oral submucous

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J Orofac Sci, 3(2)2011

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OROFACIAL SCIENCESJournal of

A R T I C L E I N F O

Article History :Received : 16 July, 2011

Received in revised form : 4 Aug, 2011Accepted : 10 Oct, 2011

*Corresponding author :Dr. Shamimul Hasan M.D.SC/o Mr. Mohd Javed Khan,C-4, Duplex Quarters (New)Sir Syed Nagar, Aligarh 202002, U.P.e-mail : [email protected]

Oral submucous fibrosis turning into malignancy-A case report and review of literatureShamimul Hasana*, Osama Sherwania, Sameer Ahmeda, Mohd Abbas KhanaaDept. of Oral Medicine & Radiology, Z. A Dental College & Hospitals, A.M.U ; Aligarh- 202002, U.P.

Oral submucous fibrosis is a disease of individuals of Indian-south east asiansubcontinent, related to the use of areca nuts, also found in Pan masala and

guthka. It is possible that it is due to the copper content which increases col-lagen cross-linking. pale, blanched mucosa and palpable fibrotic bands mayprogress to severely restricted oral opening. It can also affect the soft palate andtongue and produces epithelial atrophy. Oral submucous fibrosis is a premalig-nant condition; carcinoma develops possibly in upto 8% cases. Diagnosis isbased on history of betel chewing; typical clinical features; biopsy andhaematology. Often anaemia is present. Treatment includes discontinuation ofhabits, oral physiotherapy, nutritional supplements, intralesional steroids andplacental extracts and surgical interventions. This paper deals with a case ofmalignancy developing from oral submucous fibrosis in a 47 year old patient.

Key Words :Oral submucous fibrosis,Areca nut habitMalignant potential

2011 SIDS. All Rights Reserved

INTRINTRINTRINTRINTRODUCTIONODUCTIONODUCTIONODUCTIONODUCTION

Sushruta - a renowned Indian physician, in his book" mouth and throat diseases" mentioned about a condition

"Vidari", the features of which simulate oral submucousfibrosis1. Oral submucous fibrosis is a chronic andpotentially malignant condition of the oral cavity,characterized by a juxta-epithelial inflammatory reactionfollowed by a fibroblastic changes in the lamina propriaand associated epithelial atrophy. The disease affects mostparts of the oral cavity as well as the upper third of theesophagus2. In 1952, Schwartz described a fibrosingcondition and coined the term Atropica IdiopathicaTropica Mucosae Oris3. Although the terms Idiopathicscleroderma of the mouth4 and juxta-epithelial fibrosis5

A B S T R A C T

Case ReportCase ReportCase ReportCase ReportCase Report

have also been used, the term Oral submucous fibrosis6

is the most widely accepted. Oral Submucous fibrosis is

an oral condition described by Joshi in 19537

, and causeschanges similar to those of systemic sclerosis but limitedto oral tissues. Various etiological factors have beenproposed for OSMF. Several predisposing factors orcausative agents include chilli consumption, nutritionaldeficiency, areca nut chewing, genetic susceptibility, auto-immunity and saliva8,9. It has been reported mainly fromindia, but has also been reported in Srilanka, Malaysia,Nepal, South Vietnam, and Thailand10. Majority ofOSMF patients belong to 20-40 year old age group witha male predominance, usually presenting with intolerance


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to hot and spicy food and progressive inability to openthe mouth leading to difficulty in mastication and speech.Most OSMF cases occur in lower socio-economicgroups11. Histopathologic features are less vascularisedcollagenous submucosa with a range of atrophy in the

neighbouring striated muscle fibres, mild to moderatechronic inflammation, and epithelial changes consistingof atrophy and a variable degree of dysplasia12. Varioustreatment modalities include corticosteroids, antioxidants,physiotherapy and nutritional support13,14. The possibleprecancerous nature of submucous fibrosis was firstmentioned by Pay Master in 1956, who described thedevelopment of slow-growing squamous cell carcinomain one third of cases with submucous fibrosis15.

