Indian J Med Res 131, May 2010, pp 665-669

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Oral submucous fibrosis (OSMF) is a chronicdebilitating and a well recognized potentially malignant condition of oral cavity associated with arecanutchewingcharacterizedbygeneralizedfibrosisoforalsoft tissue resulting in marked rigidity and progressive inability toopen themouth1-3.Thisdisease ismainly

Efficacyofhydrocortisoneacetate/hyaluronidasevstriamcinoloneacetonide/hyaluronidaseinthetreatmentoforalsubmucousfibrosis

MangalSingh,H.S.Niranjan,RaviMehrotra*,DevashishSharma**&S.C.Gupta

Departments of E.N.T. & Head & Neck Surgery, *Pathology &** Statistics & Demography, M.L.N. Medical University College & S.R.N. Hospital, Allahabad, India

Received June 30, 2008

Background & objective: Oral submucous fibrosis is a common premalignant condition caused by chewing arecanut and other irritants in various forms. Its medical treatment is not yet fully standardized, although the optimal doses of its medical treatment is in the form of hydrocortisone acetate combined with hyaluronidase. The problem with the prevailing treatment was injections at weekly interval. In this study we compared the efficacy of hydrocortisone acetate and hyaluronidase at weekly interval versus triamcinolone acetonide and hyaluronidase at 15 days interval. Methods: Patients of OSMF (100) were randomly divided into two groups A and B. Group A patients received combination of hydrocortisone acetate (1.5 ml)/hyaluronidase (1500 IU) at weekly interval submucosally in pterygomandibular raphe, half dose on each side for 22 wk. Group B patients received combination of triamcinolone acetonide (10 mg/ml)/ hyaluronidase (1500 IU) at 15 days interval for 22 wk. Treatment outcome was evaluated on the basis of improvement in symptom score, sign score and histopathological improvement. Student’s ‘t’ test was applied for comparing the results.Results: No statistically significant difference in symptom score, sign score and histopathological improvement was seen between the two groups. Interpretation & conclusion: Treatment regimen of group B was more convenient to the patients because less number of visits required and cheap. No side effects were seen. A follow up study is required to see long term effects.

Key words Hyaluronidase-hydrocortisoneacetate-oralsubmucousfibrosis-tiamcinoloneacetonide

confinedtoSouthEastAsiancountriesespeciallyintheIndiansubcontinent.Pathogenesisisnotyetestablishedbutitisbelievedtobeduetomultifactorialcauses.Thedisease initially presents as burning sensation in oral cavity.Itisclinicallydividedintothreestages4. In stage 1 there is stomatitis, erythematousmucosa, vesicles,

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mucosal ulcers, melanotic mucosal pigmentation and mucosalpetechiae.Instage2,fibrosisoccursinrupturedvesiclesandulcerswhentheyheal.Thereisblanchingoforalmucosa.Verticalandcircularpalpablefibroticbands are seen in buccal mucosa. Specific findingsinclude trismus,stiffandsmall tongue,blanchedandleathery floor of mouth, fibrotic and depigmentedgingiva, rubbery soft palatewith decreasedmobility,blanched and atrophic tonsils, shrunken band likeuvulaandsinkingofcheeknotcommensuratewithageor nutritional status. In stage 3 there are sequelae intheformofleukoplakiainabout25percentofcases,speechandhearingdeficitsbecauseofinvolvementoftongue,palateandeustachiantubes5,6.

Most important aspect of medical treatment is cessationofhabitofeatingbetelquid,arecanut,otherlocalirritants, spicy and hot food, alcohol and smoking. Themost commonmode ofmedical treatment had been theuse of steroids in its various forms7-11.Usedothermethodsinclude injection of placental extract12, use of trypsin, collagenase,hyaluronidaseandelastase13 and intralesional Interferon-γ(IFN-γ)14.Oralzinchasbeenused15 as also oral pentoxiphylline16 andlycopenewithvaryingbenefits17.

