Oral Submucous Fibrosis



In 1952, Schwartz coined the term atrophica idiopathica mucosa oris to describe an oral fibrosing disease he discovered in 5 Indian women from Kenya.[1] Joshi subsequently coined the termed oral submucous fibrosis (OSF) for the condition in 1953.[2]

Oral submucous fibrosis is a chronic debilitating disease of the oral cavity characterized by inflammation and progressive fibrosis of the submucosal tissues (lamina propria and deeper connective tissues). Oral submucous fibrosis results in marked rigidity and an eventual inability to open the mouth.[3, 4] The buccal mucosa is the most commonly involved site, but any part of the oral cavity can be involved, even the pharynx.[5]

The condition is well recognized for its malignant potential and is particularly associated with areca nut chewing, the main component of betel quid.[6] Betel quid chewing is a habit practiced predominately in Southeast Asia and India that dates back for thousands of years. It is similar to tobacco chewing in westernized societies. The mixture of this quid, or chew, is a combination of the areca nut (fruit of the Areca catechu palm tree, erroneously termed betel nut) and betel leaf (from the Piper betel, a pepper shrub), tobacco, slaked lime (calcium hydroxide), and catechu (extract of the Acacia catechu tree).[3] Lime acts to keep the active ingredient in its freebase or alkaline form, enabling it to enter the bloodstream via sublingual absorption. Arecoline, an alkaloid found in the areca nut, promotes salivation, stains saliva red, and is a stimulant.

The ingredients and nomenclature of betel quid vary by region as detailed below[7, 8] :

In most patients with oral submucous fibrosis, areca nut was chewed alone more frequently than it was chewed in combination with pan (ie, betel leaf plus lime plus betel catechu, with or without tobacco)[4] or had a higher areca nut content.[9]


The pathogenesis of the disease is not well established, but the cause of oral submucous fibrosis is believed to be multifactorial. A number of factors trigger the disease process by causing a juxtaepithelial inflammatory reaction in the oral mucosa. Factors include areca nut chewing, ingestion of chilies, genetic and immunologic processes, nutritional deficiencies, and other factors.

Areca nut (betel nut) chewing

The areca nut component of betel quid plays a major role in the pathogenesis of oral submucous fibrosis.[10, 11, 12] In a 2004 study, a clear dose-dependent relationship was observed for both frequency and duration of chewing areca nut (without tobacco) in the development of oral submucous fibrosis.[13] Smoking and alcohol consumption alone, habits common to areca nut chewers, have been found to have no effect in the development of oral submucous fibrosis,[14] but their addition to areca nut chewing can be a risk for oral submucous fibrosis.[14] Commercially freeze-dried products such as pan masala, guthka, and mawa have higher concentrations of areca nut per chew and appear to cause oral submucous fibrosis more rapidly than self-prepared conventional betel quid, which contains smaller amounts of areca nut.[9]

Arecoline, an active alkaloid found in betel nuts, stimulates fibroblasts to increase production of collagen by 150%.[15] In one study, arecoline was found to elevate the mRNA and protein expression of cystatin C, a nonglycosylated basic protein consistently up-regulated in a variety of fibrotic diseases, in a dose-dependent manner in persons with oral submucous fibrosis.[16]

In 3 separate but similar studies, keratinocyte growth factor-1, insulinlike growth factor-1, and interleukin 6 expression, which have all been implicated in tissue fibrogenesis, were also significantly up-regulated in persons with oral submucous fibrosis due to areca quid chewing, and arecoline may be responsible for their enhanced expression.[17, 18, 19] Further studies have shown that arecoline is an inhibitor of metalloproteinases (particularly metalloproteinase-2) and a stimulator of tissue inhibitor of metalloproteinases, thus decreasing the overall breakdown of tissue collagen.[20]

Insertion/deletion 5A polymorphism in the promoter region of the matrix metalloproteinase-3 gene, which results in alteration of transcriptional activities, has also been found in persons with oral submucous fibrosis but not in those with oral squamous cell carcinoma.[21] Conversely, insertion/deletion 2G polymorphism in the promoter of the matrix metalloproteinase-1 gene has been implicated in oral squamous cell carcinoma but not oral submucous fibrosis.[22]

Flavanoid, catechin, and tannin in betel nuts cause collagen fibers to cross-link, making them less susceptible to collagenase degradation.[23] This results in increased fibrosis by causing both increased collagen production and decreased collagen breakdown.[4] Oral submucous fibrosis remains active even after cessation of the chewing habit, suggesting that components of the areca nut initiate oral submucous fibrosis and then affect gene expression in the fibroblasts, which then produce greater amounts of normal collagen.[24] Chewing areca quid may also activate NF-kappaB expression, thereby stimulating collagen fibroblasts and leading to further fibrosis in persons with oral submucous fibrosis.[25]

Areca nuts have also been shown to have a high copper content, and chewing areca nuts for 5-30 minutes significantly increases soluble copper levels in oral fluids. This increased level of soluble copper supports the hypothesis that copper acts as an initiating factor in persons with oral submucous fibrosis by stimulating fibrogenesis through up-regulation of copper-dependent lysyl oxidase activity.[26, 27] Further, a significant gradual increase in serum copper levels from precancer to cancer patients has been documented,[28] which may have a role in oral fibrosis to cancer pathogenesis.

