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RESEARCHOpenAccessThepathologicresponseofresectedsynovialsarcomastohyperthermicisolatedlimbperfusionwithmelphalanandTNF-α:acomparisonwiththewholegroupofresectedsofttissuesarcomasBenjaminSchwindenhammer1,LarsErikPodleska2,AndreaKutritz1,SebastianBauer3,Sien-YiSheu1,GeorgTaeger2,KurtWernerSchmid1andFlorianGrabellus1*AbstractBackground:Hyperthermicisolatedlimbperfusionwithtumornecrosisfactor-αandmelphalan(TM-HILP)hasbeensuccessfullyusedtotreatlimbsofttissuesarcomas(STSs)withhighresponserates.
ThedataontheeffectivenessofHILP-TMforthetreatmentofSTSsaremainlybasedonvariousSTStypes.
Theaimofthisstudywastoinvestigatetheresponsesofsynovialsarcomas(SS)toTM-HILP.
Methods:Atotalof125TM-HILP-treatedtumors(STSall),including14SSs,wereincludedinthestudy.
Thetumorsweresubdividedintoproximalanddistallimblocalizations.
Tumortyping(usingtheWHOclassification),resectionstatus(usingtheUICCclassification),andresponsetotherapywereassessedusinglightmicroscopy.
TheSSsweretestedfortheSYT-SSXtranslocationusingRT-PCR.
Thefollowingtestswereapplied:achi-squaredtest,attest,andtheMann-WhitneyUtest.
Results:TheSSswerelocalizeddistallymoreoftenthanweretheSTScohort(STSSS)(85.
7%vs.
32.
4%)andweresmaller(5.
8cmvs.
10.
7cm).
Therewerenodifferencesintheresponder/nonresponderratiosorthemeanpercentagesofpathologicalregressionbetweentheSSandSTSSScohorts(74.
0%vs.
76.
0%).
Agenerallocalization-dependentdifferenceinthetumorresponsestoTM-HILPcouldnotbedetectedintheSTSallcohort(distal,72.
0%vs.
proximal,78.
0%);however,aUICCR0statuswasmoreoftenobservedinproximaltumors(distal,50.
0%vs.
proximal,71.
4%).
TherewasnoassociationbetweentheSYT-SSXtypeandSSresponsestoTM-HILP.
Conclusions:Becauseofthehighresponserates,TM-HILPisrecommendedforthetreatmentofSSs.
ThedistallimblocalizationofTM-HILP-treatedSTSswasgenerally(STSallcohort)associatedwithfewerR0resections.
Keywords:Isolatedlimbperfusion,Softtissuesarcomas,Synovialsarcomas,Tumorregression,TumorresponseBackgroundSofttissuesarcomas(STSs)aremembersofaheteroge-neousgroupoftumorsthatencompassesmorethan50subtypes.
ThemajorityofSTSsarelocatedinthelimbs.
Themainstayoflocaltreatmentforsarcomasoftheex-tremitiesislimb-sparingsurgerywithcompletetumorresectionandclearsurgicalmargins[1].
Hyperthermicisolatedlimbperfusionwithtumorne-crosisfactor-α(TNF-α)andmelphalan(TM-HILP)isapromisinglocaltreatmentforlocallyadvancedSTSs,suchasnonresectableSTSsofthelimbs,andhasresultedinhightumorresponseratesandhighlimbsal-vagerates[2].
STSsrepresentaheterogeneousgroupofmalignancieswithdifferenttumorbiologyandprognoses;however,thepathologicalgrading,clinicalevaluationandtreat-mentofSTStypesfollowcommonprinciples.
PublisheddataontheeffectivenessandoutcomesofTM-HILP-treatedSTSsarebasedonmixedSTScohorts:*Correspondence:florian.
grabellus@uk-essen.
de1InstituteofPathologyandNeuropathology,UniversityHospitalofEssenandSarcomaCenterattheWestGermanCancerCenter(WTZ),UniversityofDuisburg-Essen,Hufelandstrasse55,45122,Essen,GermanyFulllistofauthorinformationisavailableattheendofthearticleWORLDJOURNALOFSURGICALONCOLOGY2013Schwindenhammeretal.
;licenseeBioMedCentralLtd.