CASE REPORCASE REPORCASE REPORCASE REPORCASE REPORTTTTT

A 47 year old male patient reported to Oral Medicineand Radiology department, Z.A Dental college andHospitals, AMU, Aligarh with a complaint of progressivedifficulty in mouth opening and burning sensations inthe mouth over the past 3 years. The patient alsocomplaint of a growth in the oral cavity since past 6months. The patient had a long standing habit of betelnut chewing (6-7 packets for more than 30 years). Patient'smedical and dental history was non significant. Patient'sgeneral examination was non-contibutory except that the

right submandibular lymph node was palpable, tender,hard in consistency and not movable. The mouth opening

was restricted (around 25mm) (Fig.1). Intraoralexamination revealed pale, blanched buccal mucosa withpalpable fibrotic bands running vertically and extendingto the retromolar region. (Fig.2). The tongue was devoidof papillae along with restricted protrusive tonguemovements. The uvula was deformed and shrunken. Thepatient was not able to blow out air with closed lips andthe usual puffed-cheek appearance was not seen,suggesting loss of cheek elasticity.

In addition, a single localized ulcero-proliferativegrowth about 4cm x 3cm was present in the right sideinvolving the buccal mucosa, alveolus, gingiva from 16to 18 region and on the palate and maxillary tuberosityarea (Fig.3).The surface of the growth was rough,ulcerated mildly tender and was covered by a whitenecrotic slough. Areas of bleeding from the surface ofthe growth was seen. Mucosa surrounding the growth

was errythmatous in nature The margin and edges wereeverted. The base was indurated The teeth associated

with the growth 17 was mobile.

Correlating the history of chronic betel nut chewing andclinical observation of limitation of mouth opening, along

with pale, blanched buccal mucosa with palpable fibroticbands, a provisional diagnosis of oral submucous fibrosis

was made.

An ulcerated , rapidly enlarging growth, with evertedmargins and indurated base was seen in the right side ofbuccal mucosa,. The rapidity of growth and the induratednature along with palpable, fixed right submandibularlymph node, suggests that it was a carcinoma.

Investigations :Investigations :Investigations :Investigations :Investigations : Radiographs were taken to depict bonyinvolvement. OPG, PA view mandible, and Para nasalsinus (PNS) view showed no abnormality in the bone.( Fig. 4,5 & 6).

MRI :MRI :MRI :MRI :MRI : Heterogeneous T2 hyper intense mass in the rightcheek infiltrating into the buccal space and retromolartrigone was seen.

A soft tissue lesion with fluid restriction was noticedin the axial DWI (Diffussion Weightage Image), featuressuggestive of a malignancy (Fig 7).

After the informed consent from the patient, anincisional biopsy was taken and histopathology revealedbuccal mucosa with irregular focal areas of acanthosis,severe dysplasia and focal cell carcinoma in situ and small

foci of early submucosal micro invasion. Rest ofsubmucosa shows dense chronic inflammation suggestiveof carcinoma(Fig.8&9).

Clinical diagnosis :Clinical diagnosis :Clinical diagnosis :Clinical diagnosis :Clinical diagnosis : Correlating the history, clinicalfindings, radiographic features and histopathology a finalclinical diagnosis of "oral submucous fibrosis progressinginto malignancy was made ". The patient was referred todept of oral and maxillofacial surgery ZA Dental collegeand hospitals, AMU, ALIGARH for surgical excision ofthe growth.

DISCUSSIONDISCUSSIONDISCUSSIONDISCUSSIONDISCUSSION

OSMF, a potentially premalignant condition of theoral cavity and oropharynx has been a subject of extensiveresearch since the last 50 years. Earlier literature emphasiseson the studies done by Joshi, Sirsat and Khanolkar, ABNRao and other workers, related to etiology, clinicalfeatures, histopathological features and malignantpotential of the disease16. Oral Submucous fibrosis is a"insidious chronic disease affecting any part of the oral

cavity and sometimes the pharynx, occasionally preceded


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by vesicle formation, always associated withjuxtraepithelial inflammatory reaction followed by afibroelastic change of lamina propria with epithelialatrophy leading to stiffness of the oral mucosa, trismusand inability to eat"13. Prevalence rate is 0.2 to 0.5%

with higher percentage reported from the southern statesin India17. Unlike other precancerous lesions, OSMF isinsidious in origin and does not regress, eitherspontaneously or with cessation of habits18. The conditionmay remain either stationary or become severe, leavingan individual handicapped both physically andpsychologically19.