Ingestion of chilies

The role of chili ingestion in the pathogenesis of oral submucous fibrosis is controversial. The incidence of oral submucous fibrosis is lower in Mexico and South America than in India, despite the higher dietary intake of chilies.[29] A hypersensitivity reaction to chilies is believed to contribute to oral submucous fibrosis.[4] One study demonstrated that the capsaicin in chilies stimulates widespread palatal fibrosis in rats,[30] while another study failed to duplicate these results.[31]

Genetic and immunologic processes

A genetic component is assumed to be involved in oral submucous fibrosis because of the existence of reported cases in people without a history of betel nut chewing[10, 32] or chili ingestion.[32] Patients with oral submucous fibrosis have been found to have an increased frequency of HLA-A10, HLA-B7, and HLA-DR3.[4]

An immunologic process is believed to play a role in the pathogenesis of oral submucous fibrosis.[33, 34] The increase in CD4 and cells with HLA-DR in oral submucous fibrosis tissues suggests that most lymphocytes are activated and that the number of Langerhans cells is increased. The presence of these immunocompetent cells and the high ratio of CD4 to CD8 in oral submucous fibrosis tissues suggest an ongoing cellular immune response that results in an imbalance of immunoregulation and an alteration in local tissue architecture.[35] These reactions may be the result either of direct stimulation from exogenous antigens, such as areca alkaloids, or of changes in tissue antigenicity that lead to an autoimmune response.[35]

Further, the major histocompatibility complex class I chain–related gene A (MICA) is expressed by keratinocytes and other epithelial cells and interacts with gamma/delta T cells localized in the submucosa. MICA has a triplet repeat (GCT) polymorphism in the transmembrane domain, resulting in 5 distinct allelic patterns. In particular, the phenotype frequency of allele A6 of MICA in subjects with oral submucous fibrosis is significantly higher and suggests a risk for oral submucous fibrosis.[36]

Some authors have demonstrated increased levels of proinflammatory cytokines and reduced antifibrotic interferon gamma (IFN-gamma) in patients with oral submucous fibrosis, which may be central to the pathogenesis of oral submucous fibrosis.[37]

Nutritional deficiencies

Iron deficiency anemia, vitamin B complex deficiency, and malnutrition are promoting factors that derange the repair of the inflamed oral mucosa, leading to defective healing and resultant scarring.[4] The resulting atrophic oral mucosa is more susceptible to the effects of chilies and betel nuts.

Other significant factors

Some authors have found a high frequency of mutations in the APC gene and low expression of the wild-type TP53 tumor suppressor gene product in patients with oral submucous fibrosis, providing some explanation for the increased risk of oral squamous cell carcinoma development in patients with oral submucous fibrosis.[10] Other studies have suggested that altered expression of retinoic acid receptor-beta may be related to the disease pathogenesis.[38]



United States

Oral submucous fibrosis is rare in the United States and is found only in the immigrant members of the South Asian population who chew betel nuts.


Worldwide, estimates of oral submucous fibrosis indicate that 2.5 million people are affected, with most cases concentrated on the Indian subcontinent, especially southern India.[3] The rate varies from 0.2-2.3% in males and 1.2-4.57% in females in Indian communities.[4] Oral submucous fibrosis is widely prevalent in all age groups and across all socioeconomic strata in India. A sharp increase in the incidence of oral submucous fibrosis was noted after pan parag came onto the market, and the incidence continues to increase. Oral submucous fibrosis also occurs in other parts of Asia and the Pacific Islands.[3] Migration of endemic betel quid chewers has also made oral submucous fibrosis a public health issue in many parts of the world, including the United Kingdom, South Africa, and many Southeast Asian countries.[39]


Oral submucous fibrosis occurs on the Indian subcontinent, in Indian immigrants to other countries, and among Asians and Pacific Islanders as a result of the traditional use of betel quid endemic to these areas.[3]


The male-to-female ratio of oral submucous fibrosis varies by region, but females tend to predominate. In a study from Durban, South Africa, a distinct female predominance was demonstrated, with a male-to-female ratio of 1:13.[40] This was later confirmed by others, with a male-to-female ratio of 1:7.[41] In addition, a female predominance in areca nut chewing was also noted in this region. Studies in Pakistan reported a male-to-female ratio of 1:2.3.[4]

Conversely, a case-control study of 185 subjects in Chennai, South India revealed a male-to-female ratio 9.9:1.[14] In Patna, Bihar (also in India), the male-to-female ratio was 2.7:1.[42] With the onset of new commercial betel quid preparations, trends in sex predominance and age of occurrence may shift.


