Muscular Tissue

30/9/2016
ChondrosarcomaUpToDate
OfficialreprintfromUpToDate
www.uptodate.com2016UpToDate
Chondrosarcoma
Authors: AJGelderblom,MD,PhD,JudithVMGBove,MD,PhD
SectionEditor: RobertMaki,MD,PhD
DeputyEditor: DianeMFSavarese,MD
Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Aug2016.|Thistopiclastupdated:Dec15,2015.
INTRODUCTIONChondrosarcomasareaheterogeneousgroupofmalignantbonetumorsthatshareincommontheproductionofchondroid
(cartilaginous)matrix[1].Chondrosarcomasarethethirdmostcommonprimarymalignancyofboneaftermyelomaandosteosarcoma[2].They
accountfor20to27percentofprimarymalignantosseousneoplasms[3].
Clinicalbehaviorisvariable.Ninetypercentareconventionalchondrosarcomas,90percentofwhicharelowtointermediategradetumors[4].These
tumorsareslowgrowingwithalowmetastaticpotential.Theyareconsideredrelativelyrefractorytochemotherapyandradiationtherapy.
Incontrast,highgradechondrosarcomas,whichinclude5to10percentofconventionalchondrosarcomasaswellassomerarevariants,haveahigh
metastaticpotentialandapoorprognosisfollowingresectionalone[4].Someoftheraresubtypesaremoreresponsivetochemotherapyandradiation.
Thistopicreviewwillprovideanoverviewoftheclassification,clinicalcharacteristics,andtherapeuticoptionsforchondrosarcoma.Therare
chondrosarcomasinvolvingtheheadandneckandskullbase,aswellasdiagnosisandbiopsytechniquesforbonesarcomasingeneral,arediscussed
separately.(See"Chordomaandchondrosarcomaoftheskullbase"and"Headandnecksarcomas"and"Bonetumors:Diagnosisandbiopsy
techniques".)
HISTOLOGICGRADINGANDPROGNOSISHistologicgradeisoneofthemostimportantindicatorsofclinicalbehaviorandprognosis[58].
Chondrosarcomasaregradedonascalefrom1to3,baseduponnuclearsize,stainingpattern(hyperchromasia),mitoticactivity,anddegreeof
cellularity(picture1).
Grade1chondrosarcomaswerereclassifiedintheupdatedWorldHealthOrganization(WHO)2013classificationsystemas"atypicalcartilaginous
tumours"(ACT/CS1)[1].Theyaremoderatelycellular,withanabundanthyalinecartilagematrix.Thechondrocyteshavesmall,roundnucleiand
areoccasionallybinucleate.Mitosesareabsent.ACT/CS1almostnevermetastasize(1percentriskinoneseriesofpatients[4])andaretherefore
nowconsideredalocallyaggressiveneoplasmratherthanamalignantsarcoma.Tenyearsurvivalis83to95percent[4,5,9].
Grade2chondrosarcomasaremorecellularwithlesschondroidmatrixthanACT/CS1tumors.Mitosesarepresent,butwidelyscattered.The
chondrocytenucleiareenlargedandcanbeeithervesicularorhyperchromatic.Themetastaticpotentialisintermediatebetweenlowgradeand
highgradechondrosarcomas(approximately10to15percent).Tenyearsurvivalisapproximately64to86percent[4,5,9].
Thevastmajorityofconventional(primaryandsecondary)chondrosarcomasareACT/CS1orchondrosarcomagrade2[4,9,10].
Grade3chondrosarcomasarehighlycellular,withnuclearpleomorphismandeasilydetectedmitoses.Chondroidmatrixissparseorabsent.High
gradechondrosarcomashaveahighmetastaticpotential(approximately32to70percent)andapoorprognosiswithsurgicalresectionalone[4,5].
The10yearsurvivalrateisapproximately29to55percent[4,9].
Inmostcases,thehistologicgradeofdifferentiationofarecurrentchondrosarcomaisthesameastheprimarylesionhowever,upto13percentof
recurrencesexhibitahighergradeofmalignancywhencomparedwiththeoriginalneoplasm[5,9,11].Thissuggeststhatchondrosarcomascan
progressbiologically.
Histologicgradingissubjecttointerobservervariability[12,13],whichcanbeproblematicsincesurgicaltherapyforACT/CS1andgrade2
chondrosarcomasisoftendifferent.Becauseofthis,thereisanurgentneedformolecularmarkersthatcanbeusedtopredictclinicalbehavior,guide
therapeuticdecisionmaking,andprovidenoveltargetsformolecularlytargetedtherapy[14].(See'Surgicaltreatment'belowand'Noveltherapies'
below.)
CLASSIFICATION,HISTOLOGY,ANDCLINICALFEATURES
PrecursorlesionsTwobenigncartilaginouslesionsthatcanprecedechondrosarcomaaredescribed:
OsteochondromaAnosteochondroma(osteocartilaginousexostosis)isacartilagecappedbonyprojectionarisingontheexternalsurfaceofa
bone(picture2andimage1)itcontainsamarrowcavitythatiscontinuouswiththatoftheunderlyingbone.Themajorityarelocatedinthelongbones,
predominantlyaroundtheknee.
Theinheritedconditionmultipleosteochondromas(hereditarymultipleexostoses)ischaracterizedbythedevelopmentoftwoormore
osteochondromasintheappendicularandaxialskeleton.Thissyndromeisinheritedinanautosomaldominantfashion.Theprevalenceinthegeneral
populationis1:50,000,andmalesareaffectedslightlymoreoftenthanfemales.(See"Benignbonetumorsinchildrenandadolescents:Anoverview",
sectionon'Osteochondromaandhereditarymultipleosteochondromas'.)
https://www.uptodate.com/contents/chondrosarcoma/print?source=machineLearning&search=cartilage%20and%20bone%20histology&selectedTitle=1~150&s...
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Almost90percentofcasesofmultipleosteochondromasarecausedbyinheritanceofagermlinemutationinoneofthetumorsuppressorgenesEXT1
orEXT2.(See'Molecularpathogenesis'below.)
Althoughmostareasymptomatic,osteochondromascancausepain,functionalproblems,anddeformitytheyalsocarryariskforfracture.Malignant
transformationisestimatedtooccurin5percentofpatientswithasolitaryormultipleosteochondromas[1520].Inoneseries,theaveragetime
betweeninitialdiagnosisandmalignanttransformationwas9.8years[19].Allchondrosarcomasarisinginthesettingofanosteochondromaare
secondaryperipheraltumors.
Achangeinthesizeofanosteochondromaornewonsetofsymptomswarrantsinvestigation,aseachmayheraldmalignanttransformation[21,22].
Osteochondromaslocatedatthepelvis,hipsandshouldergirdlearereportedtobeparticularlypronetomalignanttransformation[21,22].Among
patientswithmultipleosteochondromas,malignanttransformationappearstobeunrelatedtothepresenceorabsenceofanEXTmutation,sex,
severityofdisease,orthenumberoflesions[20].
EnchondromaEnchondromasarecommonbenigncartilaginoustumorsthatdevelopinthemedulla(marrowcavity)ofbone(image2).When
multipleenchondromasarepresent,theconditioniscalledenchondromatosis(image3),ofwhichthemostcommonformisOllierdisease(estimated
prevalence1in100,000)[23].Whenmultipleenchondromasareassociatedwithsofttissuehemangiomas,thedesignationisMaffuccisyndrome
(image4).Botharecongenitalbutnotinherited.(See"Benignbonetumorsinchildrenandadolescents:Anoverview",sectionon'Enchondroma'.)
OllierdiseaseaswellasMaffuccisyndromearecausedbysomaticmosaicmutationsintheIDH1orIDH2genes[24,25].(See'Molecularpathogenesis'
below.)
Althoughthevastmajorityareasymptomatic,clinicalproblemscausedbyenchondromasincludeskeletaldeformity,limblengthdiscrepancy,andarisk
formalignanttransformation.Malignanttransformationinasolitaryenchondromaispresumedtobeextremelyrare(<1percent)butithasbeen
described(image5)[19].TheriskofchondrosarcomainpatientswithOllierdiseaseorMaffuccisyndromeisashighas50percent[23,2630].Therisk
ishighestwithenchondromaslocatedinthepelvis[29].Malignanttransformationusuallypresentsafterskeletalmaturityandmaybeheraldedbythe
developmentofpain[19].
Thehistologicandradiographicdistinctionbetweenanenchondromaandalowgradechondrosarcomamaybedifficult,eveninexperiencedhands
(see'Histologicappearance'below).
Conventionalchondrosarcomas
CentralchondrosarcomaCentralchondrosarcomasofbonearisewithinthemedullarycavityandconstituteapproximately75percentofall
chondrosarcomas(table1).Themajorityarethoughttoariseprimarily(ie,withoutabenignprecursorlesion).However,thefindingofremnantsofa
preexistingenchondromain40percentofcentralchondrosarcomasandthefactthatmostenchondromasremainasymptomaticandclinicallysilent
haveledsometohypothesizethatmostcentralchondrosarcomascouldbesecondarytoapreexistingenchondroma[31].
Themajorityofpatientsareovertheageof50.Thereisaslightmalepredominance.
Themostcommonlyinvolvedskeletalsitesaretheproximalfemur,bonesofthepelvis(particularlytheilium),andproximalhumerus(together
accountingforabout75percentofcases),followedbydistalfemur,ribs,tibia,andmetacarpalandmetatarsalbones[3,4,32,33].Otherlessfrequently
involvedsitesincludethespine,theskullbase,andthecraniofacialbones.(See"Chordomaandchondrosarcomaoftheskullbase"and"Headand
necksarcomas".)
Localswellingandpainarethemostcommonpresentingsymptoms.Painistypicallyinsidious,progressive,worseatnight,andoftenpresentfor
monthstoyearsbeforepresentation.Apathologicfractureispresentatdiagnosisin3to17percentofpatients[3].Primaryspinalchondrosarcomas
arerarebutcancausecompressionofthespinalcord.
PeripheralchondrosarcomaBydefinition,allperipheralchondrosarcomasarisewithinthecartilagecapofapreexistingosteochondroma(table
1).Patientswithaperipheralchondrosarcomaaregenerallyyoungerthanthosewithacentralchondrosarcoma(table1)[21].Theclinicalpresentation
issimilartothatofcentralchondrosarcoma,usuallypainandlocalswelling.Themostcommonlyinvolvedbonesarethepelvisandbonesofthe
shouldergirdle,althoughinsomeseries,thelongbonespredominate[19].Thedistinctionbetweenosteochondromaandsecondaryperipheralatypical
cartilaginoustumour/chondrosarcomagradeIarisinginosteochondromacanbedifficultandshouldbemadebyamultidisciplinaryteam.Thesizeof
thecartilaginouscapisthemostimportantparameter[34].
