Deemed to Be University, Vadodara, India.
CORRESPONDING AUTHOR
Dr. Falguni Patel,
Senior Lecturer,
Department of Oral and Maxillofacial
Pathology and Microbiology,
K. M. Shah Dental College and
Hospital, Sumandeep Vidyapeeth,
Deemed to Be University, Piparia - 391760,
Vadodara, Gujarat, India.
Email : falgunihpatel1989@gmail.com
ABSTRACT
A common oral disease named as oral submucous fibrosis (OSMF) has the tendency to usually affect many areas of the oral cavity as well as involving the area of pharynx. The characteristic feature of oral submucous fibrosis is the fibrosis in submucosal area which involves maximum part of oral cavity leading to advanced lock jaw as a result of rigidity in cheeks, pharynx, lips and upper third part of the oesophageal canal progressing to dysphagia. It has been reported that OSMF occurs mainly in persons who are habituated to chew areca nut or products containing areca nut along with other ingredients. In recent years with the introduction of commercially available Gutka and other areca nut products, the incidence of OSMF is increasing especially in the younger generations. OSMF is irreversible and persists even after cessation of chewing habit and the severity increases along with the duration of habit. In 2007, the categorization of oral submucous fibrosis was done as a premalignant condition by WHO and it has higher chances of malignant transformation. Early diagnosis and application of proper treatment modality is mandatory to reduce morbidity and mortality rate. There are many classification systems that have been proposed in literature for oral submucous fibrosis, among which many are based on clinical features, some of them on functional aspects and others are based on histopathological aspects. Here is an attempt to enlighten the facts and recent updates of clinical, functional, histopathological features as well as pathogenesis and management of oral submucous fibrosis. The complete knowledge of oral submucous fibrosis is a useful to the clinicians as well as academicians and researchers for timely detection and proper management of the disease.
KEY WORDS
Oral Submucous Fibrosis, Precancerous Lesions, Precancerous Conditions, Sclerosing Stomatitis
BACKGROUND
The identification and management of pre cancer involves oral cancer control measure as a vital constituent. Oral pre cancer is grouped into precancerous lesions and precancerous conditions as per WHO, 1993.1 The definition of a precancerous lesion is a morphologically modified structure of a group of cells wherein carcinoma can readily appear compared to its normal equivalent tissue. On the other hand, a precancerous condition can be termed as a generalized state related to a significant increase in risk for outcome of cancer. According to classification provided by WHO in 2007, precancerous lesions include Erythroplakia, leukoplakia and other palatal lesions usually noticed in reverse smokers while precancerous conditions consist of actinic keratosis, lichen planus, oral submucous Fibrosis and discoid lupus erythematosus.2
Oral submucous fibrosis, a chronic disease, is a challenging one disturbing many areas of oral tissues along with involvement of pharyngeal area. Oral submucous fibrosis (OSMF) was formerly known as idiopathic palatal fibrosis, juxta-epithelial fibrosis, idiopathic scleroderma of mouth and sclerosing stomatitis.3 The characteristic of oral submucous fibrosis is the presence of fibrosis in submucosal area involving the greatest area of oral cavity leading to advanced lockjaw as a result of rigidity in cheeks, pharynx, lips and upper third part of the oesophageal canal progressing to dysphagia.4 It was first described as ‘Vidari’ in ancient medical literature by Sushruta in 600 BC which involved progressive contraction of the oral cavity, depigmentation of oral tissue and discomfort while consuming food.5 In the year 1952, it was termed as ‘Atrophica Idiopathica Mucosae Oris’ by Schwartz and the word ‘Submucous Fibrosis of Palate and the Pillars’ was coined by Joshi in 1953.6 Other terms proposed were, diffuse oral submucous fibrosis, idiopathic scleroderma of the mouth, sclerosing stomatitis and idiopathic palatal fibrosis.7
Sirsat and Pindborg in 1966 defined OSMF as “an insidious, chronic disease of the oral mucosa affecting any part of the oral cavity and sometimes the pharynx. Occasionally it is preceded by and / or associated with vesicle formation, and is always associated with a juxtaepithelial inflammatory reaction followed by fibroelastic changes of the lamina propria, with epithelial atrophy leading to stiffness of the oral mucosa causing trismus and difficulty in eating”.8 World Health Organisation in 1978 defined OSMF as “Slowly progressive disease characterized by the fibrous bands in the oral mucosa, ultimately leading to severe restriction of mouth movement including the tongue”.9 “Slowly progressive chronic fibrotic disease of the oral cavity and oropharynx, characterized by fibro elastic change and inflammation of mucosa, leading to a progressive inability to open the mouth, swallow and speak” was another definition of OSMF given by Bhattacharya I.10
It has been reported that OSMF occurs mainly in persons who are habituated to chew areca nut or products containing areca nut along with other ingredients, in recent years with the introduction of commercially available Gutka and other areca nut products, the incidence of OSF is increasing especially in the younger generations. OSMF is irreversible and persists even after cessation of chewing habit and the severity increases with duration of habit.11
