21/5/2016

Classic Kaposi sarcoma: Clinical features, staging, diagnosis, and treatment

OfficialreprintfromUpToDate
www.uptodate.com.scihub.cc2016UpToDate

ClassicKaposisarcoma:Clinicalfeatures,staging,diagnosis,andtreatment
Authors
SusanEKrown,MD
JasmeetChadhaSingh,MD

SectionEditors
RobertMaki,MD,PhD
ThomasFDeLaney,MD
JuneKRobinson,MD

DeputyEditor
SadhnaRVora,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.

Literaturereviewcurrentthrough:Apr2016.|Thistopiclastupdated:Jul10,2014.
INTRODUCTIONKaposisarcoma(KS)isanangioproliferativedisorderthatrequiresinfectionwithhuman
herpesvirus8(HHV8),alsoknownasKaposisarcomaassociatedHerpesvirus(KSHV),forits
development[13].KSisclassifiedintofourtypesbasedupontheclinicalcircumstancesinwhichit
develops:classic(thetypeoriginallydescribedbyKaposi,whichtypicallypresentsinmiddleoroldage),
endemic(severalformsdescribedinsubSaharanindigenousAfricanspriortotheAIDSepidemic),
iatrogenic(atypeassociatedwithimmunosuppressivedrugtherapy,typicallyseeninrenalallograft
recipients)andAIDSassociated(epidemicKS).Theepidemiologicandclinicalaspectsofthesefourtypesof
KSarecomparedinthetable(table1).
Thisreviewwillfocusontheclinicalpresentation,staging,diagnosis,andtreatmentofclassicKS(CKS).The
epidemiology,riskfactors,pathology,andmolecularpathogenesisofCKSarediscussedelsewhere,asare
AIDSrelatedKSandiatrogenicKSdevelopinginthesettingofimmunosuppressivetherapy.(See"Classic
Kaposisarcoma:Epidemiology,riskfactors,pathology,andmolecularpathogenesis"and"AIDSrelated
Kaposisarcoma:Clinicalmanifestationsanddiagnosis"and"AIDSrelatedKaposisarcoma:Stagingand
treatment"and"Developmentofmalignancyfollowingsolidorgantransplantation",sectionon'Kaposi
sarcoma'.)
CLINICALFEATURESClassicKaposisarcoma(CKS)occursmostofteninoldermenofMediterranean
orCentral/EasternEuropeanancestry,inwhomthelesionsusuallyoccuronthedistalextremities,
particularlythelowerlegsandfeet.(See"ClassicKaposisarcoma:Epidemiology,riskfactors,pathology,and
molecularpathogenesis".)
SkinlesionsCKSischaracterizedbytheappearanceofpurplish,reddishblue,ordarkbrown/black
macules,plaques,andnodulesontheskin(picture1AC).Nodularlesionsmayulcerateandbleedeasily.
Theskinlesionsrangeinsizefromverysmalltoseveralcentimetersindiameter,andtheycanremain
unchangedformonthstoyears,orgrowrapidlywithinafewweeksanddisseminate.(See'Naturalhistory'
below.)
Thedermatologyliteraturecontainsreferencetoatleast10differentmorphologicvariantsofthecutaneous
lesionsofKS,whicharereferredtoaspatch,plaque,nodular,lymphadenopathic(usuallyinAfrican
children),exophytic,infiltrative(thelattertwoinAfricanadultswithendemicKS),ecchymotic,telangiectatic,
keloidal,andcavernousorlymphangiomalikevariants[4].Thecavernousorlymphangiomalikevariants
arecommoninCKS,particularlyinthesettingofchroniclymphedema.Inthisvariant,lesionsdeveloponthe
lowerextremitiesthatconsistofcompressiblenodulesthatappeartobefluidfilledcysts.Histologically,
lymphangiomalikeKSconsistsofanastomosingnetworksofsmaller,irregularandcompressibledilated
lymphaticslinedbyflatandcytologicallybanalendothelialcells[57].
Theremaybeaccompanyinglymphedemaoftheaffectedextremity.Thelymphedemaisnotgenerally
associatedwiththepresenceofbulkyregionalnodaldisease,butinstead,relatedtolocaldermalinfiltration
and/ordermallymphaticinvolvement.(See"Clinicalfeaturesanddiagnosisofperipherallymphedema"and
"Clinicalstagingandconservativemanagementofperipherallymphedema".)
ExtracutaneousinvolvementDuringthecourseofthedisease(rarelyinitially[8]),mucousmembranes
ofmouthandgastrointestinal(GI)tractandregionallymphnodesmaybeaffected.GItractinvolvementis
usuallyasymptomatic,butbleeding,diarrhea,proteinlosingenteropathy,intussusception,andperforation
havebeenreported[9,10].