PeriostealchondrosarcomaLessthanonepercentofchondrosarcomasariseonthesurfaceofaboneandaredesignatedperiosteal
(previouslytermedjuxtacortical)chondrosarcomas.Theymostfrequentlyaffectadultsintheir20sand30s,andhaveaslightmalepredilection.The
metaphysesoflongbonesaremostfrequentlyinvolved,especiallyofthedistalfemur(figure1).Patientstypicallypresentwithapalpable,painless,
slowlygrowingmass[3,35,36].
Periostealchondrosarcomasusuallyhaveagoodprognosisafteradequatelocalsurgerydespitehistologicfeaturesofahighgradelesion[7,3740].
Histologicalgradingisthereforenotusedatthislocation[36].
HistologicappearanceDespitetheirdifferentoriginandlocation,primaryandsecondarychondrosarcomasappearhistologicallysimilar(picture
1).Atlowmagnification,thereisabundantcartilagematrixproduction,andtheirregularlyshapedlobulesofcartilage,oftenseparatedbyfibrousbands,
maypermeatethebonytrabeculae[1].Necrosisormitosesmaybeseeninhighgradelesions.Thehistologyofperiostealchondrosarcomasissimilar
exceptthattheappearanceisoftenmoreworrisomewithincreasedcellularityandnuclearatypia.
Thehistologic(andradiographic)distinctionbetweenabenigncartilagelesionandanatypicalcartilaginoustumour/chondrosarcomagrade1
(ACT/CS1)canbeextremelydifficult[12,41,42].ACT/CS1ishypercellularwhencomparedtobenigncartilagelesions.Thechondrocytesappearmildly
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tomoderatelyatypicalandcontainenlargedhyperchromaticnucleoli.Permeationofpreexistinghostboneandmucomyxoidmatrixchangesare
importantcharacteristicsthatcanbeusedtoseparateACT/CS1fromanenchondroma[13].Periostealchondrosarcomaisdistinguishedfrom
periostealchondromabaseduponsize(5cm)andthepresenceofcorticalinvasion.Forphalangealenchondromas,moreworrisomehistologic
featuresaretolerated,andthediagnosisofchondrosarcomaatthissiteisbaseduponthepresenceofcorticaldestruction,softtissueinvasion,and
mitoses[43].
Fortunately,thedistinctionbetweenenchondromaandACT/CS1isnotalwaysessentialforclinicaldecisionmaking,sincetreatment(curettageand
adjuvantphenolapplicationorcryosurgery)isoftensimilarforenchondromasaswellascentralACT/CS1(see'Surgicaltreatment'below).
RarechondrosarcomasubtypesInadditiontoconventionalcentral,peripheral,andperiostealchondrosarcomas,severalraresubtypesare
described,togetherconstitutinglessthan10percentofallchondrosarcomas.
DedifferentiatedchondrosarcomaDedifferentiatedchondrosarcomascontaintwojuxtaposedcomponents:awelldifferentiatedcartilagetumor
(whichcanbeeitheranenchondromaoralowgradechondrosarcoma),andahighgradenoncartilaginoussarcomawhichmostfrequentlyisan
osteosarcoma,fibrosarcoma,oranundifferentiatedhighgradepleomorphicsarcoma(previouslytermedmalignantfibroushistiocytoma)(picture3)
[44].
Bothcomponentsappeartosharesomegeneticaberrations[45,46]withadditionalgeneticchangesinthehighgradecomponent[4548].This
suggestsacommonprecursorcellwithearlydivergenceofthetwocomponents.Approximately50percentofdedifferentiatedchondrosarcomasharbor
mutationsinIDH1orIDH2.Thesemutationsarefoundinbothcomponents,confirmingacommonoriginofbothcomponents[49].
Theaverageageatpresentationisolder(between50and60years)thaninotherchondrosarcomasubtypes(table1).Themajorityoccurcentrallyin
medullarybonethemostcommonsitesofinvolvementarethepelvis,femur,andhumerus.Thetypicalpresentationiswithpain,althoughswelling,
paresthesias,andpathologicfracturesarealsocommon[50].Themajorityofpatientshaveanassociatedsofttissuemass[51].
Dedifferentiatedchondrosarcomasarebiologicallyaggressiveandtheyhaveapoorprognosis[11,51,52].Inamulticenterreviewof337patients,71
(21percent)hadmetastasesatthetimeofdiagnosistheyhada10percentchanceofsurvivalattwoyears[11].Evenforpatientswithoutmetastases
atdiagnosis,survivalwasonly28percentat10years.Poorprognosticfactorsincludepathologicfracture,pelviclocation,andolderage.
MesenchymalchondrosarcomaMesenchymalchondrosarcomasarehighlymalignanttumorsthatarecharacterizedbydifferentiatedcartilage
admixedwithsolidhighlycellularareasthatarecomposedofundifferentiatedsmallroundcells(picture3)[53].
Theaverageageis25to30years[54],youngerthanthatofothertypesofchondrosarcoma(table1).Thereisahighproportionofextraskeletal
primarytumors,whichisnotseenwithotherchondrosarcomasubtypes[55].Oftheapproximatelyonethirdofcasesthataffecttheextraskeletalsoft
tissues,themeningesareoneofthemostcommonsites[56].Alsoincontrasttoconventionalchondrosarcomas,mesenchymaltumorsmostcommonly
involvetheaxialskeleton,includingthecraniofacialbones(especiallythejaw)[57],ribs,ilium,andvertebra,andtheremaybeinvolvementofmultiple
bones.Approximately20percenthavemetastaticdiseaseatdiagnosis[58].(See"Chordomaandchondrosarcomaoftheskullbase",sectionon
'Chondrosarcoma'and"Headandnecksarcomas",sectionon'Chondrosarcoma'.)
Themainsymptomsarepainandswelling,anditisnotuncommonforsymptomstohavebeenpresentformanymonths.
Mesenchymalchondrosarcomashaveatendencytowardbothlocalanddistantrecurrences,whichmayariseaslongas20yearsfollowingtheinitial
diagnosis[59].Theprognosisismarkedlyworsethanforconventionalprimarychondrosarcomas.Reported10yearsurvivalratesrangefrom10to54
percent[54,55,5861].
ClearcellchondrosarcomaClearcellchondrosarcomaisararelowgradevariantofchondrosarcomawhichischaracterizedbythepresence
oflobulatedgroupsofblandappearingtumorcellswithlarge,centrallylocatednucleiandclear,emptycytoplasminadditiontohyalinecartilage(picture
3).Mitoticfiguresarerare.Manytumorscontainzonesofconventionalchondrosarcomawithhyalinecartilageandminimallyatypicalnuclei.
Althoughthesetumorscanariseatanyage,mostpatientsarebetweentheagesof25and50(table1).Menarethreetimesmorelikelyaswomento
developthisparticularsubtype[62].Approximatelytwothirdsoftumorsariseintheepiphysealendsofthehumerusorfemur(figure1).Pain,which
mayhavebeenpresentforlongerthanoneyear,isthemostcommoncomplaint.
Serumalkalinephosphataselevelsareoftenelevatedatdiagnosisandmayprovideausefultumormarker[63].
Despitetheirlowgradenature,marginalexcisionorcurettageisassociatedwitha70percentorhigherrecurrencerateandshouldbeavoided[63,64].
Inincompletelyexcisedcases,metastasesmaydevelop,usuallytothelungsandotherskeletalsites,andtheoverallmortalityrateisupto15percent
[62].Incontrast,enblocwidelocalexcisionisusuallycurative.
Diseaserecurrencemayoccurupto24yearsafterinitialdiagnosis[63,64].Longtermfollowupismandatory.
MyxoidchondrosarcomaItisdebatedwhethermyxoidchondrosarcomaofboneisatrueseparateentityorifitrepresentsahighgrade
conventionalchondrosarcomawithprominentmyxoidchange.Thelightmicroscopicfeaturesofmyxoidchondrosarcomaofbonearesimilartothoseof
themorecommonlydescribedextraskeletalmyxoidchondrosarcoma(EMC),asofttissuesarcomathatmostcommonlyarisesinthelowerextremities
[65,66].However,thesetwoentitiesareunrelated[67],andtheterm"chondrosarcoma"todescribeEMCisamisnomer.Wellformedhyalinecartilage
isfoundonlyinaminorityofEMCs[68,69],whileS100expression(whichispresentinallormostchondrosarcomas)isoftenveryfocalorabsent.
ExpressionofcollagenIIandaggrecan(twoothermarkersofcartilaginousdifferentiation)areabsentin86percentofEMCs[69].
Furthermore,thetranslocationt(9:22)thatisspecificforEMCisgenerallyabsentinsocalledmyxoidchondrosarcomaofbone,anditsultrastructureis
different[68,70].Thereportedcasesofmyxoidchondrosarcomaofbonethatcontainaproventranslocationoft(9:22)havealargesofttissue
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componentthatmakesdistinctionfromEMCwithsecondarybonedestructionextremelydifficult[71],althoughsomeconvincingcaseshavebeen
reported[72].(See"Pathogeneticfactorsinsofttissueandbonesarcomas",sectionon'Extraskeletalmyxoidchondrosarcoma'.)
Thus,EMCandsocalledmyxoidchondrosarcomaofboneappeartorepresenttwodifferententities.The2013WHOclassificationclassifiestheentity
EMCinthe"tumorsofuncertaindifferentiation"category[1].Myxoidchondrosarcomasofbonearenotdesignatedasauniqueentity,andthesetumors
shouldberegardedasamyxoidvariantofintermediateorhighgradeconventionalchondrosarcoma.
MolecularpathogenesisCartilaginoustumorsarenearlyalwaysfoundinbonesthatarisefromenchondralossification.Researchhasuncovered
someparallelsbetweenchondrocytegrowthanddifferentiationinthenormalgrowthplateandbothbenignandmalignantcartilaginoustumors[73].
Withinthenormalgrowthplate,restingzonechondrocytesproliferateanddifferentiate,becominghypertrophic.Thesecellsundergoapoptosis,allowing
theinvasionofvesselsandosteoblaststhatstarttoformboneandleadtolongitudinalbonegrowth.Thisphysiologicprocessistightlyregulatedby
componentsoftheIndianhedgehog(IHH)/parathyroidhormonerelated(PTHRP)proteinsignalingpathway.
Patientswithmultipleosteochondromas(previouslycalledhereditarymultipleexostoses)havegermlinemutationsintheexostosin(EXT1orEXT2)
genes[7476],withlossoftheremainingwildtypealleleinthecartilagecapoftheosteochondroma[77].TheendresultisdecreasedEXTexpression.
LossofexpressionoftheEXTgenesthroughhomozygousdeletionofEXT1isalsoseeninsolitaryosteochondromasthatareunassociatedwiththe
hereditarysyndrome[78,79].TheEXTgeneproductsareinvolvedinthebiosynthesisofheparansulfateproteoglycans(HSPGs),whichareessential
forcellsignalingthroughIHH/PTHLHandotherpathways[80].
