CHATURVEDI : ORAL SUBMUCOUS FIBROSIS

20 Pigott lD, Kouchoukos NT, Oberman A, Cutter GR. Late resultsof surgical and medical therapy for patients with coronary arterydisease and depressed left ventricular function. ] Am Coil Cardiol1985;5:1036-45.

21 Pamelia FX, Gibson RS, Watson DD, Croddock GB, Sirowatka 1,Beller GA. Prognosis with chest pain and normal thallium-201 exer-cise scintigrams. Am] CardioI1985;35:920--6.

22 Wahl 1M, Hakki AH, Iskandrian AS. Prognostic implications ofnormal exercise thallium-201 images. Arch Intern Med1985;145:253-6.

23 Brown KA, Boucher CA, Okada RD, et al. Prognostic value ofexercise thallium-201 imaging in patients presenting for evaluationof chest pain.T Am Coli CardioI1983;1:944-100l.

24 Iskandrian AS, Hakki AH, Kane-Marsch S. Prognostic implica-tions of exercise thallium 201 scintigraphy in patients with suspectedor known coronary artery disease. Am Heart] 1985;110:135-43.

25 Ladenheim ML, Pollock BH, Rozanski A, et al. Extent and severityof myocardial hypoperfusion as predictor of prognosis in patientswith suspected coronary artery disease. ] Am Coil Cardiol1986;7:464-7l.

26 Pryor DB, Harrell FE Jr , Lee KL, et al. Prognostic indicators fromradionuclide angiography in medically treated patients with coronaryartery disease. Am] CardioI1984;53:18-22.

27 Iskandrian AS, Hakki AH, Goel IP, et al. The use of rest and exerciseradionuclide ventriculography in risk stratification in patients withsuspected coronary artery disease. Am Heart] 1985;110:864-72.

28 Kronenberg MW, Pederson RW, Harston WE, Born ML, BenderHW, Friesinger Gc. Left ventricular performance after coronary

11

artery bypass surgery: Prediction of functional benefit. Ann InternMed 1983;99:305-13.

29 Kent KM, Rosing DR, Ewels CJ, Lipson L, Bonow R, Epstein SE.Prognosis of asymptomatic or mildly symptomatic patients withcoronary artery disease. Am] CardioI1982;49:1823-3l.

30 Jones RH, Floyd RD, Austin EH, Sabiston DC Jr. The role ofradionuclide angiocardiography in the pre-operative prediction ofpain relief and prolonged survival following coronary artery bypass -,grafting. Ann Surg 1983;197:743-54.

31 Rogers Wl, Smith LR, Oberman A, et al. Surgical vs. nonsurgicalmanagement of patients after myocardial infarction Circulation1980;62(2 Pt 2):167-74.

32 Bonow RO, Epstein SE. Indications for coronary artery bypasssurgery in patients with chronic angina pectoris. Implications of themulticenter randomized trials. Circulation 1985;72(6 Pt 2):V23- 30.

33 Bonow RO, Kent KM, Rosing DR, et al. Exercise induced ischemiain mildly symptomatic patients with coronary artery disease andpreserved left ventricular function. Identification of subgroups atrisk of death during medical therapy. N EnglJ Med 1984;311:1339-45.

34 Bourassa MG, Enjalbert M, Campeau L, Lesperance 1. Progressionof atherosclerosis in coronary arteries and bypass grafts: Ten yearslater. Am] CardioI1984;53:102C-107C.

35 Bashour IT, Hanna ES, Mason DT. Myocardial revascularizationwith internal mammary artery bypass: An emerging treatment ofchoice. Am Heart] 1986;111:143-5l.

36 Loop FD, Lytle BW, Cosgrove DM. Influence of the internalmammary artery graft on lO-year survival and other cardiac events.N EnglJ Med 1986;314:1-6.

Oral submucous fibrosisV. N. CHATURVEDI

INTRODUCTIONOral submucous fibrosis (OSMF) is a chronic insidiousdisease sometimes preceded by vesicle formation orstomatitis but always associated with juxta-epithelialinflammatory reaction and fibroelastic changes of thelamina propria with epithelial atrophy. It causes stiffeningof the oral mucosa which becomes dry, blanched andleathery in consistency and results in trismus (Fig. 1).