OSMF being a well-recognized oral precancerous condition worsens with increase in the grades of OSMF. A rate as high as 7.6 % has been stated for malignant transformation for over 17-year duration.12
Recognition of oral premalignant lesions showing high risk and their treatment in initial stages could be advantageous in decreasing the rate of morbidity and mortality as well as the treatment cost of OSMF. Most significant is the commitment and motivation of the examiners, physicians and dentists, by whom early diagnosis and prompt treatment are rewarded with optimal survival and minimal dysfunction.13
Prevalence
OSMF is an incurable oral pathology which creates scar and eventually leads to fibrosis of oral tissue. It is basically a pre- malignancy of oral cavity which can cause the development of oral cancer. The disease significantly affects the mortality owing to its excessive rate of malignant transformation (1.5 –15 %).14 The existence of OSMF varies with region and ethnicity which is directly related to habits, culture and diet.15,16,17 The prevalence of OSMF in people is highest in South and South - East Asia.16,18,19 In addition, South Africa also shows a high incidence of OSMF patients amounting to substantial amount of Indian migrants. The incidence of OSMF differs among South - East Asian countries. The prevalence of the disease was reported to be 0.62 – 6.42 %, 0.9 – 4.7 % and 0.15 – 14.6 % in India, China and Vietnam respectively.20,21,22 There are more than 5 million OSMF patients worldwide, based on the WHO statistics.23,24 The age group of OSMF patients span from first decade to eighth decade of life, with variable mean age among various studies.25
AETIOLOGY
On the basis of the clinical and epidemiological studies, etiologic agents such as intake of chilly, dietary deficiencies, eating areca nut, genetic predisposition, autoimmune diseases and collagen conditions can be considered as progressive factors in the pathogenic process of OSMF outcome. Areca / betel nut can be a major risk factor leading to OSMF.
The alkaloid content found in this whole fruit of areca nut and betel nut is arecoline which stimulates fibroblast to increase production of collagen in a larger amount. Due to the presence of high amount of copper content found in the areca nut, it leads to the increase of soluble copper levels in oral fluids which can also be considered as initiating factor in OSMF.26 More than the self-prepared betel quid, frozen dried forms of mawa, gutka and pan masala cause more irritation to the oral mucosa.4
OSMF can also occur due to the deficiency of vitamin B complex. Due to iron deficiency anaemia, vitamin B complex deficiency and malnutrition there is derangement in the repairing of inflamed oral mucosa leading to scarring and impaired healing.4,27
According to Rajendran et al. in 1994 chillies also play an etiological role in the occurrence of OSMF as its active content Capsaicin (vanillylamide of 8 - methyl - 6 - non-ionic acid) acts as a predisposing factor.3,28,29
The transforming growth factor - beta (TGF - β) and interferon - gamma (IFN - ɣ) levels are low in cases of OSMF due to the use of betel quid. Other diseases like rheumatoid arthritis, systemic lupus erythematous and scleroderma are associated with unique human leukocyte antigen (HLA) – DR antigens and similar association is found for OSMF.30
PATHOGENESIS
The pathogenesis of OSMF is considered to be multifactorial. Various mechanisms have been mentioned in the literate with regard to pathogenesis. The main cause that leads to the advancement of OSMF is areca / betel nut eating habit in Asian population. The constituents of areca / betel nut are 31.1 %, 18.7 %, 14 %, 10.8 % and 0.5 % of phenols, polysaccharides, fat, fibres, and alkaloids respectively. The primary alkaloid that plays an important role in the pathogenesis of OSMF is Arecoline.31-34 The arecoline stimulates the fibroblast cells that cause the expression of cytokines and growth factors that improve the deposition of collagen and represses the depletion of collagen. Abnormal expression of the altering connective tissue growth factor (CTGF), growth factor beta (TGF - β), alpha - smooth muscle actin (α - SMA), beta fibroblast growth factor (bFGF), serum c-reactive protein, tumour necrosis factor - α (TNF - α), ROS level, the tissue inhibitors of metalloproteinase (TIMP) and matrix metalloproteinase (MMP) have been specified in various clinical studies. TNF - α expression in the oral cavity accelerates cell inflammation. This activates wound healing which reduces MMP and improves TIMP expression.35-40 Degradation of extracellular matrix is the function of the MMP but this process is inhibited by TIMP. The unusual collagen deposition observed in the lesion is due to this mechanism. Inflammation reaction also promotes the demonstration of bFGF and TGFβ - 1. In OSMF patients there is over expression of bFGF in oral cells which leads to collagen deposition.35 TGFβ - 1 is also responsible for collagen production and wound contraction as it stimulates the fibroblasts to transform into myofibroblasts. After the completion of wound healing the myofibroblasts undergo apoptosis.41-43 This mechanism is disrupted in the condition of OSMF.