InosteochondromaswhereEXTisinactivated,theHSPGsseemtoaccumulateinthecytoplasmandGolgiapparatusinsteadofbeingtransportedto
thecellsurface[79].Thishampersmultiplegrowthsignalingpathways(includingtheIHH/PTHRPproteinpathways),which,asnotedabove,are
importantfornormalchondrocyteproliferationanddifferentiationwithinthenormalhumangrowthplate.
Insecondaryperipheralchondrosarcomasarisinginosteochondromas,EXTisusuallywildtype,suggestingthatthewildtypecellsinosteochondroma
arepronetomalignanttransformationthroughEXTindependentmechanisms[81].Usingamousemodel,itwasshownthatadditionalgenetic
alterationsinvolvingtheTP53orpRbpathwayareinvolvedintheprogressionfromosteochondromatosecondaryperipheralchondrosarcoma[82].In
addition,aroleforIHHsignalinghasbeensuggested,althoughthedataarenotentirelyconsistent[8387]:
PTHRPsignaling,whichisdownstreamofIHHandisinvolvedinchondrocyteproliferation,isabsentinosteochondromas,butupregulatedwith
malignanttransformationtowardssecondaryperipheralchondrosarcoma,especiallyinhighgradelesions[84,85,8891].
ThereisdecreasedexpressionofdownstreamtargetsintheIHHsignalingcascadeduringtumorprogressioninperipheralchondrosarcomas,
whiletheyarestillactiveincentralchondrosarcomas[92].
DatafrominvitroandinvivomodelsshowthattreatmentofcentralchondrosarcomacellswithrecombinantHedgehogincreasesproliferation,
whereastreatmentwithHedgehogsignalinginhibitorsinhibitstumorproliferationandgrowthinasmallsubsetoftumorsandchondrosarcomacell
cultures[87,92,93].
Amultistepgeneticmodelforthedevelopmentofsecondary(peripheral)chondrosarcomashasbeenproposed(figure2)[14].
Withregardstothemoleculargeneticsofenchondromasandthefarmorecommonprimary(central)chondrosarcomas,pointmutationsinisocitrate
dehydrogenase1andisocitratedehydrogenase2genesIDH1andIDH2havebeenidentifiedin40to56percentofcases,andseemtobeanearly
event[24,94].Also,OllierdiseaseandMaffuccisyndromearecausedbysomaticmosaicmutationsinIDH1andIDH2[24,25].TheidentificationofIDH1
andIDH2mutationsinfourchondrosarcomacelllinesprovidesaninvitromodeltostudytheroleofthesemutationsintumorigenesis[24].Isocitrate
dehydrogenaseisanenzymethatconvertsisocitratetoalphaketoglutarateintheTCA(tricarboxylicacid)cycle.MutationsinIDH1andIDH2cause
elevatedlevelsoftheoncometaboliteD2hydroxyglutarate(D2HG),whichcompetitivelyinhibitsalphaketoglutaratedependentenzymes,suchas
TET2,therebyinducingepigeneticchanges,includingDNAhypermethylationandhistonemodification,probablyaffectingdifferentiation[95].Increased
levelsofD2HGpromotechondrogenicandinhibitosteogenicdifferentiationofmesenchymalstemcells.Thus,mutationsinIDH1or2leadtoalocal
blockinosteogenicdifferentiationduringskeletogenesis,causingthedevelopmentofbenigncartilaginoustumors[96,97].Indeed,alsoinmice,mutant
IDHorD2HGcausespersistenceofchondrocytes,givingrisetorestsofgrowthplatecellsthatpersistintheboneasenchondromas[98].
Inaddition,althoughEXTisnotinvolved,involvementoftheIHH/PTHLHsignalingpathwayissuggestedbytheobservationsthatPTHRPsignalingis
activeinenchondromas[88,91],andhedgehogsignalingisactiveincentralchondrosarcomas[92].Moreover,amutationinthegeneencodingthe
receptorforPTHRP(PTH1receptororPTH1R)hasbeenidentifiedinenchondromatosisthatisclaimedtoleadtoconstitutiveactivationofIHH
signaling[86,99].ThreenewheterozygousmissensemutationshavebeendescribedinthePTH1RgeneinpatientswithOllierdisease,whichresultin
reducedreceptorfunction[100].MutationsinPTH1Rhavenotbeenfoundinsporadicchondrosarcomas,norinMaffuccisyndrome[24,25,101]this
genemaycontributetopathogenesisinonlyaverysmallsubset(<5percent)ofpatientswithOllierdisease.Moreover,usingwholeexomesequencing,
mutationswerefoundindifferentgenesinvolvedinhedgehogsignaling[102].
Whileenchondromasandlowgradechondrosarcomasareneardiploidandcarryfewkaryotypicabnormalities,highgradechondrosarcomasare
aneuploidandhavecomplexkaryotypes[43,103].Someofthefewconsistentgeneticaberrationsinclude12q1315and9p21rearrangements
[43,103106].
ChondrosarcomaprogressionhasbeenlinkedtotheCDKN2A(p16)tumorsuppressorgene,locatedat9p21[107,108]andbyalterationsinp53
[109].
MutationsinCOL2A1arefoundinasubsetofchondrosarcomas,themeaningofwhichisasyetunknown[102].
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Activationand/oroverexpressionofplateletderivedgrowthfactorreceptoralpha(PDGFRA)andbeta(PDGFRB)hasbeendescribedin
conventionalprimarychondrosarcomas,althoughactivatingmutationshavenotbeenfound[110,111].Thetherapeuticimplicationsofthisfinding
arediscussedbelow.(See'Noveltherapies'below.)
Amultistepgeneticmodelfordevelopmentofprimarychondrosarcomashasbeenproposed(figure3)[14].
DedifferentiatedchondrosarcomasalsocontainIDH1orIDH2mutationsinapproximately50percentofcases[24,49,94].
ThemajorityofmesenchymalchondrosarcomaswasshowntoharboraspecificHEY1NCOA2fusionproductcausedbyanintrachromosomal
rearrangementofchromosomearm8q[112].Alternatively,aIRF2BP2CDX1fusiongenebroughtaboutbytranslocationt(15)(q42q32)wasdescribed
[113].
Forclearcellchondrosarcoma,nospecificrecurrentalterationshavebeenfoundsofar[49].
DIAGNOSTICANDSTAGINGWORKUPThegoalsofthepreoperativeevaluationaretoestablishthetissuediagnosisandevaluatediseaseextent,
inordertoselecttheappropriatetherapeuticapproach.Onefundamentalprincipleapplyingtodiagnosisofbothtumorsofboneandcartilageisthat
boththehistologyandradiographyofbonetumorsarenotspecific.Integrationoftheclinicalhistory,radiography,andpathologyisnecessarytorender
aspecificdiagnosis.
RadiographicimagingTheinitialimagingstudyinapatientwithapainfulmusculoskeletalswellingisoftenaplainradiograph.Thelocationand
radiographicappearanceofthedifferentchondrosarcomasubtypesareoftencharacteristic[1].However,althoughplainradiographscanprovideaclue
astotheprobablehistologyofapotentiallymalignantbonelesion,evaluationoftumorsizeandlocalextentismostaccuratelyachievedbymagnetic
resonanceimaging(MRI)and/orcomputedtomography(CT)[114].
CTisoptimaltodetectmatrixmineralization,particularlywhenitissubtleorthelesionsarelocatedinananatomicallycomplexarea.Becauseof
theirhighwatercontent,mostchondrosarcomasareoflowattenuationonCT.
MRIisbetterfordelineatingtheextentofmarrowandsofttissueinvolvement.Thehighwatercontentofchondrosarcomasismanifestasveryhigh
signalintensityonT2weightedimages[3].
Inthelongbones,centralchondrosarcomasproduceafusiformexpansioninthemetaphysisordiaphysis(figure4).Thetumorhasamixedradiolucent
andscleroticappearancewiththemineralizedchondroidmatrixappearingasapunctateorringandarcpatternofcalcificationsthatmaycoalesceto
formamoreradiopaqueflocculentpatternofcalcification(thesocalledchondroidtypeofcalcification(image6)).Highergradechondrosarcomasoften
containrelativelylessextensiveareasofmineralization(image7).
Thecortexisoftenthickenedbutaperiostealreactionisscantorabsent.Theremaybefeaturesofendostealscallopingandsofttissueextension.
Evidenceofalargesofttissuemass,particularlyifunmineralized,thatisassociatedwithalesionwhoseradiologicfeaturesotherwisesuggesta
chondrosarcomashouldraisethelevelofsuspicionforahighgradetumor(image7andimage8).
ConventionalradiographsarenotreliabletodistinguishbetweenanenchondromaandcentralACT/CS1[12,41,115,116],althoughlocalizationinthe
axialasopposedtotheappendicularskeletonandsizegreaterthan5cmfavorchondrosarcoma[41,117].Thepresenceofasofttissuemassexcludes
thediagnosisofanenchondroma.ThethicknessandstainingcharacteristicsofthecartilaginouscapondynamiccontrastenhancedMRIprovidesa
fairlyreliableassessmentofthelikelihoodofmalignancyinanosteochondroma[118,119].However,anabsolutedistinctionbetweenbenignand
malignantcannotbemadeonradiologicgroundsalone[41,120,121].
Osteochondromasappearasasessileorbroadlybasedsmoothlycalcifiedlesionatthesurfaceofbone,withthecortexofthebonetypicallyextending
intothestalkoftheosteochondromaandnormaltrabeculationcentrally.ThecartilaginouscapisbestassessedonT2weightedMRIandshouldnot
exceed1.5to2cm.ThethicknessandappearanceofthecapondynamiccontrastenhancedMRIprovideafairlyreliableassessmentofthelikelihood
ofmalignancy.Athickenedcapandirregulardistributionofvaguecalcificationssuggestthedevelopmentofasecondarychondrosarcoma.
Periostealchondrosarcomasappearasaroundtoovalsofttissuemassonthesurfaceofbone,containingtypicalchondroidmatrixmineralization.
Theycausevariableamountsofcorticalboneerosionandappeartobecoveredbyanelevatedperiosteum(Codmantriangles).Themedullarycanalis
typicallynotinvolved.Theradiographicdifferentiationbetweenaperiostealchondrosarcoma,periostealosteosarcoma,andparostealosteosarcoma
canbedifficult.
Clearcellchondrosarcomashaveapredilectionfortheepiphysealendsofthefemurandhumerus(figure1).Radiographsrevealawelldefined,
predominantlylyticlesion,sometimeswithascleroticrim.Matrixmineralizationisnotasfrequentlyapparentaswithconventionalchondrosarcoma.