HISTORICAL BACKGROUNDAs early as 600 BC Sushruta (cited by Mukherjee andBiswas)! described a condition resembling OSMF andnamed it 'Vidari'. Its features were progressive narrowingof the mouth, depigmentation of the oral mucosa and painon taking food. In 1952 it was described among Indian

Mahatma Gandhi Institute of Medical Sciences, Sevagram 442102Maharashtra, India

V. N. CHA TURVEDI Department of Otolaryngology© The National Medical Journal of India, 1989

migrants in Kenya and was named atrophica idiopathica(tropicum) mucosum oris. In 1953 a report from Bombay(India) gave it the name of submucous fibrosis.? Similarcases were reported from Taiwan in 1954 and were calledidiopathica scleroderma of the mouth. 3 Since then the dis-ease has been described by various names such as 'sub-mucous fibrosis of the palate and cheek', 'idiopathicpalatal fibrosis' and 'sclerosing stomatitis'. It derives itsname from the deposition of fibrous tissue in the sub-mucosal layer of the palate, fauces and cheek which causedisabling sequelae. No other part of the body is affected.OSMF is now the most widely accepted and commonlyused term to describe this disease.I+"

PREVALENCEOral submucous fibrosis is predominantly seen in India(prevalence rate 0.2% to 0.5%), and an estimated 2.5million people suffer from the disease. IS The disease ismore common in South Indiat-Pand the state of Keralahas the highest prevalence. Epidemiological surveys show

12

FIG 1. Patient with OSMF showing trismus (Grade II).

that the prevalence of OSMF is high in Lucknow (0.51 %),Bombay (0.5%) and Trivandrum (1.22%), and low inDarbhanga (0.07%), Srikakulam (0.04%), Bhavnagar(0.2%), Ernakulam (0.4%) and Bangalore (0.lB%).LI-13Some recent reports indicate an increase in the number ofOSMF cases in eastern Uttar Pradesh.!" In Sevagram(Maharashtra) it comprises 0.97% of all new cases attend-ing the Otorhinolaryngology out-patient department.fCases of OSMF have been reported among people ofIndian origin in Taiwan.r-'? Nepal, Sri Lanka, Malaysia,Thailand, Vietnam;" Uganda'? and South Africa.P Iso-lated cases of OSMF have been reported in Indian andPakistani migrants to the UK,21 Europeans domiciled inHyderabad.F Europe.P Africa" and in a British womanmarried to a Pakistani national. 22 OSMF has also beenfound to occur frequently in workers in the cashewnutindustry."

AETIOLOGYThe aetiology of OSMF is obscure. Some of the hypothesesput forward are as follows.

Chronic irritationIt is attributed to a high intake of chillies (capsaicin), 18,25-28and chewing of betel-nut (areca-nut)? with lime,3,6,24'pan'leaves= and tobacco with lirne.? The use of 'misi' (a blackcoloured powder containing washing soda, borax, pow-dered alum, charcoal of myrobalan and Fullers' earth invarious proportions) for cleaning teeth and colouring thegums," and exposure to volatile oil vapours in the cashew-nut industry have also been implicated. 16 These agents aremore likely to be risk factors rather than specific aetiologicalagents. Experimental studies were performed wheningredients of chillies such as capsaicin'? and arecoline (anextract of areca-nutj " were applied to the oral mucosa of

THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 2, NO.1

healthy Wistar rats. These failed to produce submucousfibrosis in the oral mucosa. However, tissue cultures haverevealed that the alkaloid present in areca-nut extract hasa collagen stimulating property. 7 Tannins present inareca-nut have been shown to reduce the collagenase-activated collagen degradation products." Vitamindeficiency 7,32,33and streptococcal infection 1 are believedto precipitate OSMF.

