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. 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[6, 7] :
Pan: This is freshly prepared betel quid (with or without tobacco).
Gutka (gutkha, guttkha, or guthka): This is a manufactured version of betel quid with tobacco sold as a single-use sachet. It is primarily used on the Indian subcontinent (ie, India, Pakistan, Bangladesh). Betel quid without tobacco is mostly used in Southeast Asian countries (ie, Taiwan, Myanmar, Thailand, China, Papua New Guinea, Guam).
Pan masala: This is a commercially manufactured powdered version of betel quid without tobacco used in the Indian subcontinent.
Pan Parag: It is a brand name of pan masala and gutka used in India.
Mawa (kharra): This is a crude combination of areca, tobacco, and lime.
Mainpuri tobacco: Popular in parts of northern India, Mainpuri tobacco is a mixture of areca nut, tobacco, lime, and various condiments. Depending on local preferences, sweeteners or spices (ie, cardamom, saffron, clove, anise seed, turmeric, mustard) are also added as flavorings.
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.[8]
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.[9] 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.[10] 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,[11] but their addition to areca nut chewing can be a risk for oral submucous fibrosis.[11] 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.[8]
Arecoline, an active alkaloid found in betel nuts, stimulates fibroblasts to increase production of collagen by 150%.[12] 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.[13]
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.[14, 15, 16] 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.[17]
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.[18] 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.[19]
Flavanoid, catechin, and tannin in betel nuts cause collagen fibers to cross-link, making them less susceptible to collagenase degradation.[20] 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.[21] Chewing areca quid may also activate NF-kappaB expression, thereby stimulating collagen fibroblasts and leading to further fibrosis in persons with oral submucous fibrosis.[22]
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.[23] Further, a significant gradual increase in serum copper levels from precancer to cancer patients has been documented,[24] 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.[25] 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,[26] while another study failed to duplicate these results.[27]
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[9, 28] or chili ingestion.[28] 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.[29, 30] 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.[31] 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.[31]
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.[32]
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.[33]
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.[9] Other studies have suggested that altered expression of retinoic acid receptor-beta may be related to the disease pathogenesis.[34]
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.
International
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.[35]
Mortality/Morbidity
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]
Race
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]
Sex
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.[36] This was later confirmed by others, with a male-to-female ratio of 1:7.[37] 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.[11] In Patna, Bihar (also in India), the male-to-female ratio was 2.7:1.[38] With the onset of new commercial betel quid preparations, trends in sex predominance and age of occurrence may shift.
Age
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.[39] Generally, patient age ranges from 11-60 years[4, 38] ; most patients are aged 45-54 years and chew betel nuts 5 times per day.[4]
Oral submucous fibrosis is clinically divided into 3 stages,[40] and the physical findings vary accordingly, as follows[3, 4, 40] :
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:
Reduction of the mouth opening (trismus)
Stiff and small tongue
Blanched and leathery floor of the mouth
Fibrotic and depigmented gingiva
Rubbery soft palate with decreased mobility
Blanched and atrophic tonsils
Shrunken budlike uvula
Sinking of the cheeks, not commensurate with age or nutritional status
Stage 3: Sequelae of oral submucous fibrosis are as follows:
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.
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:
A neural network–based oral precancer stage detection method has been proposed.[35] 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.[42] 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.[43]
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).
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.
Oral submucous fibrosis is generally characterized by diffuse hyalinization of the subepithelial stroma with pigment incontinence from the overlying epithelial melanin.[44] 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.[29]
Ultrastructural changes in oral submucous fibrosis include an increase in collagen type I; however, fibrils retain the normal structure.[45]
In addition to the above clinical staging, in 1995 Khanna and Andrade[41] developed a group classification system for the surgical management of trismus.
Group I: This is the earliest stage and is not associated with mouth opening limitations. It refers to patients with an interincisal distance of greater than 35 mm.
Group II: This refers to patients with an interincisal distance of 26-35 mm.
Group III: These are moderately advanced cases. This stage refers to patients with an interincisal distance of 15-26 mm. Fibrotic bands are visible at the soft palate, and pterygomandibular raphe and anterior pillars of fauces are present.
Group IVA: Trismus is severe, with an interincisal distance of less than 15 mm and extensive fibrosis of all the oral mucosa.