Asnotedabove,aggressivechondrosarcomas,suchasthemesenchymalanddedifferentiatedsubtypes,oftencontainareasofmatrixmineralization
thatsuggestalowgradechondroidneoplasmhowever,theseareasarerelativelylessextensivecomparedwithconventionalchondrosarcomaandare
usuallyilldefined.OnCTandMRI,dedifferentiatedchondrosarcomasmaybeseentocontaintwodistinctareaswithdifferingradiographic
characteristics:thelowgradeconventionalchondrosarcomatouscomponenthaslowattenuationonCTandhighsignalintensityonT2weightedMRI
images,whilethehighgradenoncartilaginouscomponentmayhavesofttissueattenuationonCT(isointensetomuscle)andvariablesignalintensity
onMRIT2weightedimages.Theremaybeintraosseouslyticareasandanaggressivepatternofbonedestructionwithamotheatenorpermeative
pattern.Theseaggressivetumorsareoftenassociatedwithperforationofthecortexandalargesofttissuemass.
Imagingfeaturesofextraskeletalmesenchymalchondrosarcomasarenonspecific,withchondroidtypecalcificationandfocioflostsignalintensitywithin
enhancinglobules[122].
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RoleofPETTheimagingmethodsdescribedaboveprovidelimitedinformationastothebiologicactivityofasuspectedchondrosarcoma.
Positronemissiontomography(PET)scanningwithfluorodeoxyglucose(FDG)hasbeenproposedasanoninvasivemethodtoassesstumorgrade,to
distinguishbenignfrommalignantchondroidlesions,toidentifyotherwiseoccultmetastaticdisease,andtodifferentiaterecurrenttumorfrom
postoperativechange[123126].However,theoverallplaceofPETinthediagnosticandstagingevaluationremainsuncertain:
Althoughgrade2and3chondrosarcomashaveahigherglucosemetabolism(andthereforeahigherstandardizeduptakevalue[SUV]),PET
cannotdifferentiatebetweenbenigncartilagetumorsandACT/CS1[126].
ThevalueofPETscanningtoscreenformetastaticorrecurrentdiseaseisalsouncertain.
BiopsyForsuspiciouslesions,adiagnosticbiopsyisfrequentlyundertakentoestablishthediagnosisandplanthesurgicalapproach.Theinitial
percutaneousbiopsymaynotaccuratelyreflectthetruehistologicgradeofthelesionbecauseoflesionheterogeneityandthepossibilityofsampling
error[127].Ifitisundertaken,biopsyshouldalwaysbedirectedatthemoreaggressiveappearingareasasseenontheradiographicstudies(ie,the
softtissuecomponents,orthemorediffuselyenhancingregionswithlimitedornomatrixmineralization).Indifficultcases,mutationanalysisforIDH1
and2canhelptodistinguishchondrosarcomafrom(chondroblastic)osteosarcoma[128].
Specificissuessurroundingthediagnosticbiopsyforsuspectedprimarybonetumorsarediscussedseparately.(See"Bonetumors:Diagnosisand
biopsytechniques".)
StagingsystemThestagingsystemusedforbonesarcomaswasdevelopedbyEnnekingetal.attheUniversityofFloridaandbasedupona
retrospectivereviewofcasesofprimarymalignanttumorsofbonetreatedbyprimarysurgicalresection(table2)[129,130].Thissystemcharacterizes
nonmetastaticmalignantbonetumorsbygrade(lowgrade[stageI]versushighgrade[stageII])andfurthersubdividesthesestagesaccordingtothe
localanatomicextent.Thecompartmentalstatusisdeterminedbywhetherthetumorextendsthroughthecortexoftheinvolvedbone.Patientswith
distantmetastasesarecategorizedasstageIII.
TheAmericanJointCommitteeonCancer(AJCC)hadasimilarstagingsysteminits1997fifthedition[131],butthiswasmodifiedin2002,with
additionalminorrefinementsinthelatest2010edition(table3)[132].TheTNMclassificationisnotwidelyusedforprimarybonetumors.
CompletingthestagingworkupAswithothersarcomas,thelungsarethemainsiteofmetastaticdiseasemuchlesscommonly,theregional
nodesandliverareinvolved.GiventhelowrateofmetastasesinpatientswithACT/CS1(lessthan10percent),imagingofthelungsisgenerallynot
necessary.However,patientswithintermediateandhighgradechondrosarcomashaveahigherrateofmetastaticdisease(10to50percentforgrade
2lesionsand50to70percentforgrade3lesions)[3,5].Inthesepatients,thestagingevaluationshouldatleastincludeathoracicCTtoruleoutthe
presenceofpulmonarymetastases.
Asnotedabove,theplaceofPETscanning(whichinotheroncologicsettingsisgenerallymoresensitivebutlessspecificthanCTfordetectionof
metastaticdisease)isuncertain.AlthoughtheuseofPETcanrevealsitesofmetastaticdiseaseamongpatientswithgrade2or3chondrosarcomas,it
isclearthatsensitivityislowerthanthatofconventionalCTforsmalllungmetastases[126].TheutilityofintegratedPET/CThasnotbeenaddressed.
SURGICALTREATMENTForallgradesandsubtypesofnonmetastaticchondrosarcoma,surgicaltreatmentofferstheonlychanceforcure.The
optimaltypeofsurgicalmanagementdependsuponhistologicgrade,location,andtumorextent.
IntermediateandhighgradetumorsWideenbloclocalexcisionisthepreferredsurgicaltreatmentforallnonmetastaticintermediateandhigh
gradechondrosarcomas[8].Dependingonthelocationoftheprimary,wideexcisioncanleadtoconsiderablemorbidityandmayrequireademanding
reconstruction.
LowgradecentraltumorsThegoalofminimizingfunctionaldisabilityprovidestherationaleforpursuinglessextensivesurgeryforACT/CS1that
areconfinedtothebone.Inappropriatelyselectedcases,extensiveintralesionalcurettage,followedbylocaladjuvantchemicaltreatment
(phenolization)orcryotherapy,andcementationorbonegraftingofthecavityproducessatisfactorylongtermlocalcontrolwhileminimizingtheneed
forextensivereconstruction[133138].
ThebestoutcomesarewithsmallextremityconventionalACT/CS1.Forpatientswithlargetumorsize,intraarticularorsofttissueinvolvement,andthe
periosteal,clearcell,mesenchymalanddedifferentiatedsubtypes[40],intralesionalexcisionrepresentsaninadequateformoflocaltreatment,withhigh
ratesoflocalrecurrence[3,139].Widelocalresectionispreferred[139].
Forlargetumors,curettagecanbetechnicallydifficult,andsamplingerrormayresultinafocusofhighergradediseasebeingmissed.Thetumorsize
cutoffbeyondwhichawideresectionispreferredhasnotbeenstudiedandishighlydependentonlocation.
Mostauthorsalsoconsiderwidelocalexcisiontobethepreferredtreatmentforalowgradechondrosarcomainvolvingtheaxialskeletonandpelvis.
Several(butnotall[8,63,140])reportsnotehigherlocalrecurrencerateswithcurettageormarginalexcisionoftumorsatthesesites,withahigher
tendencytometastasize[139143].
Thedecisiontoperformacurettageratherthanwidelocalexcisiononthebasisofadiagnosticbiopsyiscomplicatedbytumorheterogeneityand
variationinhistopathologicinterpretation.Afailuretorecognizehighergradeareasinapredominantlylowgradechondrosarcomaispossiblewhena
needleorlimitedopenbiopsyhasbeenperformed.Thus,apresumedACT/CS1treatedbycurettageandlocaladjuvanttreatmentthatisfoundto
containfociofintermediateorhighgradedifferentiationonthefinalhistologicsectionsmightrequireadditionalsurgery.Inordertominimizethisrisk,
thediagnosticbiopsyshouldalwaysbedirectedatthemoreaggressiveappearingareasontheradiographicstudies(ie,thesofttissuecomponentsor
themorediffuselyenhancingregionswithlimitedornomatrixmineralization).(See'Histologicgradingandprognosis'aboveand'Biopsy'above.)
PeripheralchondrosarcomasForpatientswithapreexistingosteochondroma,completesurgicalremovalofthecartilagecapwiththe
pseudocapsuleprovidesexcellentlongtermclinicalandlocalresults.Inoneseriesof107patientswithatumorarisinginsolitaryormultiple
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osteochondromas,fiveand10yearlocalrecurrenceratesaftersurgerywere16and18percent,andthe10yearmortalityratewasonly5percent
[21].Ofthe63patientswhohadtheirprimarytreatmentattheauthor'sinstitution,26hadwideexcision(noneofwhomrecurred),36hadamarginal
excision(tenofwhomrecurredlocally),andtheonepatientwhohadanintralesionalexcisionalsodevelopedalocalrecurrence.Ofthe45patientswho
receivedtreatmentforalocalrecurrence,15diedoftheirdisease.
Whenthesetumorsariseinthepelvis,thelargecartilagecapcanbedifficulttoexcise,butoutcomesarebetteriftheexcisioniscomplete[139,144].As
anexample,inaseriesof61patientswithACT/CS1orgrade2secondaryperipheralchondrosarcomaofthepelvis,localrecurrenceratesafterwide
localorincompleteexcisionwere3versus23percent,respectively[144].
ManagementofrecurrentdiseaseLocalrecurrenceofanACT/CS1inthelongbonescompromisessurvival,andaggressivemanagementis
warranted[145].Ifthelocalrecurrenceissolitary,withoutprogressioningradeandlocatedinthelongbones,repeatintralesionalresectionwithlocal
adjuvanttherapyisreasonable.
Localrecurrenceofanintermediateorhighgradechondrosarcomalocatedinthelongbonesorrecurrenceofanygradehistologyintheflatbonesis
anindicationforawideexcision[140],althoughitisoftenchallengingtoreachadequatewideresectionmarginsinthesepatients.Longtermsurvivalis
achievableinasubstantialnumberofpatients.Inaseriesof28patientstreatedsurgicallyforarecurrenceofachondrosarcomaoftheextremitiesor
pelvis(grade1,2,and3in4,61,and33percent,respectively),thepostlocalrecurrencesurvivalratewas59percentatbothfiveand10years[146].
Inmultivariateanalysis,themostimportantfactorspredictingafavorablelongtermoutcomeswereageunder50yearsandalocalrecurrencefree
intervalofoneyearormore.
RADIOTHERAPYAsmostchondrosarcomasareslowgrowing,witharelativelylowfractionofdividingcellsandradiationrelatedcytotoxicityis
dependentuponcelldivision,chondrogenictumorsareconsideredrelatively(butnotabsolutely[147,148])radioresistant.Nevertheless,radiation
therapy(RT)maybeofbenefitintwosituations:afteranincompleteresectionofahighgradeconventional,dedifferentiated,ormesenchymal
chondrosarcomatomaximizethelikelihoodoflocalcontrol(potentiallycurativeintent),andinsituationswhereresectionisnotfeasibleorwouldcause
unacceptablemorbidity(palliativeintent).