Arecoline also increases the level of ROS in the serum of OSMF patients.39 This ROS in serum targets the blood vessel structure which prompts cell senescence and eventually results in DNA double-stranded breaks.44,45 Epithelial atrophy seen with OSMF patients is due to the decrease in blood flow in the oral mucosa.
The cellular inflammatory reaction and ROS stimulates the cellular area for the activation of TGF - β signalling pathways. Stimulants tend to damage the cells and by the regulation of TGF - β, it ceases the cell cycle and causes apoptosis of the unrepaired damaged cells. TGF - β activates the CTGF which promotes the fibroblast - mediated production of extracellular matrix deposition.46,47
The copper content in the areca nut takes part in the cross - linking of the collagen which leads to limited mouth opening and trismus by increasing the hardness of the oral mucosa.48,49 High copper content in the serum of the OSMF patients indicate its role in promoting the development of OSMF.48,50
CLINICAL FEATURES
Oral submucous fibrosis affects masticatory, specialized and the lining mucosa of the oral cavity but most commonly it appears in the buccal mucosa, retromolar area and the soft palates.51,52 OSMF also affects the pharynx and oesophagus. The initial symptoms seen are dry mouth feel, soreness, taste disorders, limited tongue mobility, trismus and dysphagia. The oral mucosa becomes soft and pink in colour and with time it becomes nonelastic. The oral mucosa also exhibits blanching and on palpation is tough with vertical bands, just opposite to the premolar part. During subsequent stages of the lesion, it affects the lips and the palate. There is also burning sensation in the mouth on intake of spicy food. If not treated, the lesion progresses and leads to minimal mouth opening thereby hampering the well-being of the patient.53
CLASSIFICATION
Some of the classification based on clinical and functional parameters are as follows –
According to Kerr et al.54 OSMF can be graded as -
- Grade 1: (Mild): Any features (blanching, depapillation, burning, or leathery mucosa) of the OSMF may be noted along with > 35 mm inter incisal mouth opening.
- Grade 2: (Moderate): Above mentioned features of OSMF along with limited 20 - 35 cm of inter-incisal mouth opening
- Grade 3: (Severe): Above mentioned OSMF features along with reduced mouth opening.
- Grade 4(A): Above mentioned OSMF features with presence of other potentially malignant disorders on clinical examination.
- Grade 4(B): Above mentioned OSMF features along with any grade of oral epithelial dysplasia noticed in biopsy
- Grade 5: Above mentioned OSMF features along with presence of oral squamous cell carcinoma.
Based on clinical and functional parameters of OSMF More et al.55 gave the following classification:
- 1. Clinical Staging
- Stage 1 (S1): Oral Stomatitis and / or presence of blanching of oral mucosa.
- Stage 2 (S2): Palpable fibrous bands presenting buccal mucosa and / or oropharynx, with or without presence of stomatitis.
- Stage 3 (S3): Palpable fibrous bands present in buccal mucosa and / or oropharynx, and also present in any other parts of oral cavity, with or without presence of stomatitis.
- Stage 4 (S4): A) Any one of the above-mentioned stages with presence of other potentially malignant disorders, e.g., oral leucoplakia and oral erythroplakia. B) Any one of the above-mentioned stages along with oral malignancy.
2. Functional Staging:
- M1: up to or > 35 mm of Inter-incisal mouth opening
- M2: In between 25 to 35 mm of Inter-incisal mouth opening
- M3: In between 15 to 25 mm of Inter-incisal mouth opening
- M4: Reduced Inter-incisal mouth opening
Prakash et al.56 conducted a clinico radiological study and measured the morphologic variants of soft palate. Based on such variants the author evaluated the severity of OSMF to create it as a basis for grading of OSMF. He revealed six morphologic variants as follows -
- Variant Type 1: Leaf shaped
- Variant Type 2: Rat tail shaped
- Variant Type 3: Butt shaped
- Variant Type 4: Straight line
- Variant Type 5: Deformed S
- Variant Type 6: Crook shaped
Based on cheek flexibility, Patil and Maheshwari57 suggested a new classification. In their study, a distance from midline of maxillary incisors to the cheek retractor in millimetres during retraction was measured as flexibility of cheeks. Normal range for cheek flexibility was: 35 – 45 mm for males and 30 - 40 mm for females.
- Grade 1 (Early): ≥ 30 mm of Cheek flexibility
- Grade 2 (Mild): In between 20 to 30 mm of Cheek flexibility
- Grade 3 (Moderate): ˂ 20 mm of Cheek flexibility
- Grade 4 (Severe): Any of the above mentioned condition without simultaneous presence of potential malignant lesions
- Grade 5 (Advanced): Any of the above mentioned condition with simultaneous presence of oral malignancy.
Classification According to the Histological Parameters
OSMF classification according to only on histopathological features was initially given by Pindborg JJ and Sirsat S Min 19668 which is as follows -
- Very early stage: Plump shaped young fibroblast containing abundant amount of cytoplasm. Fine fibrillar collagen distributed with marked oedema. Presence of dilated and congested blood vessels along with Inflammatory cells, mostly polymorphonuclear leukocytes with occasional eosinophils.