The age range of patients with oral submucous fibrosis is wide and regional; it is even prevalent among teenagers in India. In a study performed in Saipan, 8.8% of teenagers with a mean age of 16.3 years (± 1.5 y) were found to have oral submucous fibrosis.[43] Generally, patient age ranges from 11-60 years[4, 42] ; most patients are aged 45-54 years and chew betel nuts 5 times per day.[4]


Oral submucous fibrosis has a high rate of morbidity because is causes a progressive inability to open the mouth, resulting in difficulty eating and consequent nutritional deficiencies. Oral submucous fibrosis also has a significant mortality rate because of it can transform into oral cancer, particularly squamous cell carcinoma, at a rate of 7.6%.[4]

No treatment is effective in patients with oral submucous fibrosis, and the condition is irreversible.[44] Reports claim improvement of the condition if the habit is discontinued following diagnosis at an early stage.[45]

Patients with oral submucous fibrosis have an increased risk of developing oral cancer. The malignant potential and the origin of cancer are attributed to the generalized epithelial atrophy associated with oral submucous fibrosis.[44] Tobacco is the component of the quid believed to be most associated with cancer development. However, the carcinogenic property of the areca nut was discovered after noticing that cancer occurred in patients who chewed the nut without tobacco.[24] In vitro, betel nut extracts increase the rate of cell division, reduce cell cycle time, induce DNA strand breaks, and induce unscheduled DNA synthesis.[46] Whether the use of tobacco in addition to areca nuts is responsible for the increased risk of oral cancer is controversial because evidence is conflicting.[47, 48]

Patient Education

Instruct patients regarding the importance of discontinuing the habit of chewing betel quid.

Inform patients that eliminating tobacco from the quid product may reduce the risk of oral cancer.

Instruct patients to avoid spicy foodstuffs.

Instruct patients to eat a complete and healthy diet to avoid malnutrition.

Instruct patients regarding maintaining proper oral hygiene and scheduling regular oral examinations.

Intervention studies and public health campaigns against oral habits linked to oral submucous fibrosis may be the best way of controlling the disease at the community level. Educate the community regarding the local adverse effects of chewable agents, which although not inhaled, are still not harmless.

For patient education resources, visit the Cancer Center. In addition, see the patient education article Cancer of the Mouth and Throat.


Symptoms of oral submucous fibrosis include the following[3] :

Physical Examination

Oral submucous fibrosis is clinically divided into three stages,[49] and the physical findings vary accordingly.[3, 4, 49]

Stage 1

Stomatitis includes erythematous mucosa, vesicles, mucosal ulcers, melanotic mucosal pigmentation, and mucosal petechia.

Stage 2

Fibrosis occurs in ruptured vesicles and ulcers when they heal, which is the hallmark of this stage. Early lesions demonstrate blanching of the 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, marblelike appearance of the mucosa because of the vertical, thick, fibrous bands running in a blanching mucosa. Specific findings include the following:

Stage 3

Leukoplakia is precancerous and is found in more than 25% of individuals with oral submucous fibrosis.

Speech and hearing deficits may occur because of involvement of the tongue and the eustachian tubes.


The term oral submucosal fibrosis derives from oral (meaning mouth), submucosal (meaning below the mucosa of the mouth), and fibrosis (meaning hardening and scarring).[4] Chewable agents, primarily betel nuts (Areca catechu), contain substances that irritate the oral mucosa, making it lose its elasticity. Nutritional deficiencies, ingestion of chilies, and immunologic processes may also have a role in the development of oral submucous fibrosis.[3] See Pathophysiology.


Oral dysplasias and squamous cell carcinomas are complications of oral submucous fibrosis. In patients with oral submucous fibrosis, the risk of developing oral carcinoma is 7.6% over a 10-year period.[3]

If the palatal and paratubal muscles are involved in patients with oral submucous fibrosis, conductive hearing loss may occur because of functional stenosis of the eustachian tube.[50]

Patients with oral submucous fibrosis who require anesthesia for trismus correction, resection, and reconstructive (oncoplastic) surgery may have difficulty during laryngoscopy and intubation of the trachea.[51]

Laboratory Studies

No specific laboratory tests are available for oral submucous fibrosis, and abnormalities may be related to secondary nutritional deficiencies. Some oral submucous fibrosis studies have reported the following laboratory findings:

Other Tests

Cytologic smears may be performed.

A neural network–based oral precancer stage detection method has been proposed.[39] This new technique uses wavelet coefficients from transmission electron micrography images of subepithelial fibrillar collagen in healthy oral submucosa and in oral submucous fibrosis tissues. These wavelet coefficients are used to choose the feature vector, which, in turn, can be used to train an artificial neural network. This trained network is able to classify normal and oral precancer stages (less advanced and advanced) after obtaining the image as an input. This technology is not readily available but could theoretically be used as an adjunct to hematoxylin and eosin histologic evaluations.