WhenRTisgivenwithcurativeintent,dosesinexcessof60Gyarerequiredtoachievelocalcontrol.However,applicationofthisdosewith
conventionalhighenergyphotonsisoftenimpossibleinthevicinityofcriticalstructures,especiallyinchondrosarcomasarisingintheskullbaseand
axialskeleton.Unfortunately,itisinthisexactsituationthatpostoperativeRTisoftenindicated,asthesetumorsarelessaccessibleforradicalresection
comparedwithlesionsintheappendicularskeleton.(See"Chordomaandchondrosarcomaoftheskullbase".)
ThebenefitsofRTcanbeillustratedbyaseriesof21patientswithprimarychondrosarcomaofthespinewhounderwent28surgicalproceduresthat
includedsevencompleteand21subtotalresections[149].Themediansurvivalfortheentiregroupwassixyears,andtheadditionofRTtoresection
prolongedthemediandiseasefreeintervalfrom16to44months.Othershaveshownahighrateoflocalcontrol(90percent)withtheadditionof
neoadjuvantoradjuvantRTtosurgicalresectioninagroupof60patientswithhighriskextracranialchondrosarcoma,ofwhom50percenthadeither
anR1(microscopicallypositive)orR2(grosslypositivemargins)resection[150].
PalliativeRTisalsoareasonableoptionforlocaltreatmentofaprimaryorlocallyrecurrentchondrosarcomaifresectionisnotfeasibleorwouldcause
unacceptablemorbidity.Thisisparticularlytrueformesenchymalchondrosarcomas,which,inourexperience,aremoreradiosensitivethanareother
subtypes.
ThebenefitofRTinthissettingcanbeillustratedbyaretrospectivereviewof15patientswithmesenchymalchondrosarcoma(allbutone
nonmetastatic,mostextraosseous)treatedinseveralprotocolsoftheGermanSocietyofPediatricOncologyandHematology[55].Allpatientshad
surgicalresection,whichwascompleteineight13receivedchemotherapyandsixwereirradiated.Atamedianfollowupof9.6years,fourofseven
incompletelyresectedpatientswerestillalive,threeofwhomhadbeenirradiated.
ConventionalRTcansometimesprovidelocalcontrolandsymptomreliefforotherhistologies,aslongassufficientdosesareadministered[151,152].
InanearlyreportfromMDAndersonof20patientswithchondrosarcomawhoweretreatedforcure,5of11patientswhoreceivedRTasmonotherapy
achievedlocalcontrolwithdosesfrom40to70Gy[151].
ChargedparticleirradiationGiventhelimitationsofconventionalphotonirradiation,alternativeradiationmodalitieshavebeentested.Unlike
photons,whichlackmassandcharge,particlebeamsinteractmoredenselywithtissue,causinggreaterlevelsofionizationperunitlength,and
therefore,anincreasedradiobiologiceffect(RBE).Themostdataareavailableforprotons,butthereislimitedexperiencewithcarbonionsaswell.
ProtonbeamirradiationThetheoreticaladvantageofchargedparticleirradiationusingprotonsisinitsdosedistribution.Thephysical
characteristicsoftheprotonbeamresultinthemajorityoftheenergybeingdepositedattheendofalineartrack,inwhatiscalledaBraggpeak.
TheradiationdosefallsrapidlytozerobeyondtheBraggpeak.ProtonbeamtherapypermitsthedeliveryofhighdosesofRTtothetargetvolume
whilelimitingthe"scatter"dosereceivedbysurroundingtissues.
ProtonbeamRThasbeenstudiedmostforincompletelyresectedchondrogenictumorsoftheskullbaseandaxialskeleton.Localcontrolratesof
78to100percentwithmixedphotonprotonorprotononlyprotocols(dosesupto79cobaltGrayequivalents[CGE],or7900cGy)arereportedby
severalauthors[153157],withlimitedseverelateeffects(<10percentRTOGgrade3toxicity).(See"Chordomaandchondrosarcomaoftheskull
base".)
CarbonionsCarbonionsrepresentanotherattractiveradiationmodality,whichcombinesthephysicaladvantagesofprotonswithahigher
radiobiologicalactivity.Theavailabledataareinpatientstreatedforskullbasedchondrosarcomas,whicharediscussedseparately.(See
"Chordomaandchondrosarcomaoftheskullbase".)
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Althoughpromising,thesetechniquesarenotwidelyavailable,incontrasttophotonirradiation.Particlebeamirradiationrequiresadaptationofparticle
acceleratorsdesignedforotherpurposesorspecializeddedicatedequipment.(See"Chordomaandchondrosarcomaoftheskullbase".)
SYSTEMICTREATMENTChemotherapyhasbeengenerallyconsideredineffectiveinchondrosarcomas,especiallyforthemostfrequently
observedconventionaltypeandtherare(lowgrade)clearcellvariant(table1).Chemoresistanceinthesetumorsmaybeattributabletoseveral
factors:
Mostchondrosarcomasareslowgrowing,witharelativelylowfractionofdividingcellsmostconventionalchemotherapeuticagentsactonactively
dividingcells.
Expressionofthemultidrugresistance1gene,Pglycoprotein,bychondrosarcomacellsmayalsoplayaroleindrugresistance[158,159].
Accessofanticanceragentstothetumormaybehamperedbecauseofthelargeamountofextracellularmatrixandthepoorvascularity.
Highactivityofantiapoptoticandprosurvivalpathways(eg,highexpressionofBcl2familymembers)[160,161].
Thebenefitofchemotherapyforhighergrade(grade2or3)chondrosarcomasisdifficulttoassess.Duetotherarityofchondrosarcomasingeneral
andespeciallyofintermediateandhighgradetumors,therearefewprospectivestudies,andnorandomizedtrials.Thereportedseriesarefewin
number,retrospective,andconsistmainlyofasmallnumberofpatients.Nevertheless,retrospectivereportschallengetheprevailingviewthat
chondrosarcomasareentirelychemotherapyresistant[162,163].Aswithothercancers,thespecifichistologyalsodictatesthedegreeof
responsivenessofthatsarcomasubtype.Regardless,outcomesremaingenerallypooroverallwithconventionalcytotoxicchemotherapy,andthereisa
needforinclusionofthesepatientsinprospectivetrials.Asanexample,itishopedthatnoveltherapeuticssuchasisocitratedehydrogenase(IDH)
inhibitorswillhaveanimpactonthispatientpopulation,andtheseagentsareunderstudy,eventhoughdatafrompreclinicalmodelshavebeen
disappointing[164,165](see'Noveltherapies'below).
AdjuvantchemotherapyThereisnoroleforadjuvantchemotherapyinpatientswhoundergosurgicaltreatmentforanACT/CS1.However,its
benefitfordedifferentiatedandmesenchymalchondrosarcomasisunclear.
DedifferentiatedchondrosarcomaAtleasttwostudies(bothretrospective)suggestthatpatientswithdedifferentiatedchondrosarcomawho
aremanagedwithsurgeryandchemotherapymayhaveabetteroutcomethanthosemanagedwithsurgeryalone[166,167].However,benefitfrom
chemotherapyinpatientswithnonmetastaticdiseaseisnotauniversalobservation[11,51,52,168].
Wesuggestthateligiblepatientsconsiderenrollinginclinicaltrialstestingthevalueofadjuvantchemotherapy.Asanexample,patientswith
dedifferentiatedchondrosarcomasareallowedintheEUROBOSSadjuvantchemotherapytrialoftheScandinavianSarcomaGroup[169].
MesenchymalchondrosarcomaMesenchymalchondrosarcomaismodestlymoresensitivetochemotherapythanothersubtypesof
chondrosarcoma,butthedataarelimited.Inparticular,limitedexperiencewithadjuvant(orneoadjuvant)chemotherapyinpatientswithmesenchymal
chondrosarcomasuggestsapotentialbenefitforchemotherapy:
Experiencewith15casesofmesenchymalchondrosarcoma(allbutonenonmetastatic,mostextraosseous)wasreportedfromthesofttissueand
osteosarcomastudygroupsoftheGermanSocietyofPediatricOncologyandHematology[55].Allpatientshadsurgicalresection,whichwas
completeineight13receivedchemotherapyandsixwereirradiated.Thetreatmentregimensconsistedofavarietyofchemotherapydrugsgiven
invariouscombinationsinseveraltrials.
Responsetoinductionchemotherapycouldbeassessedinsevenpatients,fourofwhomhada50percentreductionintumorvolumeor50
percent"histologicdevitalization."Atamedianfollowupof9.6years,characteristiclaterecurrenceswerenotobserved,andtheactuarialevent
freeandoverallsurvivalratesat10yearswere53and67percent.Theauthorsconcludedthattheseoutcomeswerebetterthanexpected,and
attributedtheimprovedoutcomestocombinedmodalitytreatment.
Aretrospectiveseriesof26patientswithmesenchymalchondrosarcomatreatedattheRizzoliInstituteincluded24surgicallytreatedpatients,12
ofwhomreceivedchemotherapy[58].Afteramedianfollowupof48months,10remainedalive.The10yearratesofdiseasefreesurvivalwere
markedlyhigheramongthosewhoreceivedchemotherapy(31versus19percent)aswasoverallsurvival(76versus17percent).
Abenefitforchemotherapywasalsosuggestedinaretrospectivestudyof113patientswithmesenchymalchondrosarcomafromtheEuropean
MusculoskeletalOncologySociety(EMSOS),whichincluded95patientswithlocalizeddiseasewhoweresurgicallytreated,54ofwhomreceived
chemotherapy(21preoperatively,30postoperatively,and3both)[54].Overall,thefiveand10yearsurvivalrateswere79and60percent,
respectively.Thefiveand10yearratesofoverallsurvivalweremarkedlyhigheramongthosewhoreceivedchemotherapy(84and80percent,
respectively)comparedwiththosewhodidnot(73and46percent,respectively).
Questionswillremainastotheworthofadjuvantchemotherapyuntilrandomizedtrialsarecarriedout.However,evenintheabsenceofprospective
trials,thereismodestclinicalevidencefromnonrandomizedtrialsthatmesenchymalchondrosarcomasaresensitivetodoxorubicinbasedcombination
chemotherapyasusedinotherbonetumors.Giventheselimiteddata,adjuvantchemotherapyinpatientsisareasonableoptionforthosepatientswho
aremedicallyfit,willing,andabletotoleratesuchtherapy.Neoadjuvantchemotherapyisareasonableoption,ifthediseaseislocallyadvanced,toboth
gaugethegenuinechemotherapysensitivityofaspecificprimarytumorandtoattempttorenderapatientresectablewhenthediseaseislocally
advanced.
