Sunday, December 21, 2008
In 1952, Schwartz coined the term atrophica idiopathica mucosa oris to describe an oral fibrosing disease he discovered in 5 Indian women from Kenya.
Joshi subsequently termed the condition oral submucous fibrosis (OSMF) in 1953.
OSMF 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).
It results in marked rigidity and an eventual inability to open the mouth (Cox, 1996; Aziz, 1997).
The buccal mucosa is the most commonly involved site, but any part of the oral cavity can be involved, even the pharynx (Paissat, 1981).
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) (Cox, 1996).
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.
Freshly prepared betel quid (with or without tobacco) is simply known as pan.
Betel quid with tobacco, known as the manufactured version gutka (alternatively spelled gutkha, guttkha, or guthka), is primarily used in the Indian subcontinent (ie, India, Pakistan, Bangladesh).
Betel quid without tobacco is mostly used in Southeast Asian countries (eg, Taiwan, Myanmar, Thailand, China, Papua New Guinea, Guam).
Pan masala is a commercially manufactured powdered version without tobacco used in the Indian subcontinent.
Mawa is the combination of areca, tobacco, and lime.
Pan Parag is the brand name of a pan masala and gutka used in India. Manipuri tobacco, popular in parts of northern India, is a mixture of areca nut, tobacco, lime, and various condiments.
Depending on local preferences, sweeteners or spices (eg, cardamom, saffron, clove, anise seed, turmeric, mustard) are also added as flavorings (Centers for Disease Control and Prevention, 2006; Gupta, 1996).
In most patients with OSMF, 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) (Aziz, 1997) or had a higher areca nut content (Tilakaratne 2006).
The pathogenesis of the disease is not well established, but the cause of OSMF 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 OSF (Liao, 2001). 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 OSF (Jacob, 2004). Smoking and alcohol consumption alone, habits common to areca nut chewers, have been found to have no effect in the development of OSF (Ariyawardana, 2006; Ranganathan, 2004), but their addition to areca nut chewing can be a risk for OSF (Ranganathan, 2004). Commercially freeze-dried products such as pan masala, guthka, and mawa have higher concentrations of areca nut per chew and appear to cause OSF more rapidly than self-prepared conventional betel quid, which contains smaller amounts of areca nut (Tilakaratne, 2006).
Arecoline, an active alkaloid found in betel nuts, stimulates fibroblasts to increase production of collagen by 150% (Canniff, 1981). 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 OSF (Chung-Hung, 2006).
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 OSF due to areca quid chewing and arecoline may be responsible for their enhanced expression (Tsai, Feb 2005; Tsai, Oct 2005; Tsai, 2004). 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 (Chang, 2001).
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 OSF but not in those with oral squamous cell carcinoma (Tu, 2006). Conversely, insertion/deletion 2G polymorphism in the promoter of the matrix metalloproteinase-1 gene has been implicated in oral squamous cell carcinoma but not OSF (Lin, 2004).
Flavanoid, catechin, and tannin in betel nuts cause collagen fibers to cross-link, making them less susceptible to collagenase degradation (Harvey, 1986). This results in increased fibrosis by causing both increased collagen production and decreased collagen breakdown (Aziz, 1997). OSF remains active even after cessation of the chewing habit, suggesting that components of the areca nut initiate OSF and then affect gene expression in the fibroblasts, which then produce greater amounts of normal collagen (van Wyk, 1993; Meghji, 1987). Chewing areca quid may also activate NF-kappaB expression, thereby stimulating collagen fibroblasts and leading to further fibrosis in persons with OSF (Ni, 2006).
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 OSF by stimulating fibrogenesis through up-regulation of copper-dependent lysyl oxidase activity (Trivedy, 2000). Further, a significant gradual increase in serum copper levels from precancer to cancer patients has been documented (Khanna, 2006), which may have a role in oral fibrosis to cancer pathogenesis.
Ingestion of chilies
The role of chili ingestion in the pathogenesis of OSF is controversial. The incidence of OSF is lower in Mexico and South America than in India, despite the higher dietary intake of chilies (Pillai, 1992). A hypersensitivity reaction to chilies is believed to contribute to OSF (Aziz, 1997). One study demonstrated that the capsaicin in chilies stimulates widespread palatal fibrosis in rats (Sirsat, 1960), while another study failed to duplicate the results (Hamner, 1974).
Genetic and immunologic processes
A genetic component is assumed to be involved in OSF because of reported cases in people without a history of betel nut chewing (Liao, 2001; Seedat, Mar 1988) or chili ingestion (Seedat, Mar 1988). Patients with OSF have been found to have an increased frequency of HLA-A10, HLA-B7, and HLA-DR3 (Aziz, 1997).