Etiology :Etiology :Etiology :Etiology :Etiology :

Pillai et al 20 establishaed that OSMF has an unknown,but multifactorial etiology. A variety of factors trigger

the disease process. Factors include areca nut chewing,genetic basis, nutritional deficiencies, auto immunity, andsaliva.

1. Ar1. Ar1. Ar1. Ar1. Areca nut cheeca nut cheeca nut cheeca nut cheeca nut chewing :wing :wing :wing :wing : The introduction of chewingtobacco containing areca nut into the market has beenassociated with a sharp increase in the frequency ofOSMF21. The amount of areca nut in betel quid and thefrequency and duration of chewing betel quid are clearlyrelated to the development of OSMF22. The direct

contact of the quid mixture with oral tissues results intheir continous irritation by various components,including biologically active alkaloids (arecoline,arecaidine, arecolidine, guavacoline, guavacine) andcopper.

2. Nutritional deficiencies :2. Nutritional deficiencies :2. Nutritional deficiencies :2. Nutritional deficiencies :2. Nutrit ional deficiencies : OSMF was proposed byRamanathan as an Asian version of Sideropenic dysphagia

wherin the chronic iron deficiency leads to mucosalsusceptibility to irritants such as chilli and areca nut11.The role of deficiency of vitamins and iron has been

implicated in the etiology of OSMF. A significantalteration in serum copper and Zinc ratio is reported witha decrease in Zinc content23. Iron is essential for overallintegrity and health of epithelia of the digestive tract andits importance may lie in its contribution to normalenzymes11. The normal maturation of epithelium isdependent upon an iron containing enzyme, cytochromeoxidase. Moreover , one of the most common signs seenin OSMF is pallor or blanching of oral mucosa whichcan occur in a variety of other conditions, most

commonly being anemia1 .

3. A3. A3. A3. A3. Auto immunity :uto immunity :uto immunity :uto immunity :uto immunity : The similarities of this conditionwith other collagen disorders like scleroderma which ispresumed to have an auto immune pathogenesis hasevoked a possibility of auto immune basis for the disease16.Sirsat and Khanolkar observed refractive eosinophilic

material and marked increase in PAS positive materialwith metachromasia in ground substance of OSMF. Thus,OSMF was considered to be a localized collagen disease16.Pathak observed Hyperglobulinemia in immunologicalstudies of OSMF, thus favouring OSMF as an autoimmune disorder16. An increase in DR-3 antigen,alteration in serum immunoglobulin and presence of autoantibodies in OSMF were reported by Cannif et al. Thebetel nut alkaloids may act as haptens which may produceantibodies to parietal cells12.

4. Genetic basis :4. Genetic basis :4. Genetic basis :4. Genetic basis :4. Genetic basis : OSMF cases were observed in theabsence of any chewing habits in families (children andadults) which provoked researchers to probe thepossibility of genetic susceptibility24. HLA tissue typingshowed signifcant difference in frequencies of HLA-10,DR-3, and DR-7 in OSMF patients than the controls12.

5. Salivary constituents :5. Salivary constituents :5. Salivary constituents :5. Salivary constituents :5. Salivary constituents : OSMF was considered as alocal coagulopathy , produced by thrombin like fibrinproducing factor in saliva. Fibrin producing factor, actinglocally produced fibrin glue phenomenon in the

submucous zone of oral cavity and acting systematically,produced cryofibrinogen, which gets attached tosubmucous zone through the action of fibronectin25.

6. Allergy to capsaicin :6. Allergy to capsaicin :6. Allergy to capsaicin :6. Allergy to capsaicin :6. Allergy to capsaicin : Patients complain that thevesicles form after they eat spicy food, suggesting thepossibility of an allergic reaction to capsaicin.