- Early stage: Juxta-epithelial area indicates early hyalinization. Collagen is still arranged in separate thick bundles. Presence of moderate number of plump young fibroblasts. Evidence of dilated and congested blood vessels along with inflammatory cells mainly, lymphocytes, eosinophils and occasionally plasma cells.
- Moderately advanced stage: Moderately hyalinised Collagen is evident. Fibroblastic response is less marked. Presence of thickened collagen bundles, which are separated by slight residual oedema. Blood vessels are either normal or compressed. Inflammatory exudates composed of lymphocytes and plasma cells.
- Advanced stage: Completely hyalinised Collagen is evident. Smooth sheets without separately arranged bundles of collagen are seen. No evidence of oedema. Presence of hyalinised area lacking fibroblasts. Evidence of completely obliterated or narrowed blood vessels with inflammatory cells chiefly, lymphocytes and plasma cells.
Based on the concept of Pindborg and Sirsat, Utsunomiya H, Tilakratne W M, Oshiro K et al. (2005)58 graded OSMF histologically and modified it as follows -
- Early stage - Evidence of large number of lymphocytes in the subepithelial, connective tissue zone along with some myxedematous changes.
- Intermediate stage: Presence of hyalinization in sub epithelial zone where blood vessels are compressed by fibrous bundles. Evidence of granulation changes close to the muscle area and reduced inflammatory cells in subepithelial layer.
- Advanced stage - Marked fibrous areas with hyaline changes extending from subepithelial to superficial muscle layers. Number of blood vessels dramatically small in subepithelial zone. Inflammatory cell infiltrates hardly seen. Atrophic, degenerative changes initiated in muscle fibres.
Kiran Kumar et al. (2007)59 suggested OSMF histological grading as follows -
- Grade I: Loose, thick and thin fibres
- Grade II: Loose or thick fibres with partial hyalinization
- Grade III: Complete hyalinization
A classification was also given combining both the clinical and histological parameters. For the purpose of surgical management of OSMF, Khanna JN and Andrade NN (1995)58 established a group classification system of OSMF.
- Group I - Very early cases - Common symptom of OSMF is burning sensation in the mouth, acute ulceration and recurrent stomatitis with no mouth opening limitation.
Histology - Fine fibrillar collagen network interspersed with marked oedema, along with dilated and congested blood vessels, large collection of plump young fibroblasts presents with abundant cytoplasm and presence of inflammatory cells chiefly comprising of polymorphonuclear leukocytes with few eosinophils. The epithelium appears normal.
- Group II - Early cases - Buccal mucosa appears marble like and mottled, widespread sheets of fibrous bands palpable, inter incisal mouth opening distance of 26 to 35 mm
Histology - Presence of Juxta epithelial hyalinization, collagen is evident and thickened but arranged in separate bundles, blood vessels are dilated and congested, young fibroblasts are present in moderate number, inflammatory cells chiefly comprised of polymorphonuclear leukocytes with few eosinophils and occasionally plasma cells, shortening or flattening of epithelial rete - pegs evident with variable degree of keratinization.
- Group III - Moderately advanced cases— Trismus, inter incisal mouth opening distance of 15 to 25 mm, atrophy of vermilion border, buccal mucosa appears pale firmly attached to underlying tissues, vertical fibrous bands palpable at the soft palate, anterior faucial pillars and pterygomandibular raphe area.
Histology - Presence of Juxta-epithelial hyalinization, thickened collagen bundles, constricted blood vessels, residual oedema, mature fibroblasts with scanty cytoplasm and spindle-shaped nuclei, epithelium is noticeably atrophic with loss of rete pegs, inflammatory exudates which consists of lymphocytes and plasma cells, muscle fibres seen with thickened and densely arranged collagen fibres.
- Group IV A: Advanced cases— Presence of severe trismus, inter incisal mouth opening distance of less than 15 mm, shrunken uvula, thickened faucial pillars, presence of circular band around entire lip and mouth and restricted tongue movement.
- Group IV B: Advanced cases— Evidence of hyper keratotic leukoplakia and / or squamous cell carcinoma.
Histology - Extensive fibrosis, smooth sheet of hyalinised collagen, obliteration of mucosal blood vessels, eliminated melanocytes, absence of fibroblasts within the hyalinised areas, total loss of epithelial rete pegs, presence of mild to moderate grade of atypia and extensive degeneration of muscle fibres.