An immunologic process is believed to play a role in the pathogenesis of OSF (Canniff, 1985). The increase in CD4 and cells with HLA-DR in OSF 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 OSF tissues suggest an ongoing cellular immune response that results in an imbalance of immunoregulation and an alteration in local tissue architecture (Haque, 1997). These reactions may be the result either of direct stimulation from exogenous antigens, such as areca alkaloids, or of changes in tissue antigenicity that leads to an autoimmune response (Haque, 1997).
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 OSF was significantly higher and suggests a risk for OSF (Liu, 2004).
Some authors have demonstrated increased levels of proinflammatory cytokines and reduced antifibrotic interferon gamma (IFN-gamma) in patients with OSF, which may be central to the pathogenesis of OSF (Haque, 2000).
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 (Aziz, 1997). 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 OSMF, providing some explanation for the increased risk of oral squamous cell carcinoma development in patients with OSMF (Liao, 2001). Other studies have suggested that altered expression of retinoic acid receptor-beta may be related to the disease pathogenesis (Kaur, 2004).
OSMF 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 OSF indicate that 2.5 million people are affected, with most cases concentrated on the Indian subcontinent, especially southern India (Cox, 1996).
The rate varies from 0.2-2.3% in males and 1.2-4.57% in females in Indian communities (Aziz, 1997). OSMF is widely prevalent in all age groups and across all socioeconomic strata in India.
A sharp increase in the incidence of OSMF was noted after pan parag came onto the market, and the incidence continues to increase.
OSMF also occurs in other parts of Asia and the Pacific Islands (Cox, 1996). Migration of endemic betel quid chewers has also made it a public health issue in many parts of the world, including the United Kingdom, South Africa, and many Southeast Asian countries (Paul, 2005).
OSMF has a high rate of morbidity because is causes a progressive inability to open the mouth, resulting in difficulty eating and consequent nutritional deficiencies. OSMF also has a significant mortality rate because of it can transform into oral cancer, particularly squamous cell carcinoma, at a rate of 7.6% (Aziz, 1997).
OSMF 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 (Cox, 1997).
The male-to-female ratio of OSMF 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 (Seedat, Dec 1988). This was later confirmed by others, with a male-to-female ratio of 1:7 (van Wyk, 1997). 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 (Aziz, 1997).
Conversely, a case-control study of 185 subjects in Chennai, South India revealed a male-to-female ratio 9.9:1.0 (Ranganathan, 2004). In Patna, Bihar (also in India), the male-to-female ratio was 2.7:1 (Ahmad, 2006). 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 OSMF 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 16.3 years (± 1.5 y) were found to have OSMF (Oakley, 2005). Generally, patient age ranges from 11-60 years (Ahmad, 2006; Aziz, 1997); most patients are aged 45-54 years and chew betel nuts 5 times per day (Aziz, 1997).
Symptoms of OSMF include the following (Murti, 1992; Cox, 1996):
* Progressive inability to open the mouth (trismus) due to oral fibrosis and scarring
* Oral pain and a burning sensation upon consumption of spicy foodstuffs
* Increased salivation
* Change of gustatory sensation
* Hearing loss due to stenosis of the eustachian tubes
* Dryness of the mouth
* Nasal tonality to the voice
* Dysphagia to solids (if the esophagus is involved)
* Impaired mouth movements (eg, eating, whistling, blowing, sucking)
OSF is clinically divided into 3 stages (Pindborg, 1989), and the physical findings vary accordingly, as follows (Murti, 1992; Cox, 1996; Aziz, 1997; Pindborg, 1989):
* 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.
o Early lesions demonstrate blanching of the oral mucosa.
o 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 OSF are as follows:
o Leukoplakia is precancerous and is found in more than 25% of individuals with OSMF.
o Speech and hearing deficits may occur because of involvement of the tongue and the eustachian tubes.
* In addition to the above staging, in 1995 Khanna and Andrade developed a group classification system for the surgical management of trismus.
o Group I: This is the earliest stage and is not associated with mouth opening limitations. It refers to patients with an inter-incisal distance of greater than 35 mm.
o Group II: This refers to patients with an inter-incisal distance of 26-35 mm.
o Group III: These are moderately advanced cases. This stage refers to patients with an inter-incisal distance of 15-26 mm. Fibrotic bands are visible at the soft palate, and pterygomandibular raphe and anterior pillars of fauces are present.
o Group IVA: Trismus is severe, with an inter-incisal distance of less than 15 mm and extensive fibrosis of all the oral mucosa.
o Group IVB: Disease is most advanced, with premalignant and malignant changes throughout the mucosa.
The term oral submucosal fibrosis derives from oral (meaning mouth), submucosal (meaning below the mucosa of the mouth), and fibrosis (meaning hardening and scarring) (Aziz, 1997). 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 OSMF (Cox, 1996).
Treatment & Medical Care
The treatment of patients with OSMF 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 OSMF present with moderate-to-severe disease.
Moderate-to-severe OSMF is irreversible.