Local injection of hyaluronidase mixed withhydrocortisoneacetatehadbeenusedatourcentreforthelast20yswithsatisfactoryclinicalresultsandwithoutanysignificantsideeffects.Theproblemwith the treatmentwasthatthedosesanddurationoftreatmenthadnotbeenstandardized.Inapreviousstudy,thetreatmentregimenwas standardized with patients of OSMFwith trismusbe treated by 1.5ml (37.5mg) hydrocortisone acetatemixed with 1500 IU of hyaluronidase injection givenintralesionallyhalfdoseoneachsideatweeklyintervalfor 22 wk18.Theproblemwithprevailingtreatmentwasinjectionatweeklyinterval.So, thisstudywasplannedto see the efficacy of this treatment as compared totriamcinolone acetonide (10 mg/ml) combined withhyaluronidase(1500IU)intralesionallyoncein15daysforatotalof11injections.

Material & Methods

This prospective randomized single blindedoutcome based study was done on 100 cases of clinically diagnosed oral submucous fibrosis doneduring 2005-2006. Clinical diagnosis of OSMF wasbased on symptom of burning sensation in mouthupon consumption of spicy or hot foods, repeatedvesiculation or ulceration in oral cavity and signs observedwerevesicles/ulcers inoral cavity, areasoffibrosis investibuleofmouth,oralcavityproperand

oropharynx, partial or complete inability to protrude outthetongue(ankyloglossia)withorwithoutreducedmouth opening (trismus). After diagnosis stagingwasdoneaccordingtothecriteriaofPindborg19894. PatientsofstageIIOSMFhavingtrismuswereincludedin this study.Stage Iand IIIwereexcluded.Trismuswasdefinedasmouthopeninglessthannormal.Normalmouthopeningwasinterincisordistanceof5.25cminmales and 4.75 cm in females as measured by a caliper. Allpatientswereproperly explained about the studyandtheirconsentwastaken.ThestudywasclearedbyInstitutional Review Board.

Thesymptomsandsignswerenotedonaworkingproforma.Scoringofsymptomslikeburningsensationinmouthuponconsumptionofspicyorhotfoodsandrepeated vesicles or ulcer formation was done according toverbalcomplaintratingscaleof0-10points,where0means no symptom and 10 means severe most symptom asperceivedbythepatientsubjectivelyandsignswerescored from 0 to 10 points according to a new criteria. Trismus was scored as 0 means no trismus whereinterincisor distance was 5.25 cm or more in males and 4.75 cm or more in females, scored as 2 or grade I whereinterincisordistancewasmorethan3cmbutlessthannormal,scoredas5orgradeIIIwhereinterincisordistancewas2-3cmandscoredas10whereinterincisordistancewaslessthan2cm.Ankyloglossiawasscoredas5whenprotrusionoftonguewaspartialandscored10whentherewasinabilitytoprotrudeoutthetongue.Vesiclesorulcers inoral cavitywere scored1whenthere were unilateral single, scored 2 when bilateralsingle,scored3whenunilateralmultipleandscored4whenbilateralmultiple.Areasoffibrosiswerescored2foreacharea–softpalateincludinguvula,rightorleftanteriorfaucialpillarincludingtonsil,rightorleftbuccalmucosaincludinggingivobuccalsulcus,rightorleftretromolartrigone,tongueorfloorofmouth.

ThepretreatmenthistopathologicalexaminationofthebiopsyspecimenfromcheekmucosawasdoneineachcaseandhistopathologicalstagingofOSMFwasdoneaccordingtoPindborgandSirsatcriteria19.