CYTOLOGY
Exfoliative cytology is beneficial for the identification of oral progressive multifocal leukoencephalopathy (PML) has been a common knowledge for more than 40 years. Studies established that traditional cytology with Papanicolaou staining is able to give good quality results. The cytology findings are categorized into two broad categories, that is, inflammatory cellular atypia and non-inflammatory cellular atypia. The non-inflammatory cellular atypia includes features like cellular pleomorphism, nuclear pleomorphism, nuclear budding, prominent nucleoli, and micronuclei. The inflammatory cellular atypia includes intracytoplasmic bacterial colonies, inflammatory cells, perinuclear halo, free nuclei, and indented cellular outline indicative of cytolysis. Studies conducted on OEC in premalignant lesions / conditions have determined that the technique was useful in lesions of leukoplakia and OSF. It has been recognized to be effective for diagnosing very early malignant change.60
Based on the cytological appearance, OSMF is correlated clinically and divided into 4 stages.60
- Stage I - Two to three micronuclei, with a magenta hue in the cytoplasm, an altered shape of the cell cytoplasm is evident with a decreased and increased diameter of nucleus.
- Stage II - Three to four micronuclei, with presence of altered shape of cell and the purplish hue of cytoplasm is evident. The diameter of cell cytoplasm is even smaller, and the diameter of nucleus is increased.
- Stage III - Three to four micronuclei with purplish hue of cytoplasm, the diameter of cell cytoplasm is decreased considerably and increased N / C ratio.
- Stage IV - Plenty of keratinised cells are evident, the cytoplasmic hue is greenish in colour, many pyknotic cells are evident. There is a noticeable reduction in the diameter of cell cytoplasm.
MANAGEMENT
The management of OSF over the past decades has been varied and largely unsuccessful, and the results if any, have been palliative. Elimination or even reduction of the habit of betel quid chewing has been advocated as an essential preventive measure. Primarily, in the earlier stages of OSMF, it may decelerate progression of the condition.3,60 The current treatment strategies, which have been used to improve the treatment regimens for OSF, are discussed below. Unfortunately, none has been shown to be effective under controlled conditions.
Nutritional Support
Vitamin B complex supplementation is an important factor as its deficiency is one of the etiological agents of OSMF. Vitamin B complex helps to relive glossitis, inflammation of the tongue, cheilosis, burning sensation and limited mouth opening in OSF patients. Supplementary diets for high proteins and calories, combined with other known therapeutic agents like consumption of iodised salt and / or local uses of steroids and placental extracts should be taken into consideration while planning a treatment regimen for patients with OSMF.3,60-63
Immunomodulatory Drugs
Glucocorticoids and placental extracts can be applied both systemically and locally. It is believed that the T lymphocytes following the antigenic effect of placental extracts and glucocorticoids perform as immunosuppressive agents. Hence, inhibits or suppresses inflammatory responses, thus blocking fibrosis by reduction in increased fibroblast and collagen deposition.3,64
Physiotherapy
Forceful mouth opening and heat therapy has been tried as a part of physiotherapeutic approach towards treatment of OSMF. The latter part has proved to be effective. The heat application can be performed with the help of lukewarm or warm water rinses, or deep heating therapies with careful approach like short wave and microwave diathermy. Microwave diathermy is said to be enhanced as compared to short wave, since selective careful heating of the juxta-epithelial connective tissue area is viable, thus restricting the area of treatment.64,65
Surgical Management
Patients with severe OSMF (mouth opening less than 20 mm) require surgery. The surgeons use electrocautery, scalpel blades and lasers to cut out the fibres which limit the mouth opening, and also use the coronoidectomy to recreate soft tissue for increasing the mouth opening. Flaps for reconstruction of the surgical sites are taken from areas with well vascularization with minimum donor morbidity. The nasolabial flap, fat flap, tongue flap, palatal flap, mandibular mucoperiosteal flap and platysma myocutaneous flaps are utilized for soft tissue restoration.66-69
REFERENCES
Mehta FS, Hammer JE. Tobacco related oral mucosal lesions and conditions in India: a guide for dental students, dentists and physicians. Bombay: Jaypee Brothers Medical Publishers 1993:44-8.
Warnakulasuriya S, Johnson NW, Van Der Waal I. Nomenclature and classification of potentially malignant disorders of the oral mucosa. J Oral Path Med 2007;36(10):575-80.
CrossRef | Google Scholar | PubMedRajendran R. Oral submucous fibrosis: etiology, pathogenesis and future research. Bull World Health Organ 1994;72(6):985-96.
CrossRef | Google Scholar | PubMedGupta MK, Mhaske S, Ragavendra S, et al. Review article: oral submucous fibrosis-current concepts in etiopathogenesis. People's J Sci Res 2008;40:39-44.
CrossRef |Raina C, Raizada RM, Chaturvedi VN, et al. Clinical profile and serum beta-carotene levels in oral submucous fibrosis. Indian J Otolaryngol Head Neck Surg 2005;57(3):191-5.
CrossRef | Google Scholar | PubMedJoshi SG. Submucous fibrosis of the palate and pillars. Indian J Otolaryng 1953;4:1-4.
Behl PN. Practice of dermatology. Bombay: Allied Publishers Private Ltd 1962.