ThisisanOpenAccessarticledistributedunderthetermsoftheCreativeCommonsAttributionLicense(http://creativecommons.
org/licenses/by/2.
0),whichpermitsunrestricteduse,distribution,andreproductioninanymedium,providedtheoriginalworkisproperlycited.
Schwindenhammeretal.
WorldJournalofSurgicalOncology2013,11:185http://www.
wjso.
com/content/11/1/185undifferentiatedsarcomasandliposarcomasubtypesrepresentthemajorityofcases.
Inthesestudies,onlysporadichistopathologicalregressiondatawereobtainedafterTM-HILP,andtheSSregressionresultsarepresentedforonlysmallnumbersofcasesandwithvari-ableresults(Table1).
TheaimofthisstudywastoinvestigatetheSTSsubgroupofsynovialsarcomas(SSs)andtheirhisto-pathologicalresponsestoTM-HILPandtocomparetheresultswiththoseforthecompleteTM-HILP-treatedSTScohort(STSSS)andwiththosefoundintheliterature.
MethodsPatientsFromFebruary2002toNovember2012,164patientswithSTSs(including20withSS)weretreatedwithTM-HILPattheUniversityHospitalofEssen.
Resectionspecimenscouldbeobtainedfrom125(76.
2%)patients(STSall),including14patientswithSSs,forwhomTM-HILPwasperformedtotreatanonresectablesofttis-suesarcomamanifestation.
PatientswereselectedfortheTM-HILPprogramaccordingtotheinclusioncriteriaoutlinedbyEggermontetal.
[21].
PatientevaluationandTM-HILPtreatmentwereexclusivelyperformedbythesamespecializedteam.
Inbrief,TM-HILPwasperformedundermildhyperthermia(39°C)andleakagemonitoringwithradiolabeledserum.
Theadministereddoseofrecombin-anthumanTNF-αwasadjustedto0.
25mg/lperfusedtis-suevolume(butnotlessthan1mg/limb),andmelphalan(L-phenylalaninemustard)wasusedatconcentrationsof11mg/lforlegsand13mg/lforarms.
Allthepatientsprovidedinformedconsent,andthestudywasperformedstrictlyaccordingtotheDeclar-ationofHelsinki.
GrosspathologyAllthespecimenswerefixatedin4%neutralbufferedformalin.
Forallthespecimens,agrossestimationoftumornecrosiswasrecordedandaminimumofoneblockpercentimeterofthelargestdimensionofthetumorwascollected.
HistopathologyBasicmicroscopicevaluationofH&E-stainedslideswasperformed.
TypingandgradingTheSTSsweretypedaccordingtotheWorldHealthOrganization(WHO)classificationoftumorsforSTSsandbonetumors.
TheSTSsweregradedusingpri-marybiopsiesaccordingtotheFrenchFédérationnationaledescentresdeluttecontrelecancer.
Duringsubtyping,theSSswerefurtherdividedintospindlecell(monophasicfibrous),biphasic,andpoorlydiffer-entiatedtypes[22].
TumorregressionaftertherapyTotalregressionwasassessedusinglightmicroscopy(Figure1)andwasdeterminedasthepercentageofthedevitalizedtumorafterTM-HILP.
Tumorregressionwasgradedusingthesix-stagegradingscaleofSalzer-Kuntschik[23],andthetumorswerefurthersubdividedinto'responders'(90%;3*90%to60%Modest[11]52*80%,1*10,35,70%Modest[12]43*>90%;1*10to50%Good[13]and[14]43*≥50%;1*50%Poor[17]21*100%,1*>80%Good[18]21*80%;1*95%Good[19]2NotspecifiedforSS-[20]a11*>50%-StudieswithcompletehistopathologicalregressiondataorareportofSSregressionwereincluded;aTM-HILP+interferon-γ.
Schwindenhammeretal.
WorldJournalofSurgicalOncology2013,11:185Page2of7http://www.
wjso.
com/content/11/1/185[24].
Finally,thePCRproductswerevisualizedusingelec-trophoresiswith2%agarosegelsandethidiumbromidestaining.
TheDNAfromSYT-SSX1-andSYT-SSX2-posi-tiveSSsservedaspositivecontrols.
StatisticsStatisticalanalyseswereperformedwithIBMSPSSSta-tistics19.