PPPPPathogenesis :athogenesis :athogenesis :athogenesis :athogenesis :

The pathogenesis of OSMF is not well established,although a number of possible mechanisms have been

suggested. Pathogenesis is believed to involve juxta-epithelial inflammatory reaction and fibrosis in the oralmucosa, probably due to increased cross-linking ofcollagen through up-regulation of lysyl oxidase activity26.Fibrosis, or the build up of collagen, results from theeffects of areca nut, which increases collagen production(e.g., stimulated by arecoline, an alkaloid) and decreasescollagen degradation27,28. Thus, OSMF is now considereda collagen metabolic disorder16.

Clinical FClinical FClinical FClinical FClinical Featureatureatureatureatures:es:es:es:es: The disorder primarily affects the

males. Male- female ratio was found to be 2.3: 129. Buccal


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mucosa is the most common site of involvement16,followed by soft palate, uvula, lips, tongue and floor ofthe mouth29 .OSMF is a chronic disorder characterizedby fibrosis of the lining mucosa of the upper digestivetract involving the oral cavity, oro- and hypo pharynx

and the upper third of the oesophagus. The fibrosisinvolves the lamina propria and the sub mucosa and mayoften extend into the underlying musculature resultingin the deposition of dense fibrous bands, which give riseto the limited mouth opening which is a hallmark ofthis disorder.

The symptoms and signs of OSF are due toinflammation and, primarily, fibrosis. The mostcommon initial symptoms and signs are a burningsensation, dry mouth, blanching oral mucosa and

ulceration. The burning sensation usually occurs whilechewing spicy food. Blanching of the oral mucosa iscaused by impairment of local vascularity because ofincreasing fibrosis and results in a marble-like appearance.Blanching may be localized, diffuse or reticular. In somecases, blanching may be associated with small vesicles thatrupture to form erosions. These features can be observedat all stages of OSMF. In the more advanced stage of thedisease, the essential feature is a fibrous band restrictingmouth opening and causing difficulty in mastication,speech, swallowing and maintaining oral hygiene. Theseverity of disease and and the degree of mouth opening

were co-related by Jain P and Suman V et al as30:

Normal mouth opening- 40-60 mm

Grade - I- 40-42mm

Grade-II- 31-39mm

Grade-III- 21-30mm

Grade- IV- 10mm- 20mm

However, Rajendran et al found no such co-relation,

as the extent of mouth opening was also dependent onvarious other factors such as the site of involvement, extentof fibrosis, involvement of underlying musculature, andduration of the disease 31 .

Development of fibrous bands in the lip makes thelip thick, rubbery and difficult to retract or evert; a bandaround the lips gives the mouth opening an ellipticalshape. Fibrosis makes cheeks thick and rigid. When apatient blows a whistle or tries to inflate a balloon, theusual puffed-out appearance of the cheeks is missing. In

the tongue, depapillation of mucosa around the tip and

lateral margins may occur with blanching or fibrosis ofthe ventral mucosa. Fibrosis of the tongue and the floorof the mouth interfere with tongue movement. Hardpalate involvement includes extensively blanched mucosa.Fibrosis may extend posteriorly to involve the soft palate

and uvula. The latter may appear shrunken and, inextreme cases, budlike. Gingival involvement is relativelyuncommon and is characterized by fibrosis, blanchingand loss of normal stippling. In rare cases of extensiveinvolvement, there may be loss of hearing due to blockageof eustachian tubes and difficulty in swallowing becauseof esophageal fibrosis.

HistopathologyHistopathologyHistopathologyHistopathologyHistopathology3232323232 :::::

Very early stage (Grade I)O A finely fibrillar collagen, dispersed with marked edema.O The fibroblastic response is strong.O The blood vessels are sometimes normal, but more

often they are dilated and congested.O Inflammatory cells, mainly polymorphonuclear

leukocytes with an occasional eosinophil.

Early stage (Grade II)Early stage (Grade II)Early stage (Grade II)Early stage (Grade II)Early stage (Grade II)

O The juxta-epithelial area shows early hyalinization.