Pindborg JJ, Sirsat SM. Oral submucous fibrosis. Oral Surg Oral Med Oral Pathol 1966;22(6):764-79.
CrossRef | Google Scholar | PubMedKramer IR, Lucas RB, Pindborg JJ, et al. Definition of leukoplakia and related lesions: an aid to studies on oral precancer. Oral Surg Oral Med Oral Pathol 1978;46(4):518-39.
Google Scholar | PubMedBhattacharya I. Red and white lesions of the oral mucosa. In: Greenberg MS, Glick M, eds. Burket’s Oral Medicine. 10th edn. Spain: BC Decker Inc 2003:117-8.
Shah N, Sharma PP. Role of chewing and smoking habits in the etiology of oral submucous fibrosis (OSF): a case- control study. J Oral Pathol Med 1998;27(10):475-9.
CrossRef | Google Scholar | PubMedMurti PR, Bhonsle RB, Pindborg JJ, et al. Malignant transformation rate in oral submucous fibrosis over 17-year period. Community Dent Oral Epidemiol 1985;13(6):340-1.
CrossRef | Google Scholar | PubMedRahman MS, Ingole N, Roblyer D, et al. Revaluation of low-cost, portable imaging system for early detection of oral cancer. Head & Neck Oncol 2010;2:10.
CrossRef | Google Scholar | PubMedWang YY, Tail YH, Wang WC, et al. Malignant transformation in 5071 Southern Taiwanese patients with potentially malignant oral mucosal disorders. BMC Oral Health 2014;14:99.
CrossRef | Google Scholar | PubMedZhang X, Reichart PA. A review of betel quid chewing, oral cancer and precancer in Mainland China. Oral Oncol 2007;43(5):424-30.
CrossRef | Google Scholar | PubMedTilakaratne WM, Ekanayaka RP, Warnakulasuriya S. Oral submucous fibrosis: a historical perspective and a review on etiology and pathogenesis. Oral Surg Oral Med Oral Pathol Oral Radiol 2016;122(2):178-91.
CrossRef | Google Scholar | PubMedChattopadhyay A, Ray JG. Molecular pathology of malignant transformation of oral submucous fibrosis. J Environ Pathol Toxicol Oncol 2016;35(3):193-205.
CrossRef | Google Scholar | PubMedChang MC, Chiang CP, Lin CL, et al. Cell-mediated immunity and head and neck cancer: with special emphasis on betel quid chewing habit. Oral Oncol 2005;41(8):757-75.
CrossRef | Google Scholar | PubMedCox SC, Walker DM. Oral submucous fibrosis. A review. Aust Dent J 1996;41(5):294-9.
CrossRef | Google Scholar | PubMedLiu B, Shen M, Xiong J, et al. Synergistic effects of betel quid chewing, tobacco use (in the form of cigarette smoking) and alcohol consumption on the risk of malignant transformation of oral submucous fibrosis (OSF): a case-control study in hunan province, China. Oral Surg Oral Med Oral Pathol Oral Radiol 2015;120(3):337-45.
CrossRef | Google Scholar | PubMedReichart PA, Nguyen XH. Betel quid chewing, oral cancer and other oral mucosal diseases in Vietnam: a review. J Oral Pathol Med 2008;37(9):511-4.
CrossRef | Google Scholar | PubMedYang SF, Wang YH, Su NY, et al. Changes in prevalence of precancerous oral submucous fibrosis from 1996 to 2013 in Taiwan: a nationwide population-based retrospective study. J Med Assoc 2018;117(2):147-52.
CrossRef | Google Scholar | PubMedNigam NK, Aravinda K, Dhillon M, et al. Prevalence of oral submucous fibrosis among habitual gutkha and areca nut chewers in Moradabad district. J Oral Biol Craniofac Res 2014;4(1):8-13.
CrossRef | Google Scholar | PubMedGottipamula S, Sundarrajan S, Moorthy A, et al. Buccal mucosal epithelial cells downregulate CTGF expression in buccal submucosal fibrosis fibroblasts. J Maxillofac Oral Surg 2018;17(2):254-9.
CrossRef | Google Scholar | PubMedMaher R, Lee AJ, Warnakulasuriya KA, et al. Role of areca nut in the causation of oral submucous fibrosis: a case-control study in Pakistan. J Oral Pathol Med 1994;23(2):65-9.
CrossRef | Google Scholar | PubMedGupta S, Reddy MVR, Harinath BC. Role of oxidative stress and anti-oxidants in aetiopathogenesis and management of oral submucous fibrosis. Indian J Clin Biochem 2004;19(1):138-41.
CrossRef | Google Scholar | PubMedAziz SR. Oral submucous fibrosis: an unusual disease. J N J Dent Assoc 1997;68(2):17-9.
Google Scholar | PubMedMcGurg M, Craig GT. Oral submucous fibrosis: two cases of malignant transformation in Asian immigrants to the United Kingdom. Br J Oral Maxillofac Surg 1984;22(1):56-64.