Thefollowingtestswereapplied:achi-squaredtest,attest,andtheMann-WhitneyUtest.
Pvalues≤0.
05wereconsideredstatisticallysignificant.
ResultsPatientsThemale-to-femaleratioswere6:8forthesynovialsar-coma(SS,Table2)cohortand52:59forthecompleteSTScohort(STSSS).
ThemeanageoftheSSpatientswaslowerthanthatoftheSTSSSpatients(45vs.
57years;ttest,P<0.
01).
TheSSsweremainlyprimarytu-mors(8/14,57.
1%).
Fivetumorswererecurrences,andonetumorwasaresiduumafterpriorsurgery(STSSS:86primarytumors,77.
5%;22recurrences,19.
8%;and3residua,2.
7%).
Moreover,thetumorsintheSScohortweremoreoftenlocalizeddistally(proximal/distal:SS,2/12,85.
7%vs.
STSSS,75/36,32.
4%;chi-squaredtest,P<0.
001).
Distallocalizationwasdefineddistallyrela-tivetothekneeorelbowjoint.
ThefootwastheprimarylocalizationoftheSScohort(5/14,35.
7%),andthethighwasthemostfrequentsiteoftheSTSSScohort(60/111,54.
1%).
PathologyBasicparametersThemostfrequentSTSsubtypesoftheSTSSScohortweretheundifferentiatedpleomorphicsarcoma(28/111,25.
2%)andliposarcomatypes(23/111,20.
7%).
ThetumorgradesaccordingtotheFrenchFédérationnationaledescentresdeluttecontrelecancer(threegrades:1,2,and3)were0,8,and6fortheSScohortand7,49,and55fortheSTSSScohort.
Moreover,theSSsweresignificantlysmalleratthetimeofresectionFigure1MacroscopicandmicroscopicfeaturesoftwoSSsaftertreatmentwithTM-HILP.
(A-C)Casenumber5,nonresponder.
(A)7.
9cmSSofthefootwitharegressionof65%afterTM-HILP.
(B)Necroticareaswithyellowtumorchangesandviabletumorresiduesinproximitytoaremovedtendonsegment(*).
(C)Histopathologyofapredominatelyviabletumornexttothecross-sectionofatendon(*).
Thetumorinfiltratestheinkedmargin(arrow).
(D-F)CaseNumber6,responder.
(D)9.
0cmSSofthelowerlegwitharegressionof99%.
(E)Abundantareasofyellownecrosismixedwithglassy-whitescleroticareasaftertherapy.
(F)Histopathologyrevealedonlyafewsmallfociofviabletumor(arrows).
Theseresidueswerecompletelyremoved.
Schwindenhammeretal.
WorldJournalofSurgicalOncology2013,11:185Page3of7http://www.
wjso.
com/content/11/1/185afterTM-HILP(meansize:SS,5.
8cmvs.
STSSS,10.
7cm;Mann-WhitneyUtest,P=0.
004).
RegressionafterTM-HILPTherewere7/14(50.
0%)respondersintheSScohortaccordingtotheSalzer-Kuntschikregressiongradingscale.
Two(14.
3%)ofthoseSSsexhibitedcompletepatho-logicalregression.
TheSTSSScohortincluded66/111(59.
5%)responders,ofwhich24(21.
6%)werecompleteresponders.
Therewerenodifferencesintheresponder/nonresponderratios(chi-squaredtest,P=0.
499)orinthemeanpercentagesofpathologicalregressionbetweentheSSandSTSSScohorts(SS,74.
0%vs.
STSSS,76.
0%;Mann-WhitneyUtest,P=0.
776,Figure2).
BecauseofthepredominantdistallocalizationoftheSSsinthisstudy,wedidnotdetectanylocalization-dependent(distal/proximal)differencesinthetumorresponsestoTM-HILPaccordingtothemeanpercentagesofpathologicalregressionintheSTSallcohort(distal,N=48,72.
0%vs.
proximal,N=77;78.
0%;Mann-WhitneyUtest,P=0.
493).
TheSYT-SSXfusiontypeandresponsesOverall,tenSScaseswereSYT-SSX1-positiveandthreewereSYT-SSX2-positive.
Inonecase(seeTable1),noneofthefusionscouldbedetectedbyPCR.