Currently, oral biopsy for hematoxylin and eosin provides the most definitive diagnosis and is crucial because of the association of oral submucous fibrosis with oral cancer.[4]

Some authorities have reported benefit with immunohistochemical techniques such as Masson trichrome staining when pathology involved muscle.[53] Alteration of cytokeratin expression, as is seen in leukoplakia and oral cancer, has also been noted in oral submucous fibrosis. Increased intensity of staining for pancytokeratin and high molecular weight cytokeratin, aberrant expression of cytokeratin 8, and decreased expression of cytokeratins 5 and 14 suggest their potential as surrogate markers for malignant transformation.[54]

Histologic Findings

Histologic findings vary according to the stage of the disease.

Very early stage

Fine fibrillar collagen, marked edema, large fibroblasts, dilated and congested blood vessels, and inflammatory infiltrates (primarily polymorphonuclear leukocytes and eosinophils) are found.

Early stage

Early hyalinization is characterized by thickened collagen bundles, moderate numbers of fibroblasts, and inflammatory cells (primarily lymphocytes, eosinophils, and plasma cells).[55]

Moderately advanced and advanced stages

Dense bundles and sheets of collagen, thick bands of subepithelial hyalinization extending into the submucosal tissues (replacing fat or fibrovascular tissue), decreased vascularity, no edema, and inflammatory cells (lymphocytes and plasma cells) are found.[55]

Oral submucous fibrosis is generally characterized by diffuse hyalinization of the subepithelial stroma with pigment incontinence from the overlying epithelial melanin.[56] Other histologic findings include an atrophic epithelium and intercellular edema, with or without hyperkeratosis, parakeratosis, or orthokeratosis; epithelial dysplasia (25% of patients who underwent biopsy); squamous cell carcinoma histologically identical to typical squamous cell carcinomas; chronic inflammation and fibrosis in the minor salivary glands in the area of quid placement; and atrophy of the underlying muscle.[33]

Ultrastructural changes in oral submucous fibrosis include an increase in collagen type I; however, fibrils retain the normal structure.[57]


In addition to the above clinical staging, in 1995 Khanna and Andrade[52] developed the following group classification system for the surgical management of trismus:

Medical Care

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. Moderate-to-severe oral submucous fibrosis is irreversible. Medical treatment is symptomatic and predominantly aimed at improving mouth movements. Treatment strategies are described below.[4]  The role of these treatments is still evolving. The US Food and Drug Administration has not yet approved these drugs for the treatment of oral submucous fibrosis.


In patients with moderate oral submucous fibrosis, weekly submucosal intralesional injections or topical application of steroids may help prevent further damage.

Placental extracts

The rationale for using placental extract in patients with oral submucous fibrosis derives from its proposed anti-inflammatory effect,[58] 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.[45]


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.[59]


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.[60]


Newer studies highlight the benefit of this oral nutritional supplement at a daily dose of 16 mg. Mouth opening in 2 treatment arms (40 patients total) was statistically improved in patients with oral submucous fibrosis. This effect was slightly enhanced with the injection of intralesional betamethasone (two 1-mL ampules of 4 mg each) twice weekly, but the onset of effect was slightly delayed.[61]


In a pilot study, 14 test subjects with advanced oral submucous fibrosis given pentoxifylline at 400 mg 3 times daily were compared to 15 age- and sex-matched diseased control subjects. Statistical improvement was noted in all measures of objective (mouth opening, tongue protrusion, and relief from fibrotic bands) and subjective (intolerance to spices, burning sensation of mouth, tinnitus, difficulty in swallowing, and difficulty in speech) symptoms over a 7-month period.[62] Further studies are needed, but this could be used in conjunction with other therapies.

Surgical Care

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:


Consult an ear, nose, and throat specialist for evaluation of dysplasia and close follow-up monitoring for the development of oral cancer.

Consult a plastic surgeon for patients with severe trismus, in whom reconstructive surgery may be possible.


Dietary focus should be on reducing exposure to the risk factors, especially the use of betel quid, and correcting any nutritional deficiencies, such as iron and vitamin B complex deficiencies.[3]


Physical therapy using muscle-stretching exercises for the mouth may be helpful in preventing further limitation of mouth movements. This is often combined with medical and surgical therapy.[66]

Long-Term Monitoring

Regular physical examinations, biopsy specimen analysis, and cytologic smear testing should be scheduled to detect oral dysplasia or carcinoma, especially in patients with severe oral submucous fibrosis.

Patients with surface leukoplakias require close follow-up monitoring and repeat biopsies.

Patients with dysplasias and carcinomas should receive routine treatment for these entities.[67]

Watch for signs that indicate malignant change, which include the following:

Medication Summary

The goals of pharmacotherapy are to reduce morbidity and to prevent complications.[68] In addition to the medications listed below, placental extract has been used experimentally at a dose of 50 mcg/m2 SC 3 times per week if the patient's body surface area (BSA) is greater than 0.52 m2 or 1.5 mcg/kg/dose SC 3 times per week if the BSA is less than or equal to 0.5 m2.[69]  The adult dose below for lycopene is suggested from one study.[61]  The adult dosage for pentoxifylline is suggested by Rajendran et al.[62]

Dexamethasone (Decadron)

Clinical Context:  Dexamethasone is used for various inflammatory diseases. It decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reducing capillary permeability.