ThebestregimenisequallycontroversialpriorclinicalexperiencecitedaboveandguidelinesfromtheNationalComprehensiveCancerNetwork
(NCCN)andESMOindicateeitheranEwingsarcomabasedmultidrugregimenoranosteosarcomatypedoxorubicin/cisplatinbasedchemotherapy
regimenmaybeused[168,170].(See"Chemotherapyandradiationtherapyinthemanagementofosteosarcoma".)
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AdvanceddiseaseAlthoughthemajorityofpatientswithrecurrentormetastaticsarcomadonotrespondtotheusualchemotherapyregimensfor
advancedsarcoma,therehavebeenisolatedreportsofsuccessfultreatmentwithifosfamidealone,doxorubicinbasedchemotherapy,orsingleagent
methotrexate[55,60,162,163,171173].
Highgradechondrosarcomasseemtopreferentiallybenefit,butthisisunpredictable.InthesmallprospectiveEuropeantrialinhighgradespindlecell
sarcomasofbonedescribedabove,twoofsixpatientstreatedforanadvanceddedifferentiatedchondrosarcomahadacompleteresponseto
doxorubicinpluscisplatin,whilethebestresponseamongfivepatientswithmetastaticmesenchymalchondrosarcomawasstablediseaseintwo[168].
NoveltherapiesTherelativelackofefficacyofconventionalchemotherapyandthediscoveryofnovelsignalingpathwaysinseveralhistologic
subtypesofchondrosarcomahaspromptedinterestinmolecularlytargetedtherapies,particularlyforchemotherapyrefractorynonoperableor
metastaticchondrosarcomas[73].Asexamples:
Receptortyrosinekinasesarecommonlyactivatedinchondrosarcomas,themostactiveofwhichareAkt1/GSK3beta,thesrcpathway,andthe
plateletderivedgrowthfactorreceptor(PDGFR)[174].Activationand/oroverexpressionofPDGFRalpha(PDGFRA)andPDGFRbeta
(PDGFRB)hasbeendescribedinconventionalchondrosarcomas,althoughactivatingmutationshavenotbeenfound[110,111].Investigatorshave
shownthatSU6668,aninhibitorofseveraltyrosinekinasereceptors,includingPDGFRB,repressesthegrowthofchondrosarcomaxenografts
[175].Althoughtheroleofthesereceptorsinmolecularpathogenesisormalignanttransformationremainsuncertain,thesedatasuggesta
therapeuticpotentialforinhibitorsofthesereceptortyrosinekinases.Unfortunatelyclinicaltrialshavebeendisappointingtodate:
AphaseIItrialofimatinib,aPDGFR/CKITtyrosinekinaseinhibitor,failedtodemonstratemeaningfulclinicalactivityin26patientswith
metastaticnonresectablechondrosarcoma[176].
ThetyrosinekinaseinhibitordasatinibwasexploredinaSARCtrialwhichincludedacohortof32patientswithchondrosarcomawithinalarger
groupofindolentsarcomasubtypes[177].Thechondrosarcomacohortdidnotmeetitsprimaryendpoint(>50percentsixmonthprogression
freesurvival[PFS])andthedrugwasconsideredinactiveinthisgroup.
Modestclinicalactivityforsirolimus,aninhibitorofthemechanistic(previouslycalledmammalian)targetofrapamycin(mTOR),incombination
withcyclophosphamidewassuggestedinastudyof10consecutivepatientswithunresectablechondrosarcoma[178].Onepatienthadan
objectiveresponsewhilesixothershadstabilizationofdiseaseforatleastsixmonths.MedianPFSwas13.4months(range3to30.3).No
significantadverseeventswereobserved.Prospectivestudiesofsirolimus,intheNetherlands(COSYMO),andeverolimus,anothermTOR
inhibitorbeingstudiedinFrance,arecurrentlyunderway.
Estrogenreceptorsandaromataseactivityhavebeenidentifiedinchondrosarcomas[179181].Interferencewithestrogensignalingmayhave
therapeuticvalueinthisdisease.However,inonestudy,doseresponseassaysshowednoeffectofanyofthearomataseinhibitorsonproliferation
ofconventionalchondrosarcomainvitro,andthemedianprogressionfreesurvivalofpatientstreatedwitharomataseinhibitorsdidnotsignificantly
deviatefromuntreatedpatients[181].
Thereareotherpromisingareasofinvestigation.Antitumoreffectsofhistonedeacetylase(HDAC)andangiogenesisinhibitorshavebeen
describedinchondrosarcomacelllinesandinvivomodels[175,182].Inaddition,severalphaseIstudiesreportincidentalresponsesof
chondrosarcomastonewertargetedagents,suchasvascularendothelialgrowthfactorantisensemolecules[183],recombinanthuman
Apo2L/TRAIL[184],andafullyhumanIgG1monoclonalantibodythattriggerstheextrinsicapoptosispathwaythroughdeathreceptor5[185].
Finally,mutationsinisocitratedehydrogenase1andisocitratedehydrogenase2genesIDH1andIDH2havebeenidentifiedin40to56percentof
chondrosarcomasandseemtobeanearlyevent.ClinicaltrialstestingthevalueofIDHinhibitorsareunderway.(See'Molecularpathogenesis'
above.)
Intheabsenceofeffectivesystemictherapy,eligiblepatientsshouldbeencouragedtoenrollinphaseIormultitumortypetrialstestingnovelstrategies
(www.clinicaltrials.gov).
POSTTREATMENTSURVEILLANCEAswithotherbonesarcomas,therearenoprospectivedatathataddresstheappropriatescheduleor
selectionoftestsforsurveillanceafterinitialtreatmentforlocalizeddisease.ConsensusbasedguidelinesfromtheNationalComprehensiveCancer
Network(NCCN)recommendphysicalexamination,completebloodcount,andchestaswellaslocalimagingeverythreemonthsforthefirsttwoyears,
everyfourmonthsduringyear3,everysixmonthsforyears4and5,thenannually[186].Routineposttreatmentsurveillanceshouldbeextendedto10
years,aslaterecurrencescanoccur[7].
Ourpracticeistoperformmagneticresonanceimaging(MRI)ofthelesionone,two,andfiveyearsafterinitialsurgery.
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,TheBasicsandBeyondtheBasics.TheBasics
patienteducationpiecesarewritteninplainlanguage,atthe5thto6thgradereadinglevel,andtheyanswerthefourorfivekeyquestionsapatient
mighthaveaboutagivencondition.Thesearticlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easytoreadmaterials.
BeyondtheBasicspatienteducationpiecesarelonger,moresophisticated,andmoredetailed.Thesearticlesarewrittenatthe10thto12thgrade
readinglevelandarebestforpatientswhowantindepthinformationandarecomfortablewithsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremailthesetopicstoyourpatients.(Youcanalso
locatepatienteducationarticlesonavarietyofsubjectsbysearchingonpatientinfoandthekeyword(s)ofinterest.)
Basicstopics(see"Patienteducation:Chondrosarcoma(TheBasics)"and"Patienteducation:Bonecancer(TheBasics)")
SUMMARYANDRECOMMENDATIONS
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Chondrosarcomasareaveryheterogeneousgroupofmalignantbonetumorsthatshareincommontheproductionofchondroid(cartilaginous)
matrix.Clinicalbehaviorisvariableandpredictedbythehistologicgrade.Ninetypercentareconventionalchondrosarcomas,themajorityofwhich
arelowgradetumorsthatareslowgrowingwithalowmetastaticpotential.Highgradechondrosarcomas,whichinclude5to10percentof
conventionalchondrosarcomasaswellasthededifferentiatedandmesenchymalsubtypes,haveahighmetastaticpotentialandapoorprognosis
followingresectionalone.(See'Introduction'above.)
Experiencedassessmentofradiographicimagingstudies(conventionalXray,magneticresonanceimaging[MRI],andcomputedtomography
[CT])andhistopathologicgradeasassessedonadiagnosticbiopsyareusedtoguidetreatmentdecisions.(See'Diagnosticandstagingworkup'
above.)
SurgicalresectionForallgradesandsubtypesofnonmetastaticchondrosarcoma,surgicaltreatmentofferstheonlychanceforcure.Theoptimal
typeofsurgicalmanagementdependsuponhistologicgrade,location,andtumorextent.Thegoalofsurgeryiscompleteexcisionwhileminimizing
functionaldisability.(See'Surgicaltreatment'above.)
Forsmall,centralACT/CS1involvinganextremitythatareconfinedtothebone,wesuggestintralesionalcurettagewithlocaladjuvanttherapy
(phenolapplicationorcryosurgeryfollowedbycementationorbonegraftofthecavity)ratherthanwidelocalexcision(Grade2C).
Forallotherpatientswithintermediateorhighgradehistology(includingthemesenchymalanddedifferentiatedsubtypes),largetumorsize,
intraarticularorsofttissueinvolvement,periostealorclearcellsubtypes,alowgradecentralchondrosarcomainthepelvisoraxialskeleton,or
aperipheralchondrosarcoma,werecommendwidelocalresection(Grade1B).
Locallyrecurrentchondrosarcomasshouldbemanagedaggressively,astheymaybeofhigherhistologicalgradethantheoriginaltumor,
increasingtheriskofmetastasesandfataloutcome.FornonmetastaticrecurrenceofanACT/CS1,wesuggestrepeatintralesionalresection
withlocaladjuvanttherapyifthelocalrecurrenceissolitary,withoutprogressioningradeandlocatedinthelongbones(Grade2C).
Otherwise,widelocalexcisionispreferred.(See'Managementofrecurrentdisease'above.)
RoleofradiotherapyWhilemostlowgradechondrosarcomasareconsideredrelativelyradioresistant,radiationtherapy(RT)maybeofbenefitin
twosituations(see'Radiotherapy'above):
Wegenerallysuggestadjuvantradiotherapyforincompletelyexcisedhighgradeconventional,dedifferentiated,ormesenchymal
chondrosarcomas(Grade2C).Dosesofmorethan60Gyareneededformaximallocalcontrolafterincompleteresection,anddependingon
thetumorsite,thismaynotbefeasiblewithconventionalphotonbeamirradiation.Insuchcases,referralfortreatmentusingnewer
techniques,suchasprotonbeamirradiation,isappropriate,whereavailable.
PalliativeRTisareasonableoptionforlocaltreatmentofpatientswithaprimaryorlocallyrecurrentchondrosarcomaifresectionisnot
feasibleorwouldcauseunacceptablemorbidity,aswellasforthosewithsymptomaticmetastaticdisease.
ChemotherapyConventionallowgradeandclearcellchondrosarcomasarechemotherapyresistant.Chemotherapyispossiblyeffectiveinthe
mesenchymalsubtype,particularlythosethatcontainahighpercentageofroundcells,andisofuncertainvalueindedifferentiatedchondrosarcoma
bothsubtypesarerareandbearapoorprognosis.(See'Systemictreatment'above.)