O Plump young fibroblasts are present in moderatenumbers.

O The blood vessels are dilated and congested.

O The inflammatory cells are mostly mononuclearlymphocytes, eosinophils and an occasional plasma cell.

Moderately advanced stage (Grade III)Moderately advanced stage (Grade III)Moderately advanced stage (Grade III)Moderately advanced stage (Grade III)Moderately advanced stage (Grade III)

O The collagen is moderately hyalinized.

O The fibroblastic response is less marked, the cellspresent being mostly adult fibrocytes.

O Blood vessels are normal or constricted.

O The inflammatory exudates consist of lymphocytesand plasma cells, although an occasional eosinophilis seen.

Advanced stage (Grade IV )Advanced stage (Grade IV )Advanced stage (Grade IV )Advanced stage (Grade IV )Advanced stage (Grade IV )

O The collagen is completely hyalinized.

O The hyalinized areas are devoid of fibroblasts.

O Blood vessels are completely obliterated or narrowed.

O The inflammatory cells are Lymphocytes and plasma cells.

Grading and treatment modalitiesGrading and treatment modalitiesGrading and treatment modalitiesGrading and treatment modalitiesGrading and treatment modalities3333333333 :::::

Grade IGrade IGrade IGrade IGrade I ::::: Only blanching of oral mucosa without symptoms


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Grade IIGrade IIGrade IIGrade IIGrade II ::::: Burning sensations ; Dryness of mouth ;vesicles / ulcers in the mouth without tongueinvolvement

Grade IIIGrade IIIGrade IIIGrade IIIGrade III::::: In addition to grade II restriction of mouthopening

Grade IVGrade IVGrade IVGrade IVGrade IV::::: In addition to grade III palpable bands allover the mouth without tongueinvolvement

Grade VGrade VGrade VGrade VGrade V ::::: Grade IV and tongue involvement

GradeVIGradeVIGradeVIGradeVIGradeVI ::::: Oral submucous fibrosis along withhistologicaly proven oral cancer.

The various treatment modalities used in OSMF canbe divided into different groups :

GRGRGRGRGROUP I :OUP I :OUP I :OUP I :OUP I :

O Removal of etiological factors :Removal of etiological factors :Removal of etiological factors :Removal of etiological factors :Removal of etiological factors : Discontinuationof habits ( paan, beetel nut, tobacco chewing andintake of spicy food )

O NNNNNutritionalutritionalutritionalutritionalutritional Therapy :Therapy :Therapy :Therapy :Therapy : Multivitamin therapy andIron therapy to boost up the nutritional status of thepatients.

GRGRGRGRGROUP II :OUP II :OUP II :OUP II :OUP II :

O TTTTTopicalopicalopicalopicalopical Therapy :Therapy :Therapy :Therapy :Therapy : For patient's in grade I & II andto prevent relapse after other treatment modalities.

O Triamcinolone acetate 0.1 % with neomycin - to beapplied to the oral mucosa three times daily and thepatients were advised to let the saliva drool for 15minutes. This one month course was repeated aftertwo months.

O Pappain and urea mixture : to be applied intra orally2-3 times daily for 15 days and to be repeated afterone month

PPPPPapain mixturapain mixturapain mixturapain mixturapain mixture :e :e :e :e : The mode of action of papain mixture

is by biogenic stimulation and the proteolytic action.UREA :UREA :UREA :UREA :UREA : is a keratolytic agent, induces surface lysis ofkeratin layer of oral mucosa and early absorption at thelesional site , breaking the fibro peptide linkages of thefibrous layer, leading to slight laxity of the oral mucousmembrane stiffness33.

GRGRGRGRGROUP III :OUP III :OUP III :OUP III :OUP III :

O Injectable therapy : For patients in grade III, IV, V

O Injectable Hyaluronidase 1500 I.U, 0.5 ml injected

intra lesionally twice a week for 10 weeks.

O Dexamethasone 1.5 ml with 0.5 ml of lignocaineHCL intra lesionally biweekly for 5 weeks.