Triamcinolone (Aristospan, Kenalog IV, Trivaris)

Clinical Context:  Triamcinolone suppresses the immune system by reducing the activity and volume of the lymphatic system. It treats inflammatory mucosal lesions that are responsive to steroids. It decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and by reversing capillary permeability.

Betamethasone valerate (Diprosone)

Clinical Context:  Betamethasone valerate is for inflammatory reactions responsive to steroids. It decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and by reversing capillary permeability. It affects the production of lymphokines and has an inhibitory effect on Langerhans cells.

Class Summary

These can be used in pharmacologic doses for their anti-inflammatory and immunosuppressant properties and their effects on blood and lymphatic systems in the palliative treatment of various diseases.

Hyaluronidase (Wydase Injection)

Clinical Context:  Hyaluronidase stimulates hydrolysis of hyaluronic acid, one of the chief ingredients of tissue cement, which offers resistance to the diffusion of liquids through tissues. It is used to aid in the absorption and dispersion of injected drugs.

Class Summary

Extravasation antidotes can enhance the diffusion of locally irritating or toxic drugs in the management of intravenous extravasation.

Interferon gamma (Actimmune)

Clinical Context:  Interferon gamma is believed to act via the ability to counteract cell surface expression of proinflammatory or proadhesion molecules on immune cells, among other effects. More studies are needed to fully understand its mechanisms of action.

Class Summary

Interferons are naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. Alpha-, beta-, and gamma-interferons may be given topically, systemically, or intralesionally.

Lycopene (LycoRed)

Clinical Context:  Lycopene is considered an antioxidant and has antiproliferative properties in animal and laboratory studies, although activity in humans remains controversial.

Class Summary

These have been found to possess antioxidant and antiproliferative properties in animal and laboratory studies, although activity in humans remains controversial. The adult dose below is suggested from one study.

Pentoxifylline (Trental)

Clinical Context:  Pentoxifylline is a methylxanthine derivative that has vasodilating properties and may increase mucosal vascularity.

Class Summary

These are methylxanthine derivatives that have vasodilating properties and may increase mucosal vascularity. The adult dosage is suggested by Rajendran et al.


Nektarios I Lountzis, MD, Consulting Staff, Advanced Dermatology Associates, Ltd, Lehigh Valley Health Network

Disclosure: Nothing to disclose.


Amy Howard, MD, Fellow, Department of Dermatopathology, Emory University

Disclosure: Nothing to disclose.

Nada Macaron, MD, Consultant Pathologist, Institute of Pathology and Laboratory Medicine, Sheikh Khalifa Medical city, UAE

Disclosure: Nothing to disclose.

Tammie Ferringer, MD, Dermatopathology Section Head, Dermatopathology Fellowship Director, Departments of Dermatology and Pathology, Geisinger Medical Center

Disclosure: Nothing to disclose.

Specialty Editors

David F Butler, MD, Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

Disclosure: Nothing to disclose.

Drore Eisen, MD, DDS, Consulting Staff, Dermatology of Southwest Ohio

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD, Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Naked Biome<br/>Received income in an amount equal to or greater than $250 from: Elsevier; WebMD<br/>StatPearls; Editor.