Medical treatment is symptomatic and aimed at improving mouth movements.
Treatment includes the following (Aziz, 1997):
* Steroids: In patients with moderate OSMF, weekly submucosal intralesional injections or topical application of steroids may help prevent further damage.
* Placental extracts: The rationale for using placental extract (PE) in patients with OSF derives from its proposed anti-inflammatory effect (Sur, 2003), hence, preventing or inhibiting mucosal damage. Cessation of areca nut chewing and submucosal administration of aqueous extract of healthy human PE (Placentrex) has shown marked improvement of the condition (Anil, 1993).
* Hyaluronidase: The use of topical hyaluronidase has been shown to improve symptoms more quickly than steroids alone. The combination of steroids and topical hyaluronidase shows better long-term results than either agent used alone (Kakar, 1985).
* IFN-gamma: This plays a role in the treatment of patients with OSF because of its immunoregulatory effect. IFN-gamma is a known antifibrotic cytokine. Patients treated with an intralesional injection of IFN-gamma experienced improvement of symptoms. IFN-gamma, through its effect of altering collagen synthesis, appears to be a key factor to the treatment of patients with OSF, and intralesional injections of the cytokine may have a significant therapeutic effect on OSF (Haque, 2001).
* The role of PEs, hyaluronidase, and interferon is still evolving. The US Food and Drug Administration has not yet approved these drugs for the treatment of OSF.
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 OSF may be due to changes in the temporalis tendon secondary to OSF; therefore, skin grafts may relieve symptoms (Canniff, 1986).
* Nasolabial flaps and lingual pedicle flaps: Surgery to create flaps is performed only in patients with OSF in whom the tongue is not involved (Kavarana, 1987; Hosein, 1994).
* 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 (Cox, 1996).
Muscle stretching exercises for the mouth may be helpful to prevent further limitation of mouth movements.
The goals of pharmacotherapy are to reduce morbidity and to prevent complications. In addition to the medications listed below, PE 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.
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.
For various inflammatory diseases. Decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reducing capillary permeability.
4 mg IV/IM (suggested in studies)
Base dose on severity of disease and response rather than age, body weight, or BSA
Effects decrease with coadministration of barbiturates, phenytoin, and rifampin; decreases effect of salicylates and vaccines used for immunization
Documented hypersensitivity; active bacterial or fungal infection
C - Safety for use during pregnancy has not been established.
Increases risk of multiple complications, including severe infections; monitor adrenal insufficiency when tapering drug; abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression, and infections are possible complications; caution with individuals exposed to viral illnesses, such as chickenpox or measles
Triamcinolone acetonide (Aristocort, Kenaject)
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.
Dental paste (for oral inflammatory or ulcerative lesions): Apply thin film bid/tid pc and hs IM: 40-80 mg (studies have used 10 mg/mL diluted in 1 mL of lidocaine 2% to avoid tissue irritation and facilitate proper distribution of drug)
Coadministration with barbiturates, phenytoin, and rifampin decreases effects; effects of vaccine and toxoid may be reduced
Documented hypersensitivity; fungal, viral, and mycobacterial mucosal infections
C - Safety for use during pregnancy has not been established.
Multiple complications (eg, severe infections, hyperglycemia, edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis, euphoria, psychosis, myasthenia gravis, growth suppression) may occur; abrupt discontinuation may cause adrenal crisis
Betamethasone valerate (Diprosone)
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.
Suggested dose: 0.05% topically q6h for 3 wk
Documented hypersensitivity; paronychia; cellulitis; impetigo; angular cheilitis; erythrasma; erysipelas; rosacea; perioral dermatitis; acne
C - Safety for use during pregnancy has not been established.
Do not use on skin with decreased circulation; can cause atrophy of groin, face, and axillae; may cause striae distensae and rosacealike eruption; may increase skin fragility; rarely may suppress HPA axis; if infection develops and is not responsive to antibiotic treatment, discontinue until infection is under control; do not use monotherapy to treat widespread plaque psoriasis
Can enhance diffusion of locally irritating or toxic drugs in the management of intravenous extravasation.
Hyaluronidase (Wydase Injection)
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.
150 U added to vehicle solution and administered SC/ID
Administer as in adults
Salicylates, cortisone, corticotropin, estrogens, and antihistamines may decrease effects
C - Safety for use during pregnancy has not been established.
Avoid injecting into inflamed or cancerous areas; perform intradermal skin test for sensitivity before initiating infusion; discontinue if sensitivity or extravasation occur
Naturally produced proteins with antiviral, antitumor, and immunomodulatory actions. Alpha-, beta-, and gamma-interferons may be given topically, systemically, or intralesionally.
Interferon gamma (Actimmune)
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.
BSA >0.5 m2: 50 mcg/m2 SC 3 times/wk
BSA <0.5 m2: 1.5 mcg/kg/dose SC 3 times/wk
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