O Placental extracts (PLACENTRIX) -2 ml intralesionally once a week for 4 weeks ; along withinjection ranidone ( Iodine & vit B complex ) I.M

O HYALURONIDASE causes collagen destruction ascollagen of OSMF patients ( as compared to controls)is attacked rapidly by Hyaluronidase.

Also it breaks down Hyaluronic acid and causeslowered viscosity of intercellular cementingsubstance34.

O STERSTERSTERSTERSTEROIDS :OIDS :OIDS :OIDS :OIDS : Functions as immune suppressiveagents by opposing the action of the soluble factorsreleased by the sensitized lymphocytes following

activation by non specific antigens.Also suppresses the inflammatory reaction. Thus

fibrosis is prevented by a decrease in fibroblasticproliferation and deposition of collagen.

O Placentrix :Placentrix :Placentrix :Placentrix :Placentrix : Acts by biogenic stimulation.

O Ranidone , an iodine and vit B complex preparationstimulates the metabolic processes in the body.

O Vit B complex potentiates the action of Iodine andmakes it non toxic.

GRGRGRGRGROUP IV :OUP IV :OUP IV :OUP IV :OUP IV :O Micro wave Diathermy using " microtone 200 " unit

producing microwaves of 2450 MC / S : for patientsin grade IV & V

O One sitting of 20 min a day for 15 days to give anenergy of 20 watts

O Microwave Diathermy causes physio fibrolysis ofbands.

GRGRGRGRGROUPOUPOUPOUPOUP V :V :V :V :V :

O Surgical treatment for patients with grade IV & V orwith isolated bands in retromolar region and inpatients in grade VI

O Forceful mouth opening : Patients with severe trismusand having unerupted / partially erupted 3rd molarshad their mouth forcefully opened, and the patients

were asked to apply Kamillosan ointment to reducescar formation and promote healing. Topical steroidsare used to prevent relapse.

O Rotated tongue flap or skin grafting- for patients with

Isolated bands in retromolar region and trismus .


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OSMF AND CANCER :OSMF AND CANCER :OSMF AND CANCER :OSMF AND CANCER :OSMF AND CANCER :

OSMF is considered as a premalignant condition. Amalignant transformation rate of 7.6% over a period of10 years was described in an Indian cohort and the relativerisk for malignant transformation may be as high as

397.3.35

Thomas et al from South India suggested tobaccochewing was the most important risk factor for multipleoral premalignant lesions and may be a major etiologicalfactor for cancers on the oral epithelium in the Indianpopulation36. Reactive oxygen species produced duringthe auto oxidation of areca nut poly phenols in the salivaof commercial areca nut chewers are crucial in theinitiation and promotion of oral cancer37. Nitrosationof areca nut alkaloids also produces areca nut specific

nitrosamines that have been demonstrated to bemutagenic, genotoxic and are capable of inducing tumoursin experimental animals. Oral cancer can develop in

individuals who use areca nut but donot use tobacco inany form38.

Epithelial atrophy and lack of proper maturation ofepithelium are the two important histological changesobserved in the oral mucosa of patients with iron

deficiency anaemia39. Further Fe deficiency results inimproper vascular channel formation and concomitantdecreased vascularity, thus making easy percolation ofesters of arecoline. These esters stimulate fibrogenesis andthe resultant fibrous tissue deposition could manifest asfibrotic bands. Cytochrome oxidase, an Fe containingenzyme is responsible for the normal maturation ofepithelium. In Fe deficiency anaemia, low levels of thisenzyme are seen, thus epithelial atrophy and lack ofmaturation occurs. It is well documented that Post

cricoids carcinoma, esophageal carcinoma and oralcarcinomas show an increased inherent association withFe deficiency anaemias. Malignant transformation inOSMF could be explained in a similar manner.