  1. Schwartz J. Atrophia Idiopathica Mucosae Oris. London: Demonstrated at the 11th Int Dent Congress; 1952.
  2. Joshi SG. Fibrosis of the palate and pillars. Indian J Otolaryngol. 1953. 4:1:
  3. Cox SC, Walker DM. Oral submucous fibrosis. A review. Aust Dent J. 1996 Oct. 41(5):294-9. [View Abstract]
  4. Aziz SR. Oral submucous fibrosis: an unusual disease. J N J Dent Assoc. 1997 Spring. 68(2):17-9. [View Abstract]
  5. Paissat DK. Oral submucous fibrosis. Int J Oral Surg. 1981 Oct. 10(5):307-12. [View Abstract]
  6. Chattopadhyay A, Ray JG. Molecular Pathology of Malignant Transformation of Oral Submucous Fibrosis. J Environ Pathol Toxicol Oncol. 2016. 35 (3):193-205. [View Abstract]
  7. Centers for Disease Control and Prevention. Fact Sheet. Betel Quid with Tobacco (Gutka). Centers for Disease Control and Prevention. Available at http://www.cdc.gov/tobacco/data_statistics/fact_sheets/smokeless/betel_quid.htm. Accessed: February 2007.
  8. Gupta PC. UICC Tobacco Control Fact Sheet No. 17: Areca Nut. International Union Against Cancer. Available at http://www.globalink.org/tobacco/fact_sheets/17fact.htm. Accessed: February 1996.
  9. Tilakaratne WM, Klinikowski MF, Saku T, Peters TJ, Warnakulasuriya S. Oral submucous fibrosis: review on aetiology and pathogenesis. Oral Oncol. 2006 Jul. 42(6):561-8. [View Abstract]
  10. Liao PH, Lee TL, Yang LC, Yang SH, Chen SL, Chou MY. Adenomatous polyposis coli gene mutation and decreased wild-type p53 protein expression in oral submucous fibrosis: a preliminary investigation. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2001 Aug. 92(2):202-7. [View Abstract]
  11. Chang MC, Chen YJ, Chang HH, Chan CP, Yeh CY, Wang YL, et al. Areca Nut Components Affect COX-2, Cyclin B1/cdc25C and Keratin Expression, PGE2 Production in Keratinocyte Is Related to Reactive Oxygen Species, CYP1A1, Src, EGFR and Ras Signaling. PLoS One. 2014. 9(7):e101959. [View Abstract]
  12. Pant I, Rao SG, Kondaiah P. Role of areca nut induced JNK/ATF2/Jun axis in the activation of TGF-β pathway in precancerous Oral Submucous Fibrosis. Sci Rep. 2016 Oct 6. 6:34314. [View Abstract]
  13. Jacob BJ, Straif K, Thomas G, et al. Betel quid without tobacco as a risk factor for oral precancers. Oral Oncol. 2004 Aug. 40(7):697-704. [View Abstract]
  14. Ranganathan K, Devi MU, Joshua E, Kirankumar K, Saraswathi TR. Oral submucous fibrosis: a case-control study in Chennai, South India. J Oral Pathol Med. 2004 May. 33(5):274-7. [View Abstract]
  15. Canniff JP, Harvey W. The aetiology of oral submucous fibrosis: the stimulation of collagen synthesis by extracts of areca nut. Int J Oral Surg. 1981. 10:163-7. [View Abstract]
  16. Chung-Hung T, Shun-Fa Y, Yu-Chao C. The upregulation of cystatin C in oral submucous fibrosis. Oral Oncol. 2007 Aug. 43(7):680-5. [View Abstract]
  17. Tsai CH, Yang SF, Chen YJ, Chou MY, Chang YC. Raised keratinocyte growth factor-1 expression in oral submucous fibrosis in vivo and upregulated by arecoline in human buccal mucosal fibroblasts in vitro. J Oral Pathol Med. 2005 Feb. 34(2):100-5. [View Abstract]
  18. Tsai CH, Yang SF, Chen YJ, Chu SC, Hsieh YS, Chang YC. Regulation of interleukin-6 expression by arecoline in human buccal mucosal fibroblasts is related to intracellular glutathione levels. Oral Dis. 2004 Nov. 10(6):360-4. [View Abstract]
  19. Tsai CH, Yang SF, Chen YJ, Chou MY, Chang YC. The upregulation of insulin-like growth factor-1 in oral submucous fibrosis. Oral Oncol. 2005 Oct. 41(9):940-6. [View Abstract]
  20. Chang YC, Yang SF, Tai KW, Chou MY, Hsieh YS. Increased tissue inhibitor of metalloproteinase-1 expression and inhibition of gelatinase A activity in buccal mucosal fibroblasts by arecoline as possible mechanisms for oral submucous fibrosis. Oral Oncol. 2002 Feb. 38(2):195-200. [View Abstract]
  21. Tu HF, Liu CJ, Chang CS, et al. The functional (-1171 5A-->6A) polymorphisms of matrix metalloproteinase 3 gene as a risk factor for oral submucous fibrosis among male areca users. J Oral Pathol Med. 2006 Feb. 35(2):99-103. [View Abstract]
  22. Lin SC, Chung MY, Huang JW, Shieh TM, Liu CJ, Chang KW. Correlation between functional genotypes in the matrix metalloproteinases-1 promoter and risk of oral squamous cell carcinomas. J Oral Pathol Med. 2004 Jul. 33(6):323-6. [View Abstract]