Thereisnoroleforadjuvantchemotherapyaftercompleteresectionofaconventionallowgradechondrosarcoma.
Theroleofchemotherapyaftercompleteresectionofadedifferentiatedchondrosarcomaisunknown.Retrospectivestudiessuggestthat
patientswhoaremanagedwithsurgeryandchemotherapyhaveabetteroutcomethanthosemanagedwithsurgeryalone.Werecommend
thateligiblepatientsbeenrolledonclinicaltrialstestingadjuvantchemotherapy.Iftheprotocolisnotavailableorifpatientsareunableor
unwillingtoparticipate,wemanagethesepatientsonacasebycasebasis,discussingtherisksanduncertainbenefitofadjuvant
chemotherapy.Ifthehighgradecomponentisanosteosarcoma,wetreatthepatientasperosteosarcomaprotocols.(See'Adjuvant
chemotherapy'above.)
Forpatientswithcompletelyresectedmesenchymalchondrosarcoma,retrospectivestudiessuggestthatthosewithasubstantialroundcell
componentaresensitivetodoxorubicinbasedcombinationchemotherapy.Retrospectiveanalysesofrelativelysmallnumbersofpatients
suggestthatadjuvantdoxorubicinbasedchemotherapyisareasonablechoiceforsuchpatients,aslongastheyaremedicallyfitandableto
toleratethetherapythelimiteddataprecludeaspecificrecommendationeitherfororagainstthispractice.Initialinductionchemotherapyisa
reasonableoptionifthediseaseislocallyadvanced,andaresponsetotherapymightincreasethelikelihoodofcompleteresectionorfunction
preservingsurgery.(See'Adjuvantchemotherapy'above.)
Thebenefitofconventionalchemotherapyislimitedinadvanceddisease,withtheexceptionofmesenchymalchondrosarcomas,whichexhibit
modestresponsivenesstochemotherapy.Wesuggestthatpatientsbeenrolledinclinicaltrialstestingnewstrategies.Iftrialenrollmentisnot
availableornotfeasible,weuseadoxorubicinpluscisplatincombinationasisusedforotherbonesarcomas.(See"Chemotherapyand
radiationtherapyinthemanagementofosteosarcoma".)
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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157.DeLaneyTF,LiebschNJ,PedlowFX,etal.PhaseIIstudyofhighdosephoton/protonradiotherapyinthemanagementofspinesarcomas.IntJ
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158.WymanJJ,HornsteinAM,MeitnerPA,etal.Multidrugresistance1andpglycoproteininhumanchondrosarcomacelllines:expressioncorrelates
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161.vanOosterwijkJG,MeijerD,vanRulerMA,etal.Screeningforpotentialtargetsfortherapyinmesenchymal,clearcell,anddedifferentiated
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162.vanMaldegemAM,GelderblomH,PalmeriniE,etal.Outcomeofadvanced,unresectableconventionalcentralchondrosarcoma.Cancer2014
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165.LiL,PazAC,WilkyBA,etal.TreatmentwithaSmallMoleculeMutantIDH1InhibitorSuppressesTumorigenicActivityandDecreasesProduction
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179.CletonJansenAM,vanBeerendonkHM,BaeldeHJ,etal.Estrogensignalingisactiveincartilaginoustumors:implicationsforantiestrogen
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180.GrifoneTJ,HauptHM,PodolskiV,BrooksJJ.Immunohistochemicalexpressionofestrogenreceptorsinchondrosarcomasandenchondromas.
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181.MeijerD,GelderblomH,KarperienM,etal.Expressionofaromataseandestrogenreceptoralphainchondrosarcoma,butnobeneficialeffectof
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182.SakimuraR,TanakaK,YamamotoS,etal.Theeffectsofhistonedeacetylaseinhibitorsontheinductionofdifferentiationinchondrosarcoma
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183.LevineAM,TulpuleA,QuinnDI,etal.PhaseIstudyofantisenseoligonucleotideagainstvascularendothelialgrowthfactor:decreaseinplasma
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184.HerbstRS,EckhardtSG,KurzrockR,etal.PhaseIdoseescalationstudyofrecombinanthumanApo2L/TRAIL,adualproapoptoticreceptor
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http://www.nccn.org/professionals/physician_gls/f_guidelines.asp(AccessedonFebruary27,2016).
Topic7724Version28.0
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GRAPHICS
Histologyofgrade1,2,and3chondrosarcoma
Whilecellularityislowinagrade1chondrosarcoma(nowreferredtoasanatypical
cartilaginoustumour/chondrosarcomagrade1[ACT/CS1])(A)withchondroidmatrixand
absentmitoses,ingrade2chondrosarcoma(B)mitosesarefound(inset).Ingrade3
chondrosarcoma(C),ahighcellularitywithmucomyxoidmatrixchangesisseenwith
cytonuclearatypia(hematoxylinandeosinstaining,500X).
Reproducedwithpermissionfrom:GelderblomH,HogendoornPCW,DijkstraSD,etal.The
clinicalapproachtowardschondrosarcoma.Oncologist200813:320.Copyright2008
AlphaMedPress.
http://www.TheOncologist.com
Graphic74562Version4.0
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Osteochondromacrosssection
Thecrosssectionofanosteochondromashowsthecapofcalcifiedcartilage
overlyingpoorlyorganizedcancellousbone.
Reproducedwithpermissionfrom:RubinR,StrayerDS.Rubin'sPathology:
ClinicopathologicFoundationsofMedicine,FifthEdition.Philadelphia:Lippincott
Williams&Wilkins,2008.Copyright2008LippincottWilliams&Wilkins.
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Osteochondromaofthehumerus
Aradiographofanosteochondromaofthehumerusshowsalesionthatis
directlycontiguouswiththemarrowspace.
Reproducedwithpermissionfrom:RubinR,StrayerDS.Rubin'sPathology:
ClinicopathologicFoundationsofMedicine,FifthEdition.Philadelphia:Lippincott
Williams&Wilkins,2008.Copyright2008LippincottWilliams&Wilkins.
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Solitaryenchondromaofthefemur
Enchondromaofthedistalfemurdemonstratesflocculentmatrixresembling
rings,orCsandOs.Calcificationisconcentratedinthecenterofthelesion.
Reproducedwithpermissionfrom:DaffnerRH.ClinicalRadiology:TheEssentials,
3rdEdition.Philadelphia:LippincottWilliams&Wilkins,2007.Copyright2007
LippincottWilliams&Wilkins.
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Multipleenchondromatosis(Ollierdisease)
A)Hand.Observethegeographic,expansile,soapbubblelesionsaffectingnearlyevery
bonevisualizedwithinthehand.Slightmatrixcalcificationisnotedinthemetacarpal
bones.
B)Foot.Observethemultiple,geographic,expansilelesionsscatteredthroughoutthe
proximalphalangesofthefoot.Thefirstmetatarsalandthediaphysisofthefourth
metatarsalalsocontainexpansileenchondromas.Theexpansionofbonehaswidenedthe
diaphysisofmostoftheaffectedbones.
Reproducedwithpermissionfrom:YochumTR,RoweLJ.YochumandRowe'sEssentialsof
SkeletalRadiology,ThirdEdition.Philadelphia:LippincottWilliams&Wilkins,2004.Copyright
2004LippincottWilliams&Wilkins.
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Maffuccisyndrome
A)Plainradiographdemonstratesmultiplesofttissuemassesandcalcifiedthrombiin
associationwithexpansilebonylesions.
B)Latefilmfromanarteriogramshowscontrastmaterialfillingmanycavernous
hemangiomasofthesofttissues.
Reproducedwithpermissionfrom:EisenbergRL.AnAtlasofDifferentialDiagnosis,Fourth
Edition.Philadelphia:LippincottWilliams&Wilkins,2003.Copyright2003Lippincott
Williams&Wilkins.
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Solitaryenchondromatochondrosarcoma:Malignant
degeneration
Observethegrosslyexpansile,primarilylyticlesionofthemetaphysisand
proximaldiaphysisofthefemur.Thereischaracteristicstippledmatrix
calcificationthroughoutthelesion(arrows).Thereisdisruptionofthecortexwith
thepresenceofasofttissuemassonthemedialsurfaceofthefemur
(arrowheads).Theradiographicsignsofcorticaldisruption,apoorzoneof
transitionsurroundingthelesion,andalargesofttissuemasssupportthebiopsy
diagnosisofmalignantdegenerationofapreexistingbenignenchondromatoa
secondarychondrosarcoma.Malignantdegenerationofbenigncartilaginous
tumorsoccursinbonesclosesttotheaxialskeletonandismuchmorecommon
inthelongtubularbonesthaninthesmallbonesofthehandsorfeet.
Reproducedwithpermissionfrom:YochumTR,RoweLJ.YochumandRowe's
EssentialsofSkeletalRadiology,ThirdEdition.Philadelphia:LippincottWilliams&
Wilkins,2004.Copyright2004LippincottWilliams&Wilkins.
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Overviewofclinicalcharacteristicsandtherapeuticoptionsinallsubtypesofchondrosarcomaofbone
Conventional
central
chondrosarcoma
Conventional
peripheral
chondrosarcoma
Periosteal
chondrosarcoma
Dedifferentiated
chondrosarcoma
Mesenchymal
chondrosarcoma
Clearcell
chondrosarcoma
Percentofall
chondrosarcomas
~75percent
~10percent
<1percent
~10percent
<2percent
<2percent
Precursorlesion
Enchondroma(upto
40percent?)
Osteochondromas
(100percent)
None
Conventional
chondrosarcoma
None
None
Occurrence
withinsyndrome
Enchondromatosis
(Ollierdisease)
Multiple
osteochondromas
None
Rarelyinmultiple
osteochondromasor
enchondromatosis
None
None
Age
>50years
Youngerthancentral
chondrosarcoma
Peakatfourthdecade
Medianage59years
Anyage(peakat
secondtothird
decade)
Anyage(peakinthird
tofifthdecade)
Preferential
location
Pelvis,proximalfemur,
proximalhumerus,
distalfemur,ribs
Pelvis,shouldergirdle
bones
Distalfemurand
humerus
Femurandpelvis
65to86percent
skeleton(jawbones,
ribs,ilium,vertebrae)
Epiphysisofhumeral
orfemoralhead
14to43percent
extraosseous
(meninges)
Histological
grading
Atypicalcartilaginoustumour/chondrosarcoma
grade1(ACT/CS1),grade2or3
Survival
ACT/CS1:83percent
Prognosisusually
gooddespite
worrisomehistology
Highgrade
Highgrade
Lowgrade
24percentatfive
years
28percentat10years
89percentat10years
Grade2:64percent
Grade3:29percent
Allat10years
Sensitivityto
conventional
chemotherapy
None
None
None
Uncertain
Possibly,ifhigh
percentageroundcells
None
Sensitivityto
radiotherapy
Low
Low
Low
Low
Possiblyhigh
Low
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Componentsofalongbone
Thisillustrationdepictsthemajorcomponentsofalongbone.