Fig.1 Fig.2 Fig.3 Fig.4

FFFFFig.1:ig.1:ig.1:ig.1:ig.1: Reveals restricted mouth opening of 26 mm. FFFFFig.2 :ig.2 :ig.2 :ig.2 :ig.2 : Pale blanched buccal mucosa with palpable fibrotic bands, showing loss of cheekelasticity. FFFFFig.3 :ig.3 :ig.3 :ig.3 :ig.3 : An ulcero-proliferative growth involving right maxillary tuberosity ,gingiva and palate with everted margins and induratedbase. FFFFFig.4, 5& 6 :ig.4, 5& 6 :ig.4, 5& 6 :ig.4, 5& 6 :ig.4, 5& 6 : Radiographs (OPG, PA SKULL & PNS View) do not reveal any bony involvement. FFFFFig.7:ig.7:ig.7:ig.7:ig.7: Diffussion Weightage ImageMRI: shows soft tissue lesion with fluid restriction, appearing white in colour, suggestive of a malignant lesion. FFFFFig 8&9:ig 8&9:ig 8&9:ig 8&9:ig 8&9: Histopathologyrevealing buccal mucosa with irregular focal areas of acanthosis, severe dysplasia and focal cell carcinoma in situ and small foci of early submucosalmicro invasion. Rest of submucosa shows dense chronic inflammation suggestive of carcinoma.

Fig.5 Fig.6 Fig.7 Fig.8 Fig.9


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REFERENCESREFERENCESREFERENCESREFERENCESREFERENCES

1. Murti PR, Bhonsle RB, Gupta PC , Daftari DK, Pindborg JJ,Mehta FS. Etiology of oral submucous fibrosis with specialreference to role of arecanut chewing. J. Oral Pathol Med. 1995;24: 145-52.

2. Tilakratne WM, Klini Kowski NF, Saku T, Peters TJ,

Warnakulasuriya S: Oral submucous fibrosis: Review on etiologyand pathogenesis. Oral oncol 2005: 30: 30-32.

3. Schwartz J. Atropha Idiopathica tropica mucosa oris. 11th IntDent Congress, London,1952.

4. Su J P. Idiopathic scleroderma of the mouth. Report of threecases. Arch otolaryngeol 1952; 59; 330-332.

5. Pindborg JJ, Chawla TN, Shrivastava AN, Gupta D, MalhotraNI. Clinical aspects oral submucous fibrosis. Acta Odont Scand1964; 22; 679-691.

6. Lal D. Diffuse OSMF. J. All india- Dent Assoc 1953: 26: 1-3.

7. Dayal PK, Joshi HN, Dayal JP. Concomittent occurrence of

OSMF, Pemphigus and Squamous cell carcinoma. Indian J. PatholMicrobiol. 1988; 31: 334-7.

8. Pathak AG: Oral submucous fibrosis: Fibrin producing factors,growth factors and modulation of collagen gen. Proceedings of7th national conference of IAOP, Nagpur, Nov. 1998, 31-36.

9. Pathak AG: Fibrin producing factor in OSMF. Indian J. OfOtolaryngeol. 1979; 31(4): 103-104.

10. Pindborg JJ, Mehta FS, Gupta PC, Daftari DK. Prevelance oforal submucous fibrosis among 50,915 Indian Villagers. BritishJ. Cancer.1968: 22: 646-54.

11. Ramanathan K. OSMF-An alternative hypothesis as to its causes.

Med J. Malaysia 1981: 36: 243-5.12. Canniff JP, Harvey W, Harris M. Oral Submucous Fibrosis; Its

pathogenesis and management. British Dent J.1986:160: 429-34.

13. Shafer WG, Hine MK, Levi MB: A text book of Oral Pathology.4th edition, Philadelphia, Saunders.

14. Prabhu SR, Walson DF, Daftari DK and Jonson NW: OralDiseases in the tropics, 1993: Oxford university press.

15. Paymaster JC. Cancer of the buccal mucosa; A clinical 650 casesin Indian patients. Cancer 1956; 9: 431-5.

16. Rao ABN: Idiopathic Palatal fibrosis. Br. J. Surgery. 1962:50:23-25.

17. Hamner JE, Looney PD, Chusad TN; Submucous fibrosis Oral

Surg, Oral Med, Oral Pathol. 1974: 37: 412-21.18. Gupta PG, Mehta FS, Pindborg JJ et al: Primary prevention trial

of oral cancer in India: A 10 year follow up study. J. Oral PatholMed 1992; 21:433-439.