DespitethenegativemolecularpathologicalresultsforSYT-SSX1andSYT-SSX2,thistumorwastypedasSSbythreesar-comaexpertsatthreedifferentinstitutionsbecauseofitsconventional,immunohistochemicalcharacteristicsandaborderlinefluorescenceinsituhybridizationresult.
TheSSswiththesegeneticsignaturesincludedbothrespondersandnonresponders(seeTable1),andtherewerenosignificantdifferencesamongtheresponsestoTM-HILP.
TheSYT-SSX2fusiontypewasexclusivelyfoundinfemalepatients(3/3).
ResectabilityTheinvestigationoftheresectionstatus(UICC,Rclassi-fication)found8/14(57.
1%)completeresections(R0sta-tus)intheSScohort.
Bothcompleteresponders(100%pathologicaldevitalization)intheSSgrouphadanR1status.
Completeresectionwasobservedin71/111(64.
0%)STSSStumors.
Thisdifferencebetweenthegroupswasnotstatisticallysignificant(chi-squaredtest,P=0.
618).
BothproximalSSs(2/2)and6/12ofthedis-talSSswerecompletelyresected,whichisprincipallyinlinewiththeresultsbelow,butwasnotsignificantforFigure2Boxplotsshowacomparisonoftheregressionresults(%)betweenthesynovialsarcomas(SS,N=14)andthecomparisongroup(STSSS,N=111).
Nosignificantdifferencesweredetected.
Table2CharacteristicsofthesynovialsarcomasTumornumberAgeofpatientSexofpatientSStypeSYT-SSXfusiontypeLocalizationSize(cm)Regression(%)152FemaleSpindlecellSSX2Foot3.
599244MaleSpindlecellSSX1Forearm3.
23324FemaleSpindlecellSSX2Lowerleg2.
585424MaleSpindlecellSSX1Thigh6.
298575FemaleBiphasicSSX1Foot7.
965629FemaleBiphasicSSX2Lowerleg9.
099738FemaleSpindlecellSSX1Thigh16.
020865MaleSpindlecellSSX1Foot5.
580970FemaleBiphasicSSX1Forearm3.
51001046MaleSpindlecellSSX1Lowerleg7.
0301110FemalePoorlydifferentiatedWildtypeFoot4.
01001245MaleBiphasicSSX1Lowerleg10.
0651358MaleSpindlecellSSX1Foot3.
0991450FemaleSpindlecellSSX1Forearm1.
298Schwindenhammeretal.
WorldJournalofSurgicalOncology2013,11:185Page4of7http://www.
wjso.
com/content/11/1/185theSSgroupalone.
However,theresectionstatusresultsoftheproximalanddistallimblocalizationsindicatedbetterresectabilityforproximalSTSsintheSTSSSco-hortaccordingtotheR0status(53/71R0proximal,74.
6%vs.
22/40R0distal,55.
0%;chi-squaredtest,P=0.
034).
Thisresultremainedstatisticallysignificantwhenthe14SSswereincludedinthecalculation(STSall:55/77,71.
4%vs.
24/48,50.
0%;chi-squaredtest,P=0.
016).
DiscussionThetreatmentofSTSsisincreasinglydeterminedbytheidentificationofhistologicalsubtypesinafamilyofun-commoncancersthatcomprisesmorethan50subtypes[25].
PublisheddataontheeffectivenessandoutcomesofTM-HILP-treatedSTSsarebasedonstudiesinwhichcommonandrareSTSentitiesweremixed[2].
Histologyisrelevantfortargettherapiesandnowforthepreciseapplicationofconventionalchemotherapyregimens;therefore,wesuggestthattheeffectofTM-HILPonSTSsubentitiesshouldbeconfirmed.
ThefrequenciesandsizesoftheSSsSSsrepresentapproximately5%to10%ofallSTSs.
Be-causeoftheirpredominantlocalizationwithinthelimbs,thefrequencyofSSsatlimbsiteshasrangedfrom12%to15%ofalllimbSTSs[26].
ThefrequencyofSSsinthisinvestigationwas11.
2%inalimbSTScohort,whichiswithintherangeofpreviouslypublisheddata.
Add-itionally,weobservedasmallermediantumorsize(4.
2cm)thanthatreportedforlargeSScohorts(6to7cm)[27-30].