All the four histopathological stages viz., very early, early, moderately advanced and advanced stage were given scores of 1, 2, 3 and 4 respectively. Patients were randomly divided into groupA and Baccording to a lottery system by keeping a mixtureof50chitseachofgroup‘A’andgroup‘B’.Patientswere asked to pick up one chit and his treatmentgroupwasdecided.Patientsofgroup‘A’(n=50)were

treated by a combination of hydrocortisone acetate(1.5 ml 25 mg/ml) and hyaluronidase (1500 IU) atweeklyintervalfor22wkandgroup‘B’weretreatedbyacombinationoftriamcinoloneacetonide,10mg/ml and hyaluronidase (1500 IU) at 15 days intervalfor 22 wk, i.e.11injectionsin22wk.Injectioninallpatients were given submucosally in retromolar trigone andadjacentsoftpalateandcheek,halfdoseoneachside by one observer and response to treatment was assessedbyanotherobserver.Theotherclinicianwhowas observing response to treatment was not aware of the treatment group. After completion of treatment,repeat biopsy andhistopathological examinationwasdone to look forhistopathological improvement.Thehistopathologist who was evaluating post-treatmentbiopsies was not aware of the treatment group.The response to treatment was assessed by notingsubjective improvement in symptom score, objectiveimprovementinsignscoreandhistopathologicalscore.Sideeffectsoftreatmentbothlocalaswellassystemice.g.,weightgain,bloodpressureetc., were also noted. Periodofpost-treatmentfollowupwasthreemonths.Alltheregisteredpatientswerefollowedup.

Results

Patients of OSMF were between 14-65 yr old,a majority in their 30 (average 34 yr). The male to

femaleratiowas6.14:1.71percentwereinthehabitofusingpanmasalaordohra.Only22percentusedthemwith betel quid and 7 per cent used betel quid only.Pre-treatment histopathological staging showedmostpatientsinmoderatelyadvancedstage(55%)followedbyearlystage(43%)andadvancedstage(2%).

Allthepatientswhowereregisteredwerefollowedupfor3monthsaftercompletionoftreatment.Therewerenodropouts.Allthepatientswereawareofthefactthattheyarebeingtreatedforapre-cancerouslesion.Therewasnodelayfromdiagnosistocommencementoftherapy.Butmanypatientsalthoughinitiallyagreedfor a post-treatment biopsy, refused biopsy after completion of treatment.

Table I shows pre-treatment and post-treatmentsymptom and sign scores, improvement in total (i.e. symptom+sign)scoreandhistopathologicalscoreingroupA and B.A comparison between both groupsdidnotprovideanystatisticallysignificantdifference(P>0.05).

Table II shows the details of change inhistopathological stage of OSMF in both treatmentgroups. Figs 1 and 2 show the photograph ofhistopathologyslidesofapatientfromgroup‘A’whichshows change in stage frommoderately advanced to

Table I. Pretreatmentandpost-treatmentsymptomandsignscore,improvementintotal(i.e.symptom+sign)scoreandhistopathologicalscoreingroup‘A’(n=50)andgroupB(n=50)(Dataaremean±SD)

ScoreGroupA GroupB

Pre-treatment Post-treatment Reduction in score Pre-treatment Post-treatment Reduction in scoreSymptomsBurning sensation in mouthuponconsumption of spicy orhotfoods

336.56±27.16 42.48±7.26 294.48±15.76 328.18±31.43 37.67±9.11 291.04±16.41

Repeatedvesicle/formationin oral mucosa

147.33±15.58 22.49±5.67 124.89±15.24 149.71±12.69 19.88±6.42 129.27±14.72

Signtrismus 304.17±19.58 133.33±11.48 170.42±16.27 292.59±17.97 127.35±13.67 165.89±15.11Ankyloglossia 205.54±16.67 95.47±8.59 110.72±17.51 195.83±19.13 90.28±9.81 105.67±16.76Vesicles/Ulcers 46.26±5.72 11.16±2.76 35.61±7.24 44.52±5.78 10.57±2.89 33.94±8.41Fibrosis 680.59±47.86 360.43±27.51 320.76±54.76 688.59±47.46 354.73±29.21 333.86±61.53Total(Symtom+sign)Score

1707.42±77.41 659.28±49.87 1049.01±97.14 1695.49±81.57 633.48±41.56 1036.01±86.95