Group IVB: Disease is most advanced, with premalignant and malignant changes throughout the mucosa.
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 include the following[4] :
Steroids: 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,[46] 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.[47]
Hyaluronidase: 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.[48]
IFN-gamma: 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.[49]
Lycopene: 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.[50]
Pentoxifylline: 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.[51] Further studies are needed, but this could be used in conjunction with other therapies.
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.
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:
Simple excision of the fibrous bands: Excision can result in contracture of the tissue and exacerbation of the condition.
Split-thickness skin grafting following bilateral temporalis myotomy or coronoidectomy: Trismus associated with oral submucous fibrosis may be due to changes in the temporalis tendon secondary to oral submucous fibrosis; therefore, skin grafts may relieve symptoms.[29]
Nasolabial flaps and lingual pedicle flaps: Surgery to create flaps is performed only in patients with oral submucous fibrosis in whom the tongue is not involved.[52]
Use of a KTP-532 laser release procedure was found to increase mouth opening range in 9 patients over a 12-month follow-up period in one study.[53]
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.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications.[54] 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.
Clinical Context:
For various inflammatory diseases. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability.
Clinical Context:
Suppresses immune system by reducing activity and volume of lymphatic system. Treats inflammatory mucosal lesions that are responsive to steroids. Decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and by reversing capillary permeability.
Clinical Context:
For inflammatory reactions responsive to steroids. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and by reversing capillary permeability. Affects production of lymphokines and has inhibitory effect on Langerhans cells.
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.
Clinical Context:
Stimulates hydrolysis of hyaluronic acid, one of the chief ingredients of tissue cement, which offers resistance to diffusion of liquids through tissues. Used to aid in absorption and dispersion of injected drugs.
Clinical Context:
Believed to act via ability to counteract cell surface expression of proinflammatory or proadhesion molecules on immune cells, among other effects. More studies needed to fully understand mechanisms of action.
Naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. Alpha-, beta-, and gamma-interferons may be given topically, systemically, or intralesionally.
Clinical Context:
Considered an antioxidant and has antiproliferative properties in animal and laboratory studies, although activity in humans remains controversial.
Has been found to possess antioxidant and antiproliferative properties in animal and laboratory studies, although activity in humans remains controversial. Adult dose below suggested from 1 study.[50]
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.[55]
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.[56]
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.[57]
No treatment is effective in patients with oral submucous fibrosis, and the condition is irreversible.[58] Reports claim improvement of the condition if the habit is discontinued following diagnosis at an early stage.[47]
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.[58] 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.[21] In vitro, betel nut extracts increase the rate of cell division, reduce cell cycle time, induce DNA strand breaks, and induce unscheduled DNA synthesis.[59] 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.[60, 61]
Nektarios I Lountzis, MD, Consulting Staff, Departments of Dermatology and Pathology, Geisinger Wyoming Valley Medical Center
Disclosure: Nothing to disclose.
Coauthor(s)
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, Abu Dhabi, 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
Alexa F Boer Kimball, MD, MPH, Associate Professor of Dermatology, Harvard University School of Medicine; Vice Chair, Department of Dermatology, Massachusetts General Hospital; Director of Clinical Unit for Research Trials in Skin (CURTIS), Department of Dermatology, Massachusetts General Hospital
Disclosure: Nothing to disclose.
David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic, Northside Clinic
Disclosure: Nothing to disclose.
Drore Eisen, MD, DDS, Consulting Staff, Department of Dermatology, Dermatology Research Associates of Cincinnati
Disclosure: Nothing to disclose.
Joel M Gelfand, MD, MSCE, Medical Director, Clinical Studies Unit, Assistant Professor, Department of Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania
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: Elsevier Royalty Other
References
Schwartz J. Atrophia Idiopathica Mucosae Oris. London: Demonstrated at the 11th Int Dent Congress; 1952.
Joshi SG. Fibrosis of the palate and pillars. Indian J Otolaryngol. 1953;4:1.
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.
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.
International Agency for Research on Cancer. Tobacco habits other than smoking, betel-quid and areca nut chewing, and some related nitrosamines. Lyon, France: International Agency for Research on Cancer; 1984. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans.