19. Mehta FS et al: Tobacco related oral mucousal lesions andconditions in India basic dental research unit. Tata Institute offundamental research, Bombay, 1993.

20. Pillai R, Balaram P, Reddiar KS. Pathogenesis of Oral submucousfibrosis. Relationship to risk factors associated with oral cancer.Cancer . 1992, 69: 2011-2020

21. Nair U, Bartsh H, Nair J. Alert for an epidemic of oral cancer dueto the use of betel quid substitutes gutka and pan masala: Areview of agents and causative mechanisms. Mutagenesis 2004:19(4); 251-262

22. Rajalalitha P, Vali S. Molecular pathogenesis of oral submucousfibrosis- a collagen metabolic disorder. J Oral Pathol Med 2005;

34(6):321-8.23. Rajendran R et al: Serum levels of some trace and bulk elements

in oral submucous fibrosis.1992 :63(6); 251-255

24. Mc Guerk M, Craig GT: Oral submucous fibrosis: Two case ofmalignant transformation in asian immigrants to united kingdom:Br J of oral and maxillofacial surgery. 1984; 22: 56-64

25. Pathak AG: Oral submucous fibrosis: A chronic disseminatedintravascular coagulation syndrome with local coagulaopathy:GUT 1993: Letter to the editorial: 713

26. Trivedy CR, Warnakulasuriya KA, Peters TJ, Senkus R, HazareyVK, Johnson NW. Raised tissue copper levels in oral submucousfibrosis. J Oral Pathol Med 2000; 29(6):241-8.

27. Shieh TY, Yang JF. Collagenase activity in oral submucous fibrosis.Proc Natl Sci Counc Repub China B 1992; 16(2):106-10.

28. Yang SF, Hsieh YS, Tsai CH, Chen YJ, Chang YC. Increasedplasminogen activator inhibitor-1/tissue type plasminogenactivator ratio in oral submucous fibrosis. Oral Dis 2007;13(2):234-8.

29. Dave RP: Oral submucous fibrosis: A clinical and etiologicalstudy .JIDA: 1987: (59) :46-51

30. Jain P, Suman V: Oral submucous fibrosis: A new approachtowards its management .Stomatologica India 1988: 2(1); 7-12

31. Bulletin of WHO 1994: 72(6); 985-986

32. Pindborg JJ, Odont , Sirsat SM: Oral submucous fibrosis. OralSurg, Oral Med, Oral Pathol 1966, 22:764-79.

33. Gupta Dinesh Chandra S, Dolas Rameshwar S, Ali Iqbal.Treatment of Oral submucous fibrosis : How they stand today?A Study of 600 cases. Ind J of Oral and Maxillo surg 1992(7);43

34. Lamipathy G. Hylase in Submucous fibrosis in oral cavity. Jaipur,India. 32nd Annual Conference of Otolaryngologistsof India

35. Gupta PC, Nandakumar A. Oral cancer scene in India. OralDis. 1999; 5:1-2.

36. Thomas G, Hashibe M, Jacob BJ, Ramadas K, Mathew B,Sankaranarayan R, et al.: Risk factors of multiple oral

premaliganant lesions. Int J Cancer 2003, 107:285-91.37. Jeng JH, Chang MC, Hahn LJ. Role of areca nut in betel quid

associated carcinogenesis; current awareness and futureperspectives: Oral Oncol Sept. 2001: 37;6; 477-492

38. Gupta PC, Pindborg JJ, Mehta FS. Comparison ofcarcinogenicity of betel quid with or without tobacco: Anepidemiological review "Ecology of disease" 1982: 1: 213-219

39. Rannie JS, Mac Donald DG, Dagg JH. Qualitative analysis ofhuman oral epithelium in iron deficiency anaemias. J of OralPath. 1982: 11: 39-46

oral submucous

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