  23. Harvey W, Scutt A, Meghji S, Canniff JP. Stimulation of human buccal mucosa fibroblasts in vitro by betel-nut alkaloids. Arch Oral Biol. 1986. 31(1):45-9. [View Abstract]
  24. van Wyk CW, Stander I, Padayachee A, Grobler-Rabie AF. The areca nut chewing habit and oral squamous cell carcinoma in South African Indians. A retrospective study. S Afr Med J. 1993 Jun. 83(6):425-9. [View Abstract]
  25. Ni WF, Tsai CH, Yang SF, Chang YC. Elevated expression of NF-kappaB in oral submucous fibrosis--evidence for NF-kappaB induction by safrole in human buccal mucosal fibroblasts. Oral Oncol. 2007 Jul. 43(6):557-62. [View Abstract]
  26. Trivedy CR, Warnakulasuriya KA, Peters TJ, Senkus R, Hazarey VK, Johnson NW. Raised tissue copper levels in oral submucous fibrosis. J Oral Pathol Med. 2000 Jul. 29(6):241-8. [View Abstract]
  27. Mohammed F, Manohar V, Jose M, Fairozekhan Thapasum A, Mohamed S, Halima Shamaz B, et al. Estimation of copper in saliva and areca nut products and its correlation with histological grades of oral submucous fibrosis. J Oral Pathol Med. 2014 Jul 22. [View Abstract]
  28. Khanna SS, Karjodkar FR. Circulating immune complexes and trace elements (Copper, Iron and Selenium) as markers in oral precancer and cancer : a randomised, controlled clinical trial. Head Face Med. 2006 Oct 16. 2:33. [View Abstract]
  29. Pillai R, Balaram P, Reddiar KS. Pathogenesis of oral submucous fibrosis. Relationship to risk factors associated with oral cancer. Cancer. 1992 Apr 15. 69(8):2011-20. [View Abstract]
  30. Sirsat SM, Khanolkar VR. Submucous fibrosis of the palate in diet-preconditioned Wistar rats. Induction by local painting of capsaicin--an optical and electron microscopic study. Arch Pathol. 1960 Aug. 70:171-9. [View Abstract]
  31. Hamner JE 3rd, Looney PD, Chused TM. Submucous fibrosis. Oral Surg Oral Med Oral Pathol. 1974 Mar. 37(3):412-21. [View Abstract]
  32. Seedat HA, van Wyk CW. Submucous fibrosis in non-betel nut chewing subjects. J Biol Buccale. 1988 Mar. 16(1):3-6. [View Abstract]
  33. Canniff JP, Harvey W, Harris M. Oral submucous fibrosis: its pathogenesis and management. Br Dent J. 1986 Jun 21. 160(12):429-34. [View Abstract]
  34. Rajendran R, Deepthi K, Nooh N, Anil S. a4ß1 integrin-dependent cell sorting dictates T-cell recruitment in oral submucous fibrosis. J Oral Maxillofac Pathol. 2011 Sep. 15(3):272-7. [View Abstract]
  35. Haque MF, Harris M, Meghji S, Speight PM. An immunohistochemical study of oral submucous fibrosis. J Oral Pathol Med. 1997 Feb. 26(2):75-82. [View Abstract]
  36. Liu CJ, Lee YJ, Chang KW, Shih YN, Liu HF, Dang CW. Polymorphism of the MICA gene and risk for oral submucous fibrosis. J Oral Pathol Med. 2004 Jan. 33(1):1-6. [View Abstract]
  37. Haque MF, Meghji S, Khitab U, Harris M. Oral submucous fibrosis patients have altered levels of cytokine production. J Oral Pathol Med. 2000 Mar. 29(3):123-8. [View Abstract]
  38. Kaur J, Chakravarti N, Mathur M, Srivastava A, Ralhan R. Alterations in expression of retinoid receptor beta and p53 in oral submucous fibrosis. Oral Dis. 2004 Jul. 10(4):201-6. [View Abstract]
  39. Paul RR, Mukherjee A, Dutta PK, et al. A novel wavelet neural network based pathological stage detection technique for an oral precancerous condition. J Clin Pathol. 2005 Sep. 58(9):932-8. [View Abstract]
  40. Seedat HA, van Wyk CW. Betel-nut chewing and submucous fibrosis in Durban. S Afr Med J. 1988 Dec 3. 74(11):568-71. [View Abstract]
  41. VanWyk CW. Oral submucous fibrosis. The South African experience. Indian J Dent Res. 1997 Apr-Jun. 8(2):39-45. [View Abstract]
  42. Ahmad MS, Ali SA, Ali AS, Chaubey KK. Epidemiological and etiological study of oral submucous fibrosis among gutkha chewers of Patna, Bihar, India. J Indian Soc Pedod Prev Dent. 2006 Jun. 24(2):84-9. [View Abstract]
  43. Oakley E, Demaine L, Warnakulasuriya S. Areca (betel) nut chewing habit among high-school children in the Commonwealth of the Northern Mariana Islands (Micronesia). Bull World Health Organ. 2005 Sep. 83(9):656-60. [View Abstract]
  44. Murti PR, Bhonsle RB, Pindborg JJ, Daftary DK, Gupta PC, Mehta FS. Malignant transformation rate in oral submucous fibrosis over a 17-year period. Community Dent Oral Epidemiol. 1985 Dec. 13(6):340-1. [View Abstract]
  45. Anil S, Beena VT. Oral submucous fibrosis in a 12-year-old girl: case report. Pediatr Dent. 1993 Mar-Apr. 15(2):120-2. [View Abstract]