Histopathologicalscore

39.05±4.89 29.43±3.78 9.67±1.72 40.58±5.06 30.55±4.78 10.23±2.05

ComparisonbetweenmeanreductionofscorebetweenGroupAandGroupBshowsnostatisticalsignificantdifferencebetweensymptoms,signscore,improvementintotal(symptom+sign)scoreandhistopathologicalscore(P>0.05)

SINGHet al:EFFICACyOFHyDROCORTISONEACETATEVSTRIAMCINOLONEACETONIDEINOSMF 667

668 INDIANJMEDRES,MAy 2010

earlystageandFigs3and4showedsimilarchangeingroup‘B’.Nolocalorsystemicsideeffectswerefoundineithertreatmentgroups.

Discussion

Despite much progress in understandingpathogenesis9,20 treatment of OSMF in the absence

of properly designed trials and lack of standardized dosesanddurationof treatmentwehad standardizedand recommended the treatment18. The problemwiththis treatment was injections at weekly interval.triamcinolone acetonide is a better corticosteroid for intralesional injection as it has better local potency,longer duration of action and lesser systemic absorption. Itwashypothesizedthatifitwillbegivenat15daysintervalasinthetreatmentofkeloidandhypertrophicscar,thenitwillbeconvenienttothepatients.However,therewasnotasinglebigstudy.Onlycasereportswereavailable10.Wehadfollowedanewscoringsysteminwhicheachsymptom,signandhistopathologicalstageofOSMFwasgivenaparticularscorebeforeandaftercompletionoftherapy.Objectivityofthestudywasthusincreased by observing improvement in symptom score and by measuring pre and post-treatment interincisor distance with a caliper and seeing histopathological

Table II. Pre-treatmenthistopathologicalstagingandpost-treatmenthistopathologicalstagingofbothgroupA(n=15)andgroupB(n=15)Histopathological staging

GroupA GroupBPre-

treatmentPost-

treatmentPre-

treatmentPost-

treatmentVery early 0 2 0 2Early 6 12 5 11Moderately advanced

9 1 10 2

Advanced 0 0 0 0

Figs 1-4.Photographsofhistopathologyslidesofapatientfromgroup‘A’(Figs 1 & 2)andgroup‘B’(Figs 3 & 4)whichshowchangeinstage from moderately advanced to early stage.

(1)

(3)

(2)

(4)

Reprint requests:DrMangalSingh,Professor,DepartmentofENT&Head&NeckSurgery,M.L.NMedicalUniversityCollege& S.R.N.Hospital,Allahabad211001,India

e-mail:drmangalsingh@rediffmail.com

improvement.Noneof thepreviousstudieshadusedthistypeofoutcomemeasures.Itisclearfromourstudythattherewasstatisticallysignificantimprovementinsymptomscore,signscore,histopathologicalscoreinbothgroups after treatment and further therewasnostatistically significant difference in outcome in bothgroups‘A’and‘B’.Therewerenosideeffectsineithergroup. Therefore, it is obvious that both treatmentregimenshavesimilaroutcome.Treatmentregimenofgroup‘B’ismoreconvenienttothepatient’sbecauseitrequireslessnumberofvisitstotheconsultantsand,therefore,itischeaperalso.Henceitisrecommendedthat triamcinolone acetonide (10 mg/ml) combinedwith 1500 IU of hyaluronidase should be givenintralesionally particularly in retromolar trigone area half dose each side at 15 days interval for a total of11 injections in 22 wk. This treatment regimen wasbetter than IFN-γbecause in thepresent study,meanimprovement in trismus was 18 mm in group 'B' as comparedtogainof8±4mmwithIFN-γandtherewerenosideeffectsascomparedtoIFN-γ14.

Inhistopathologicalstagingnopatientwasfoundinearlystagemaybetothefactthatwehaveincludedonly stage II cases of OSMF2. total improvement in histopathological score in group ‘A’ and ‘B’was9.67+1.72 and 10.23+2.05 respectively. None ofthe earlier study looked at post treatment histo-pathologicalchanges.Ourstudysomeshortcomingslike long term effects after completion of therapycould not be done.

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