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Histologyofrarechondrosarcomasubtypes
A)Histologyofdedifferentiatedchondrosarcomawithasharpinterfacebetween
conventionalchondrosarcoma(left)andanaplasticsarcoma(right).B)Mesenchymal
chondrosarcomawithundifferentiatedsmallblueroundcells(below)andcartilage
differentiation(top).C)Clearcellchondrosarcomademonstratingchondrocyteswith
abundantclearcytoplasm,cartilaginousmatrix,anddepositionofosteoid(hematoxylinand
eosinstaining,500X).
Reproducedwithpermissionfrom:GelderblomH,HogendoornPCW,DijkstraSD,etal.The
clinicalapproachtowardschondrosarcoma.Oncologist200813:320.Copyright2008
AlphaMedPress.
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Proposedmultistepgeneticmodelforperipheral
chondrosarcomadevelopmentandpotentialtargetsfor
treatment
Arrowshowscandidateadjuvanttreatmentstrategiesbasedonidentificationof
molecularchangesduringchondrosarcomaprogression.
Modifiedfrom:BoveJV,CletonJansenAM,TaminiauAH,HogendoornPC.
Emergingpathwaysinthedevelopmentofchondrosarcomaofboneandimplications
fortargetedtreatment.LancetOncol20066:599.Allrightsreserved.
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Proposedmultistepgeneticmodelforcentralchondrosarcoma
developmentandcandidatesfortargetedtreatment
Arrowsshowcandidateadjuvanttreatmentstrategiesbasedonidentificationofmolecular
changesduringchondrosarcomaprogression.Candidatetargetsbasedonsingle
immunohistochemicalstudies(COX2,matrixmetalloproteinases[MMP],cathepsin,andplatelet
derivedgrowthfactorreceptor[PDGFR])arealsoshown.Theseshouldbeconfirmedinlarger
seriesinthedifferentsubtypesofconventionalchondrosarcomabyuseofadditional
techniques.
IDH:isocitratedehydrogenase.
Modifiedfrom:BoveJV,CletonJansenAM,TaminiauAH,HogendoornPC.Emergingpathwaysin
thedevelopmentofchondrosarcomaofboneandimplicationsfortargetedtreatment.LancetOncol
20066:599.Allrightsreserved.
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Commonlocationsofbonetumors
Chondroblastomafavorstheepiphysisintheskeletallyimmaturepatient.Roundcelllesions
favorthediaphysis.Themajorityofotherlesionsfavorthemetaphysis.Giantcelltumorswill
extendtothejointsurfaceinaskeletallymaturepatient.
Reproducedwithpermissionfrom:DaffnerRH.ClinicalRadiology:TheEssentials,3rdEdition.
Philadelphia:LippincottWilliams&Wilkins,2007.Copyright2007LippincottWilliams&Wilkins.
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Radiologicalpresentationofaconventionallowgrade
chondrosarcoma
(A)Conventionallowgradechondrosarcomaintheproximalhumeruswithchondroid
mineralizationonconventionalradiograph.
(B)DiscreteendostealscallopingoftheanteriorcortexisseenontheT1weighted
magneticresonanceimage.
(C)AxialT1weightedmagneticresonanceimagewithfatsuppressionafterIVcontrast
injectiondemonstratesthetypicalperipheralringandarcpatternofenhancement.No
softtissueextensionisnoted.
IV:intravenous.
Reproducedwithpermissionfrom:GelderblomH,HogendoornPCW,DijkstraSD,etal.
Theclinicalapproachtowardschondrosarcoma.Oncologist200813:320.Copyright
2008AlphaMedPress.
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Radiologicalpresentationofahighgradepelvic
chondrosarcoma
(A)AxialT1weightedmagneticresonanceimageofhighgradechondrosarcoma
arisingfromthepelviswithcortexdestructionandalargesofttissuecomponent.
(B)AxialT1weightedmagneticresonanceimagewithfatsuppressionafterIV
contrastinjectionshowsareasofsolidperipheralenhancement.
(C)Computedtomographyimagedemonstratesthebonedestructionoftheright
osiliumandossacrumwithalargesofttissuemasswithonlyperipheral
mineralization.
IV:intravenous.
Reproducedwithpermissionfrom:GelderblomH,HogendoornPCW,DijkstraSD,et
al.Theclinicalapproachtowardschondrosarcoma.Oncologist200813:320.
Copyright2008AlphaMedPress.
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Computedtomographyimageofmesenchymal
chondrosarcomaarisingfromtheposteriorchestwall
Thelargetumorcontainsextensiveareasofmatrixmineralization.Aggressive
lyticdestructionoftheposteriorpartoftheribandthethoracicvertebralbody
isnoted.Histologyoftheselyticareasshowsundifferentiatedsmallroundcells.
Reproducedwithpermissionfrom:GelderblomH,HogendoornPCW,DijkstraSD,et
al.Theclinicalapproachtowardschondrosarcoma.Oncologist200813:320.
Copyright2008AlphaMedPress.
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MusculoskeletalTumorSociety(MSTS)stagingsystemforsarcomas
Stage
Grade
StageIA
Lowgrade,intracompartmental
StageIB
Lowgrade,extracompartmental
StageIIA
Highgrade,intracompartmental
StageIIB
Highgrade,extracompartmental
StageIII
Systemicorregionalmetastases
Reproducedwithpermissionfrom:EnnekingWF,SpanierSS,GoodmanMA.Asystemforthesurgicalstagingofmusculoskeletalsarcoma.ClinOrthopRelatRes1980
153:106.Copyright1980WoltersKluwerHealth,LippincottWilliams&Wilkins.Unauthorizedreproductionofthismaterialisprohibited.
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DefinitionofTNMforbonetumorsotherthanlymphomaandmyeloma
Primarytumor(T)
TX
Primarytumorcannotbeassessed
T0
Noevidenceofprimarytumor
T1
Tumor8cmorlessingreatestdimension
T2
Tumormorethan8cmingreatestdimension
T3
Discontinuoustumorsintheprimarybonesite
NX
Regionallymphnodescannotbeassessed
N0
Noregionallymphnodemetastasis
N1
Regionallymphnodemetastasis
Regionallymphnodes(N)*
Distantmetastasis(M)
M0
Nodistantmetastasis
M1
Distantmetastasis
M1a
Lung
M1b
Otherdistantsites
Histologicgrade(G)
Gradeisreportedinregistrysystemsbythegradevalue.Atwograde,threegrade,orfourgradesystemmaybeused.Ifagradingsystemisnotspecified,
generallythefollowingsystemisused:
GX
Gradecannotbeassessed
G1
Welldifferentiatedlowgrade
G2
Moderatelydifferentiatedlowgrade
G3
Poorlydifferentiatedhighgrade
G4
Undifferentiatedhighgrade
Anatomicstage/prognosticgroups
StageIA
T1
N0
M0
G1,2Lowgrade,GX
StageIB
T2
N0
M0
G1,2Lowgrade,GX
T3
N0
M0
G1,2Lowgrade,GX
StageIIA
T1
N0
M0
G3,4Highgrade
StageIIB
T2
N0
M0
G3,4Highgrade
StageIII
T3
N0
M0
G3,4Highgrade
StageIVA
AnyT
N0
M1a
AnyG
StageIVB
AnyT
N1
AnyM
AnyG
AnyT
AnyN
M1b
AnyG
NOTE:cTNMistheclinicalclassification,pTNMisthepathologicclassification.
*Becauseoftherarityoflymphnodeinvolvementinbonesarcomas,thedesignationNXmaynotbeappropriateandcasesshouldbeconsideredN0unlessclinicalnode
involvementisclearlyevident.
Ewing'ssarcomaisclassifiedasG4.
UsedwiththepermissionoftheAmericanJointCommitteeonCancer(AJCC),Chicago,Illinois.TheoriginalsourceforthismaterialistheAJCCCancerStagingManual,
SeventhEdition(2010)publishedbySpringerNewYork,Inc.
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ContributorDisclosures
AJGelderblom,MD,PhD Nothingtodisclose JudithVMGBove,MD,PhD Nothingtodisclose RobertMaki,MD,PhD Grant/Research/Clinical
TrialSupport:ABIM[Medicaloncology]AADi[Medicaloncology(Nabrapamycin)]Bayer[Medicaloncology(Regorafenib)]Eisai/Morphotek[Medical
oncology(MorAb004)]GemPharmaceuticals[Medicaloncology(GPX150)]GSK[Medicaloncology(Pazopanib)]ImmuneDesign[Medical
oncology(LV305+G305)]Janssen/PharmaMar[Medicaloncology(Trabectedin)]Karyopharm[Medicaloncology(Selinexor)]Lilly/Imclone[Medical
oncology(Olaratumab)]SarcomaAllianceforResearchthroughCollaboration(SARC)[Medicaloncology(Regorafenib,pembrolizumab)].Speakers
Bureau:ABIM[Medicaloncology]AADi[Medicaloncology(Nabrapamycin)]Bayer[Medicaloncology(Regorafenib)Eisai/Morphotek[Medical
oncology(MorAb004)]GemPharmaceuticals[Medicaloncology(GPX150)]GSK[Medicaloncology(Pazopanib)]ImmuneDesign[Medical
oncology(LV305+G305)]Janssen/PharmaMar[Medicaloncology(Trabectedin)]Karyopharm[Medicaloncology(Selinexor)]Lilly/Imclone[Medical
oncology(Olaratumab)]SarcomaAllianceforResearchthroughCollaboration(SARC)[Medicaloncology(Regorafenib,pembrolizumab)].
Consultant/AdvisoryBoards:ABIM[Medicaloncology]AADi[Medicaloncology(Nabrapamycin)]Bayer[Medicaloncology(Regorafenib)
Eisai/Morphotek[Medicaloncology(MorAb004)]GemPharmaceuticals[Medicaloncology(GPX150)]GSK[Medicaloncology(Pazopanib)]Immune
Design[Medicaloncology(LV305+G305)]Janssen/PharmaMar[Medicaloncology(Trabectedin)]Karyopharm[Medicaloncology(Selinexor)]
Lilly/Imclone[Medicaloncology(Olaratumab)]SarcomaAllianceforResearchthroughCollaboration(SARC)[Medicaloncology(Regorafenib,
pembrolizumab)]. DianeMFSavarese,MD Nothingtodisclose
Contributordisclosuresarereviewedforconflictsofinterestbytheeditorialgroup.Whenfound,theseareaddressedbyvettingthroughamultilevel
reviewprocess,andthroughrequirementsforreferencestobeprovidedtosupportthecontent.Appropriatelyreferencedcontentisrequiredofall
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Muscular Tissue

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Muscular Tissue

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30/9/2016

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