  46. Jeng JH, Kuo ML, Hahn LJ, Kuo MY. Genotoxic and non-genotoxic effects of betel quid ingredients on oral mucosal fibroblasts in vitro. J Dent Res. 1994 May. 73(5):1043-9. [View Abstract]
  47. Maher R, Lee AJ, Warnakulasuriya KA, Lewis JA, Johnson NW. Role of areca nut in the causation of oral submucous fibrosis: a case-control study in Pakistan. J Oral Pathol Med. 1994 Feb. 23(2):65-9. [View Abstract]
  48. Mehrotra D, Agarwal GG, Kumar S, Shukla A, Asthana A. Development and Validation of a Questionnaire to Evaluate Association of Tobacco Abuse With Oral Submucous Fibrosis. Asia Pac J Public Health. 2011 Dec 22. [View Abstract]
  49. Pindborg JJ. Oral submucous fibrosis: a review. Ann Acad Med Singapore. 1989 Sep. 18(5):603-7. [View Abstract]
  50. Gupta SC, Khanna S, Singh M, Singh PA. Histological changes to palatal and paratubal muscles in oral submucous fibrosis. J Laryngol Otol. 2000 Dec. 114(12):947-50. [View Abstract]
  51. Eipe N. The chewing of betel quid and oral submucous fibrosis and anesthesia. Anesth Analg. 2005 Apr. 100(4):1210-3. [View Abstract]
  52. Ahmed A, Amjad M. Localized morphoea associated with oral submucous fibrosis. J Coll Physicians Surg Pak. 2006 Feb. 16(2):141-2. [View Abstract]
  53. Rooban T, Saraswathi TR, Al Zainab FH, Devi U, Eligabeth J, Ranganathan K. A light microscopic study of fibrosis involving muscle in oral submucous fibrosis. Indian J Dent Res. 2005 Oct-Dec. 16(4):131-4. [View Abstract]
  54. Ranganathan K, Kavitha R, Sawant SS, Vaidya MM. Cytokeratin expression in oral submucous fibrosis--an immunohistochemical study. J Oral Pathol Med. 2006 Jan. 35(1):25-32. [View Abstract]
  55. Kadani M, B N V S S, B M, K M P, Hugar D, Allad U, et al. Evaluation of plasma fibrinogen degradation products and total serum protein concentration in oral submucous fibrosis. J Clin Diagn Res. 2014 May. 8(5):ZC54-7. [View Abstract]
  56. Pindborg JJ. Oral precancer. Barnes L, ed. Surgical Pathology of the Head and Neck. New York, NY: Marcel Dekker; 1995. 279-331.
  57. van Wyk CW, Seedat HA, Phillips VM. Collagen in submucous fibrosis: an electron-microscopic study. J Oral Pathol Med. 1990 Apr. 19(4):182-7. [View Abstract]
  58. Sur TK, Biswas TK, Ali L, Mukherjee B. Anti-inflammatory and anti-platelet aggregation activity of human placental extract. Acta Pharmacol Sin. 2003 Feb. 24(2):187-92. [View Abstract]
  59. Kakar PK, Puri RK, Venkatachalam VP. Oral submucous fibrosis--treatment with hyalase. J Laryngol Otol. 1985 Jan. 99(1):57-9. [View Abstract]
  60. Haque MF, Meghji S, Nazir R, Harris M. Interferon gamma (IFN-gamma) may reverse oral submucous fibrosis. J Oral Pathol Med. 2001 Jan. 30(1):12-21. [View Abstract]
  61. Kumar A, Bagewadi A, Keluskar V, Singh M. Efficacy of lycopene in the management of oral submucous fibrosis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2007 Feb. 103(2):207-13. [View Abstract]
  62. Rajendran R, Rani V, Shaikh S. Pentoxifylline therapy: a new adjunct in the treatment of oral submucous fibrosis. Indian J Dent Res. 2006 Oct-Dec. 17(4):190-8. [View Abstract]
  63. Hosein M. Oral cancer in Pakistan. The problem and can we reduce it?. Oral Oncology. Kluwer Academic: 1994.
  64. Nayak DR, Mahesh SG, Aggarwal D, Pavithran P, Pujary K, Pillai S. Role of KTP-532 laser in management of oral submucous fibrosis. J Laryngol Otol. 2008 Oct 10. 1-4. [View Abstract]
  65. Chaudhry Z, Gupta SR, Oberoi SS. The Efficacy of ErCr:YSGG Laser Fibrotomy in Management of Moderate Oral Submucous Fibrosis: A Preliminary Study. J Maxillofac Oral Surg. 2014 Sep. 13(3):286-94. [View Abstract]
  66. Kale S, Srivastava N, Bagga V, Shetty A. Effectiveness of Long Term Supervised and Assisted Physiotherapy in Postsurgery Oral Submucous Fibrosis Patients. Case Rep Dent. 2016. 2016:6081905. [View Abstract]
  67. Borle RM, Borle SR. Management of oral submucous fibrosis: a conservative approach. J Oral Maxillofac Surg. 1991 Aug. 49(8):788-91. [View Abstract]
  68. Chole RH, Gondivkar SM, Gadbail AR, Balsaraf S, Chaudhary S, Dhore SV, et al. Review of drug treatment of oral submucous fibrosis. Oral Oncol. 2011 Dec 27. [View Abstract]
  69. Shah PH, Venkatesh R, More CB, Vassandacoumara V. Comparison of Therapeutic Efficacy of Placental Extract with Dexamethasone and Hyaluronic Acid with Dexamethasone for Oral Submucous Fibrosis - A Retrospective Analysis. J Clin Diagn Res. 2016 Oct. 10 (10):ZC63-ZC66. [View Abstract]