Collagen disorderIt was Su3 who first suggested that OSMF was a collagendisorder. In OSMF changes similar to those ofrheumatoid arthritis and scleroderma have been shownon histopathological.Fv' electron microscopic, histo-chemical and enzymatic studies.v-" However, otherworkers feel that OSMF is a localized collagen disordersimilar to idiopathic retroperitoneal or mediastinal fibro-sis, or Dupuytren's contracture.F The presence ofhyperglobulinaemia, mononuclear cell infiltration incollagen fibres, increased levels of serum mucoproteinsand mucopolysaccharides' has further supported the col-lagen nature of OSMF. However, L.E. cells have notbeen found in cases of OSMF. I

Immunological disorderThe occurrence of OSMF in teenagers and in cases withoutany history of using irritants suggests that an immunemechanism may cause OSMF. Humoral studies haveshown consistent hyperimmunoglobulinaernias-v-" butthe observations on various fractions of immunoglobulinshave been inconsistent. Serum IgG levels which havebeen related to the severity of the disease were foundraised in two studies=? and normal in one." Serum IgMand IgA were found to be norrnals-'? but in the advancedstages the level of IgA was found to be decreased,"whereas other studies have shown raised levels of IgM,IgA, IgD and IgE.38 Immunofluorescence andimmunoperoxidase techniques have demonstrated thepresence of immunoglobulins in tissue from OSMFlesions.t? Cellular immunity in OSMF has revealed anincreased absolute null cell count, a decrease in the absolutenumber of T cells and a normal population of B cells.t? C3has been observed to be normal. 40

Salivary studies in patients of OSMF have shown anincreased pH, salivary amylase, alkaline phosphatase andpotassium," and low to normal levels of calcium. 42Salivaryimmunoglobulins have been reported to be within normallimits." The unusual feature of saliva in patients of OSMFis the presence of a heat-labile fibrin producing factoralong with an increased level of plasma fibrinogen. 42,43

Genetic disorderA theory of genetic predisposition has been proposed asOSMF runs in families, predominantly Indian and ofIndian origin;" OSMF has been shown to be associated·with HLA A110, DR3, DR7 and probably B7 and haplo-types A10/DR3, BB/DR3 and AlO/BB.44

At present it appears that OSMF has a multifactorialaetiology with a strong interaction between these factors.A possible mechanism is outlined in Fig. 2.

CHATURVEDI : ORAL SUBMUCOUS' FIBROSIS 13

RISKFACTORS{ BETEL-NUT(ARECA-NUl]

~COLLAGEN t COLLAGEN

DEGRA~N /SYNTHESIS ALTERED

-......... ~ IMMUNEt FIBROBLAST MECHANISM

FORMATION GENETIC

~ 70SITION

OSMFiAMYLASE (IRREVERSIBLE)t ALKALINE PHOSPHATASE

~ NORMAL CALCIUM ~

t FIBRINOGENRICH DIET

tPLASMAFIBRINOGEN

TANNIN

tSALIVARYFIBRINOGEN

RISK FACTORS

SALIVA

t pH

TOBACCO

CHILLIES

LIMECASHEWNUTINDUSTRYWORKERS

ARECOLINE

MECHANICALTRAUMA

HYPERSENSITIVITY

CHEMICAL BURNS

RISK FACTORSCONTINUE

CARCINOMAORAL MUCOSA

FiG 2. Proposed aetiopathogenesis of OSMF.

HISTOPATHOLOGY OF OSMFThe squamous epithelium of the oral cavity shows thick-ening with deep invagination of epithelial rete pegs intothe adjacent lamina propria. The submucosal layer revealsincreased and dense collagen fibrils with marked hyalinedegeneration and the presence of increased PAS-positivematerial in the connective tissue.35,36 Based on the histo-pathological changes OSMF has been classified into fourdifferent stages: 18

L Very early stage showing fine dispersed fibrillarcollagen with marked oedema and presence ofpolymorphs and occasional eosinophils (Fig. 3a)

II. Early stage showing early hyaline degeneration ofjuxta-epithelial area and a thickened separate collagenbundle (Fig. 3b)

III. Showing moderately hyalinized collagen, adult sizedfibroblasts with elongated, spindle shaped nuclei andscanty cytoplasm. The blood vessels are constrictedand other cells are similar to those seen in stage II(Fig.3c)

IV. Advanced stage showing complete hyalinization ofcollagen in the form of a smooth sheath without anyseparate bundle being discernible (Fig. 3d).