CrossRef | Google Scholar | PubMedShiau YY, Kwan HW. Submucous fibrosis in tiwan. Oral Surg 1979;47(5):453-7.
CrossRef | Google Scholar | PubMedBinnie WH, Cawson RA. A new ultrastructural finding in oral submucous fibrosis. Br J Dermatol 1972;86(3):286-90.
CrossRef | Google Scholar | PubMedZhang Y, Zhang JJ, Kang WY, et al. Advances of chemical constituents and pharmacological activities of Myristica genus. Zhongguo Zhong Yao Za Zhi 2014;39(13):2438-49.
Google Scholar | PubMedAngadi PV, Rekha KP. Oral submucous fibrosis: a clinicopathologic review of 205 cases in Indians. Oral Maxillofac Surg 2011;15(1):15-9.
CrossRef | Google Scholar | PubMedJain A, Taneja S. Oral submucous fibrosis in pediatric patients: a systematic review and protocol for management. Int J Surg Oncol 2019;2019:3497136.
CrossRef | Google Scholar | PubMedDeshpande A, Kiran S, Dhillon S, et al. Oral submucous fibrosis: a premalignant condition in a 14-year-old Indian girl. BMJ Case Rep 2013;2013:bcr2013200786.
CrossRef | Google Scholar | PubMedBishen KA, Radhakrishnan R, Satyamoorthy K. The role of basic fibroblast growth factor in oral submucous fibrosis pathogenesis. J Oral Pathol Med 2008;37(7):402-11.
CrossRef | Google Scholar | PubMedGabbiani G, Chaponnier C, Huttner I. Cytoplasmic filaments and gap junctions in epithelial cells and myofibroblasts during wound healing. J Cell Biol 1978;76(3):561-8.
CrossRef | Google Scholar | PubMedShinde AV, Humeres C, Frangogiannis NG. The role of alpha-smooth muscle actin in fibroblast-mediated matrix contraction and remodeling. Biochim Biophys Acta Mol Basis Dis 2017;1863(1):298-309.
CrossRef | Google Scholar | PubMedGosavi SR, Torkadi AA. Serum C-reactive protein in oral submucous fibrosis and oral squamous cell carcinoma: a cross-sectional study. J Oral Maxillofac Pathol 2020;24(1):46-51.
CrossRef | Google Scholar | PubMedShakunthala GK, Annigeri RG, Arunkumar S. Role of oxidative stress in the pathogenesis of oral submucous fibrosis: a preliminary prospective study. Contemp Clin Dent 2015;6(Suppl 1):S172-4.
CrossRef | Google Scholar | PubMedRajendran R, Rajeesh MPK, Shaikh S, et al. Expression of matrix metalloproteinases (MMP-1, MMP-2 and MMP-9) and their inhibitors (TIMP-1 and TIMP-2) in oral submucous fibrosis. Indian J Dent Res 2006;17(4):161-6.
CrossRef | Google Scholar | PubMedLee IT, Lin CC, Wu YC, et al. TNF-alpha induces matrix metalloproteinase-9 expression in A549 cells: role of TNFR1/TRAF2/PKCalpha-dependent signaling pathways. J Cell Physiol 2010;224(2):454-64.
CrossRef | Google Scholar | PubMedCarswell EA, Old LJ, Kassel RL, et al. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci U S A 1975;72(9):3666-70.
CrossRef | Google Scholar | PubMedHinz B. Formation and function of the myofibroblast during tissue repair. J Investig Derm 2007;127(3):526-37.
CrossRef | Google Scholar | PubMedDavalli P, Mitic T, Caporali A, et al. Cell senescence and novel molecular mechanisms in aging and age-related diseases. Oxid Med Cell Longev 2016;2016:3565127.
CrossRef | Google Scholar | PubMedBautista-Nino PK, Portilla-Fernandez E, Vaughan DE, et al. DNA damage: a main determinant of vascular aging. Int J Mol Sci 2016;17(5):748.
CrossRef | Google Scholar | PubMedArnott JA, Lambi AG, Mundy C, et al. The role of connective tissue growth factor (CTGF/CCN2) in skeletogenesis. Crit Rev Eukaryot Gene Exp 2011;21(1):43-69.
CrossRef | Google Scholar | PubMedLipson KE, Wong C, Teng Y, et al. CTGF is a central mediator of tissue remodeling and fibrosis and its inhibition can reverse the process of fibrosis. Fibrogenesis Tissue Repair 2012;5(Suppl 1):S24.
CrossRef | Google Scholar | PubMedOpsahl W, Zeronian H, Ellison M, et al. Role of copper in collagen cross-linking and its influence on selected mechanical properties of chick bone and tendon. J Nutr 1982;112(4):708-16.
CrossRef | Google Scholar | PubMedTom A, Baghirath V, Krishna B, et al. Ultrastructural changes of collagen in different histopathological grades of oral submucous fibrosis. J Pharm Bioallied Sci 2019;11(Suppl 1):S309-13.