Thisfindingmaybeaconsequenceofthevari-oustumorsinthisstudy,whichincludedprimarytu-mors(5.
5cm)andrecurrencesandresidualtumorsaftersurgery(3.
7cm).
LocalizationoftheSSsMostSSsarelimb-basedtumors.
Approximately67%to86%ofSSsarisewithintheextremities[27-31].
OfthoseSSs,distallocalizationwasfoundin47%to71%[27,29,31]ofcases,whichisapproximatelytwiceashighastheratesforlimbSTSs[32,33].
Additionally,ahigherratewasfoundinthisstudy(86.
7%),whichisahallmarkofisolatedlimbperfusion(ILP)studies.
ResponsesofSSstoTM-HILPTheclinicalandpathologicalresponseratesofsarcomastoTM-HILParetypicallyhigh.
ThemeanclinicaloverallresponseinTM-HILPstudiesaccordingtotheWHOcriteria[34]wasinitiallyreportedtobemorethan90%withcompleteresponsesinmorethan80%ofcases[35].
Todate,thelargeststudieshaveadjustedtheseclinicaldatadownwardtoanoverallresponserateofapproxi-mately70%andacompleteresponserateof20%[36].
Interestingly,clinicalandpathologicalresponseevaluationshaveoftendifferedsubstantially,whichwehaverecentlydemonstratedtobetheresultofaninsufficiencyinsize-basedclinicalresponsecriteriathatwouldindicateactualtumorresponses(measuredbyapathologicalinvestigationasthegoldstandard)[37].
TheSScohortexhibitedameanpathologicalresponseratethatwasapproximatelyidenticaltothatoftheSTSSSinthiscohortofresectedSTS.
ThisindicatesthatTM-HILPcanberecommendedforthisSTSsubtypedespitethedisproportionatenumberofdistallimblocalizations.
ResponsesofthegeneticsubtypestoTM-HILPThet(X;18)translocation,whichresultsfromtheSYT-SSX1andSYT-SSX2genefusions,isfoundinapproxi-matelyallSSs[26].
Thisgeneticalterationhasnotyetbeenfoundinanyotherhumanmalignancy;therefore,thesegeneticsignatureshavesignificantdiagnosticvalue.
TheimpactoftheSYT-SSXfusiontypeontheclinicalbehaviorofSSsisthesubjectofscholarlydiscoursewithcontrastingresults[28,38].
Theinfluenceofthetrans-locationtypeontheresponsetotreatmenthasnotbeeninvestigatedtodatebutmightbereflectedbytheprog-nosticsignificanceofthetypeaccordingtometastaticpotentialandoverallsurvivaltimes[38,39].
ThisstudydidnotfindvaryingresponsestoTM-HILPamongtheSYT-SSXtranslocationtypesinoursmallSScohort.
ResectabilityoftheSSsafterTM-HILPThemainstayofsurgicaltreatmentforSTSsislimb-sparingresectionwithclearsurgicalmargins[1].
Thereisdisagreementregardingthesizeofanadequatewidesurgi-calmargin[1].
TM-HILPisindicatedonlyforthesub-groupofSTSpatientswhoarecandidatesfordisablingsurgeryoramputation.
Inthisstudy,asurgicalapproachwithoncologicaladequacyofmarginwidthwasnotpos-sible.
EvenafterTM-HILP,themarginsizeandqualityisgenerallypoor[40].
However,wehavepreviouslydemon-stratedthatlocaltumorcontrolafterTM-HILPandresec-tionissuperiorcomparedwithnonpretreatedSTSs,mostprobablyduetothestrongtoxiceffectsofTM-HILPonthetumorperiphery[3,40].
Thisstudydemonstratedahighrateofdistallylocatedtumors(40%),whichistypicalforILP-treatedSTScohortscomparedwithmostnon-ILP-treatedcohorts.
Becauseofthespecificanatomicconditionsthatarefoundinthedistalpartsoftheextremities,therateofcompleteresectionswithclearsurgicalmarginsisgener-allylow[41].
Tumorsarefrequentlyratedas'primarilyunresectable'andarepossiblecandidatesforTM-HILPprograms.
Severallargestudieshavedemonstratedprox-imalanddistallocalizationsofSTSsbutonlyprovidedthehistologicalmarginstatusforthecompletecohort(≈10%to20%R1-resections)[33,42,43].