14

FIG3a. Microphotograph of stage IOSMF (H & E, x400).

FIG3b. Microphotograph of stage IIOSMF (H & E, x400).

The presence of refractile eosinophilic material andmetachromasia in the ground substance are also describedin OSMF.22 Other changes described are irregularity anddetachment of the epithelium with a varying degree ofkeratosis, parakeratosis and orthokeratosis, a reductionin the number of epithelial layers including atrophicchanges and a thinning of the basement membrane whichremains intact. 45Atrophic changes are distinct and impor-tant features of OSMF.22,46--48

EXFOLIATIVE CYTOLOGYCytology of early cases of OSMF shows markedpleomorphism of the cells in the superficial and deep

THE NATIONAL MEDICAL JOURNAL OF INDIA VOL. 2, NO.1

FIG3c. Microphotograph of stage IIIOSMF (H & E, x 110).

FIG3d. Microphotograph of stage IV OSMF (H & E, x 110).

layers of epithelium. In the more advanced stages groupsof cells show large nuclei with a distinct nuclear membraneand a rarified centre which does not contain muchchromatin. Interpretation is difficult when cells showmarked atypia and degeneration. Advanced lesions showonly a few cells, some cell shadows'? and an increase inthe number of keratinized squamous cells.49,50Wahi et at. 51observed large exfoliated cells with a predominance ofsurface cells and a peculiar rarified chromatin pattern inthe nuclei. With an increasing severity of OSMF the nuclearchanges become more marked and there is a progressiveincrease in dyskaryotic changes. Alkaline phosphatasehas been found to be raised in the exfoliated cells."

CHATURVEDI : ORAL SUBMUCOUS FIBROSIS

Though the cellular changes are typical of OSMF, theymay not help to diagnose a malignant change. Thusexfoliative cytology can only be used as an adjunct and nota substitute for biopsy.

CLINICAL FEATURESOSMF affects a wide age range (10 to 70 years) with thehighest reported incidence in patients aged between 30and 40.37,52However, our studies have shown the mostcommonly affected age group to be between 20 and 40.8The male to female ratio is variable. 2,4,10,17,26,33

The early symptoms are recurrent episodes of vesiculareruption, pin-head sized multiple shallow ulcers, excessivesalivation and burning sensation in the mouth, intoleranceof hot and spicy foods and a progressive increase in trismus.In the advanced stage, the patient is unable to blowouthis cheek or whistle. Impairment of taste is uncommon,being seen in 6.6% of cases= while electrogustometry hasrevealed impairment of taste in 48%.54 OSMF has aninsidious onset of symptoms with an average duration of 2to 5 years. 14,26

The normal, pink and supple mucosa of the oral cavityis replaced by dry, blanched and leathery mucosa. How-ever, black pigmentation of the mucosa has beenobserved in patients using 'Misi' for dental hygiene.!'Different clinical classifications have been used to gradethe cases depending upon the severity of the symptoms.s-"Depending on the degree of fibrosis, trismus and ankylo-glossia the most common classification divides the casesinto the following grades.

FIG4. Mild fibrosis with decreased mouth bite-Grade I OSMF.

15

I. Mild fibrosis with slight decrease in mouth bite (Fig. 4)II. Moderate symptoms of disease and fibrosis extend-

ing from the cheek and uvula to the palatal area (Fig. 1)III. Marked involvement of the cheek, uvula and lips

with narrow opening of the mouth and ankyloglossia(Fig. 5).

TREATMENTPrevention of OSMF is more important than treatment.Since the aetiology of OSMF remains uncertain, the treat-ment is aimed at ameliorating the discomfortingsymptoms, reducing the fibrosis and improving the mouthbite.