CrossRef | Google Scholar | PubMedYadav A, Kumar L, Misra N, et al. Estimation of serum zinc, copper and iron in the patients of oral submucous fibrosis. Natl J Maxillofac Surg 2015;6(2):190-3.
CrossRef | Google Scholar | PubMedDionne KR, Warnakulasuriya S, Zain RB, et al. Potentially malignant disorders of the oral cavity: current practice and future directions in the clinic and laboratory. Int J Cancer 2015;136(3):503-15.
CrossRef | Google Scholar | PubMedChole RH, Gondivkar SM, Gadbail AR, et al. Review of drug treatment of oral submucous fibrosis. Oral Oncol 2012;48(5):393-8.
CrossRef | Google Scholar | PubMedShen YW, Shih YH, Fuh LJ, et al. Oral submucous fibrosis: a review on biomarkers, pathogenic mechanisms and treatments. Int J Mol Sci 2020;21(19):7231.
CrossRef | Google Scholar | PubMedKerr AR, Warnakulasuriya S, Mighell AJ, et al. A systematic review of medical interventions for oral submucous fibrosis and future research opportunities. Oral Dis 2011;17(Suppl 1):42-57.
CrossRef | Google Scholar | PubMedMore CB, Das S, Patel H, et al. Proposed clinical classification for oral submucous fibrosis. Oral Oncol 2012;48(3):200-2.
CrossRef | Google Scholar | PubMedMohan RPS, Verma S, et al. Morphometric evaluation of soft palate in oral submucous fibrosis: a digital cephalometric analysis. West Afr J Radiol 2014;21(1):7-11.
Google Scholar |Patil S, Maheshwari S. Proposed new grading on check flexibility. J Clin Exp Dent 2014;6(3):e255-8.
CrossRef | Google Scholar | PubMedRangnathan K, Mishra G. An overview of classification schemes for oral submucous fibrosis. J Oral Maxillofac Pathol 2006;10(2):55-8.
Kumar KK, Saraswathi TR, Rangnathan K, et al. Oral submucous fibrosis: a clinico-histopathological study in Chennai. Indian J Dent Res 2007;18(3):106-11.
CrossRef | Google Scholar | PubMedJaiswal S, Jahan S, Srivastava RK, et al. Cytological grading of oral submucous fibrosis. Era’s Journal of Medical Research 2018;5(2):155-61.
Google Scholar |Krishnapa A. Oral submucous fibrosis. Dent J Malaysia Singapore 1965;7:32-9.
Maher R, Aga P, Johnson NW, et al. Evaluation of multiple micronutrient supplementation in the management of oral submucous fibrosis in Karachi, Pakistan. Nutr Cancer 1997;27(1):41-7.
CrossRef | Google Scholar | PubMedMartin H, Koop EG. Precancerous mouth lesions of avitaminosis B: their aetiology, response to therapy and relationship to intraoral cancer. Am J Surg 1942;57(2):195-9.
Google Scholar |Sirsat SM, Khanolkar VR. Submucous fibrosis of the palate in diet preconditioned wister rats: Induction by local painting of capsaicin, optical and electron microscope study. Arch Pathol 1960;70:171-9.
Google Scholar | PubMedGupta D, Sharma SC. Oral submucous fibrosis--a new treatment regimen. J Oral Maxillofac Surg 1988;46(10):830-3.
CrossRef | Google Scholar | PubMedGupta DS, Gupta M, Oswal RH. Oral submucous fibrosis; clinical study and management by physiofibrolysis. J Indian Dent Assoc 1980;52(1):375-8.
Kapre M, Sudhanshu K. Surgery of trismus in oral submucous fibrosis. 2018. https://www.springer.com/gp/book/9789811048906 (Accessed on 31 August 2020).
Lai DR, Chen HR, Lin LM, et al. Clinical-evaluation of different treatment methods for oral submucous fibrosis-a 10-year experience with 150 cases. J Oral Pathol Med 1995;24(9):402-6.
CrossRef | Google Scholar | PubMedKholakiya Y, Jose A, Rawat A, et al. Surgical management of oral submucous fibrosis with seagull-nasolabial flap combined with short-term oral pentoxifylline for preventing relapse. J Stomatol Oral Maxillofac Surg 2020;121(5):512-6.
CrossRef | Google Scholar | PubMedDISCLOSURE AND FUNDING
Disclosure forms provided by the authors are available with the full text of this article at jemds.com
ICMJE Forms
Financial or other competing interests: None.
Disclosure forms provided by the authors are available with the full text of this article at jemds.com.
COPYRIGHT
Copyright © 2021 Falguni Patel et al. This is an open access article distributed under Creative Commons Attribution License [Attribution 4.0 International (CC BY 4.0)]
How to cite this article
Patel F, Shah SN, James C. Oral submucous fibrosis - a review. J Evolution Med Dent Sci 2021;10(32):2665-2671, DOI: 10.14260/jemds/2021/544