Studiesthathaveselectivelyinvestigated'distalSTSs'havenotSchwindenhammeretal.
WorldJournalofSurgicalOncology2013,11:185Page5of7http://www.
wjso.
com/content/11/1/185includedhistopathologicaldataconcerningthesurgicalmargins[44-48].
Thisstudyfoundacomparativelyhighrateofincom-pletelyresectedtumorsafterTM-HILP(38.
4%),whichisinagreementwithresultsfromstudiesinRotterdam[15,36].
Inaddition,thisstudyfoundasignificantlyre-ducedresectability(intermsoftheR0classification)rateindistallimblocalizations[15].
Interestingly,theaveragewidthofthemarginsoftheR0resectedtumorsdidnotvarysignificantlyaccordingtolocalizationandwaslow:theproximalmeanwas0.
8mm,andthedistalmeanwas1.
2mm.
AworseningoftheeffectivenessofTM-HILPondis-tallylocatedSTSs,possiblyduetoimpairedbloodflow,wasnotdetectedinourstudy.
Derooseetal.
[15]re-centlyinvestigatedSTSsofdistallimbsandfoundalimbsalvagerateof87%afterTM-HILP.
Theystated,'TM-ILPisaneffectivetreatmentmodalityinpatientswithdistalSTS,'buttheyfoundaconsiderablyloweraveragepercentageofpathologicalregressionthanthatinthisstudy(33.
4%vs.
70.
0%).
ConclusionInconclusion,wefoundthatthepreoperativetreat-mentTM-HILPisaseffectiveforthesubentityofSSsasforthecompletegroupofSTSs.
Accordingly,TM-HILPisrecommendedforthistumortypeeventhoughitisoftenlocateddistally.
AdistallocalizationresultedinreducedresectabilityintheSTSallcohortaccordingtotheR0rate,butthemarginsizeofthecompletere-sectionsdidnotdiffersignificantlybetweenbothtypesoflocalization.
AbbreviationsH&E:hematoxylinandeosin;ILP:isolatedlimbperfusion;RT-PCR:reversetranscriptasepolymerasechainreaction;SS:synovialsarcomasorcohortofSSofthisstudy;STS:softtissuesarcomas;STSall:allsofttissuesarcomasofthepresentstudy(SSincluded);STSSS:softtissuesarcomasofthepresentstudy,excludingSS(comparisongroup);TM-HILP:hyperthermicisolatedlimbperfusionwithTNF-αandmelphalan;TNF-α:tumornecrosisfactor-α;UICC:UnionforInternationalCancerControl;WHO:WorldHealthOrganization.
CompetinginterestsTheauthorsdeclarethattheyhavenocompetinginterests.
Authors'contributionsBS,LEP,AK,GTandFGmadesubstantialcontributionstoconceptionanddesign,oracquisitionofdata,oranalysisandinterpretationofdata.
BSwasresponsibleforhistopathology.
LEPandGTwereresponsiblefortheclinicaldata.
AKwasresponsibleforgenetictesting.
FGwasresponsibleforhistopathologyandstatistics.
BS,LEP,SSandFGwereinvolvedindraftingthemanuscriptorrevisingitforimportantintellectualcontent.
BSandKWSdesignedthestudyanddraftedthemanuscript.
Allauthorsreadandapprovedthefinalmanuscript.
Authordetails1InstituteofPathologyandNeuropathology,UniversityHospitalofEssenandSarcomaCenterattheWestGermanCancerCenter(WTZ),UniversityofDuisburg-Essen,Hufelandstrasse55,45122,Essen,Germany.
2DepartmentofTraumaSurgery(MusculoskeletalSurgicalOncology),UniversityHospitalofEssenandSarcomaCenterattheWestGermanCancerCenter(WTZ),UniversityofDuisburg-Essen,Essen,Germany.
3DepartmentofInternalMedicine(CancerResearch),UniversityHospitalofEssenandSarcomaCenterattheWestGermanCancerCenter(WTZ),UniversityofDuisburg-Essen,Essen,Germany.
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:ThepathologicresponseofresectedsynovialsarcomastohyperthermicisolatedlimbperfusionwithmelphalanandTNF-α:acomparisonwiththewholegroupofresectedsofttissuesarcomas.
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