Systemic treatmentIt is of doubtful value. In the past gold, arsenic trioxideand large doses of iodide followed by liver extract,2 highdoses of vitamin A and iron preparations have been triedwithout much success. Corticosteroids have also beenused with partial relief of the symptoms.Pv"

Local treatment1. Medical treatment: Submucosal infiltration ofhyaluronidase,' fibrinolysin.F collagenase.> aqueousextract of human placenta-" chymotrypsin and variousforms of steroids like hydrocortisone,4,14,26,57 methylpred-nisolone= and triamcinolone= either alone or in combina-tion8,59,6ohave been used. The most common treatment atpresent is a combination of 1 ml of hydrocortisone and1500 IU of hyaluronidase infiltrated submucosally, in the

FIG5. Marked fibrosis with ankyloglossia-Grade III OSMF.

16

mouth, at 2 or 3 different sites by a tuberculin syringe,given twice weekly for a total of 24 sittings. 59

Hyaluronidase has been found to be an effective pallia-tive for the burning sensation.v This symptom is producedby the effect of local by-products of hyaluronic acid whichis a ground substance in the connective tissue.Hyaluronidase rapidly breaks down the hyaluronic acidand lowers the viscosity of the intercellular cementingsubstance.s? An initial course of hyaluronidase is followedby the addition of dexamethasone. 60 The relief from varioussymptoms including an improvement in the suppleness ofthe oral mucosa is temporary and may last from a fewmonths to a few years. A recurrence of the symptomsrequires another course of treatment.

2. Surgical treatment: In the past it has involved forcingopen the mouth and cutting the fibrous bands under generalanaesthesia, which results in more disability.s-" Coveringthe raw areas after excising the fibrous band with skin(either full or split thickness) grafts has met with a highrate of failure. As the posterior third of the tongue is notinvolved by OSMF, a tongue flap pedicle graft basedeither anteriorly or posteriorly has been used to cover theraw area created after making linear incisions in theretromolar region. This has met with some success.v'-"

3. Physical agents: Microwaves at the rate of 2450 persecond have been used. This radiation is given by a 'Micro-tome 200 Unit' for 20 minutes a day at each site with 20 to25 watts energy for a total of 15 sittings.P Along with themedical or surgical treatment acrylic moulds of progres-sively increasing sizes or dental props have been used tohelp maintain the mouth bite.44,61

OSMF AS A PREMALIGNANT CONDITIONSlow growing squamous cell carcinoma has been observedin 23 to 30 per cent of cases of OSMF. 63,64 A routine histo-pathological examination of the OSMF lesion hasrevealed histological evidence of carcinoma in 5% to 6%of cases without any clinical evidence of the same."Studies in our institution have shown associated carcinomain less than 1% of cases.

A recent investigation of trace elements in OSMF hasrevealed raised serum levels of copper and-normal levelsof zinc. The rise of serum copper level was highest in casesof Stage I OSMF.65

SUMMARYOral submucous fibrosis is seen predominantly in Indiawith a prevalence rate of 0.12 to 0.5 per cent. The diseasereceives its nomenclature from its well developed statewhich includes the deposition of fibrous tissue in the sub-mucosal layer of the palate, fauces and cheek and causesdisabling sequelae without affecting any other part of thebody. It probably has a multifactorial aetiology with welldefined risk factors such as chewing of betel-nut, 'pan'leaves, tobacco with lime and excess intake of chillieswhich act either by mechanical irritation, hypersensitivityor by producing chemical burns, with a strong underlyingimmune mechanism and genetic predisposition. At presentthere is no curative treatment. The various modalitiestried so far include local infiltration of hyaluronidase, cortico-

THE NATIONAL MEDICAL JOURNAL OF INDIA VOL.2, NO.1

steroids either alone or in combination with other agents,excision of the fibrotic areas and covering with amyocutaneous tongue flap, microwave diathermy andphysiotherapy using acrylic mould screws or dental propsto maintain the mouth bite. A regular follow up of thesecases is essential as OSMF is known to be precancerous.

ACKNOWLEDGEMENTSThe author wishes to thank Dr N. Samal, Professor andHead, Department of Pathology for selecting the slidesand Dr J. Anbalagan for the microphotography.

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17

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