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Ingeneral,GItract/oralmucosalinvolvementislesscommonthanwithAIDSrelatedKS,affecting10
percentofpatients[1113].(See"AIDSrelatedKaposisarcoma:Stagingandtreatment".)
However,inonereport,anextraordinary82percentofGreekpatients(71of87)withbiopsyprovenCKS
whowereinvestigatedwithuppergastrointestinalendoscopyhadGIlesionsall71hadstomachlesions,19
hadesophageallesions,eighthadlesionsoftheproximalduodenum,andtwohadbothesophagealand
duodenallesions[14].Althoughthisfindingcouldbeinterpretedassuggestingtheneedforscreening
endoscopyinpatientswithnewlydiagnosedCKS,italsosupportstheviewthatthepresenceof
asymptomaticGIinvolvementprobablyhaslittleeffectonprognosis.Inpractice,routineendoscopyisnot
performedinpeoplediagnosedwithCKSwhodonothavesymptomsreferabletotheGItract.
Regionalnodalinvolvementisrelativelyuncommonanditisrarelybulky.Nodalinvolvementwasreportedin
15percentof66GreekpatientswithCKSinonestudy[11].Thepresenceofnodaldiseaseprobablydoes
notworsenoverallprognosis,althoughthishasbeendemonstratedinAIDSrelatedKS,notclassicKS.
Involvementofvisceralorgansotherthantheliningofthealimentarytract(eg,lung,liver,bone,bone
marrow)isextremelyrare[11,1517].
NaturalhistoryInmostcases,CKShasachronic,indolentcourse,anditrarelyinfluencessurvival.
Giventheaffectedagegroup,deathfromunrelatedcausesismorecommon[1820].Asanexample,ina
seriesof438AmericanpatientswithCKSwhowerefollowedforanaverageof4.8years,24percentdiedof
secondmalignancies,22percentdiedofothermedicalconditions,andonly2percentdiedofwidespread
disease[21].
Yet,thediseaseoccasionallyhasanacuteonsetandrapidlyprogressivecourse,orpreviouslyindolent
diseasecanundergosuddenworsening,leadingtodisabilityandevendeath[18,19,22].Infact,Kaposis
original1872paperdescribedthediseaseas"incurableanddeadly",statingthat"thediseaseleadstodeath
anditdoessowithinashortperiodoftwotothreeyears"[23].
DIAGNOSISANDSTAGINGThediagnosisofClassicKaposisarcoma(CKS)isusuallysuspectedbased
upontheappearanceofthecharacteristiclesions(purplish,reddishblue,ordarkbrown/blackpatches,
plaquesornodules)andtheirdistribution(ontheskin,mostoftenofthelowerextremities).
DifferentialdiagnosisInthelowerextremity,thelesionscanbemistakenfortheskinlesionsof
peripheralvasculardisease,aconditionwhichiscommonintheelderlypatientswhoareatgreatestriskfor
CKS.
OtherlesionswhichmaymimictheappearanceofCKSincludebacillaryangiomatosis,angiosarcoma,and
benignvascularlesions,suchashemangiomas.BacillaryangiomatosisiscausedbyBartonellaspecies,a
slowgrowing,fastidious,gramnegativebacillus,andisreadilytreatedwithantibiotictherapy.Theskin
lesionsofbacillaryangiomatosisusuallyappearasnumeroussmallredtopurplepapulesthatmaygradually
expandintolargepedunculatedlesionsornodulesthatmaybecomefriable.Therashmaybeassociated
withsymptomssuchasfever,chills,malaise,headache,andanorexia.S.schenckii(sporotrichosis)andM.
marinumskininfectionscouldalsobeconfusedwiththenodularformofKaposisarcoma.(See"Clinical
features,diagnosis,andtreatmentofBartonellaquintanainfections"and"Clinicalfeaturesanddiagnosisof
sporotrichosis"and"Epidemiologyofnontuberculousmycobacterialinfections".)
AvarietyoflesscommondermatologiclesionsmayalsobemistakenforCKS[4].
BiopsyBiopsyisrequiredfordefinitivediagnosis.Inadditiontoobservingtypicalhistologicalfeatureson
standardmicroscopy,polymerasechainreactioncanbeperformedoftheskinlesionstodetectamplified
HHV8DNAsequences,andimmunohistochemicalstainingofbiopsyspecimenscanalsobeperformedto
detectthepresenceofHHV8latencyassociatednuclearantigen(LANA1)withinthespindlecells,thus
confirmingthediagnosis.(See"ClassicKaposisarcoma:Epidemiology,riskfactors,pathology,and
molecularpathogenesis".)
RadiographicevaluationAsymptomaticpatientswithCKSrarelyrequireradiographicevaluationofthe
affectedextremitybecauseofthechronicusuallyindolentcourse.Screeningfordistantorganinvolvementis
notneededduetothelowfrequencyofradiographicallyevidentmetastaticdisease.Whenpresent,mucosal
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involvementoftheGItractisnotgenerallyvisibleonradiographicstudies.Asnotedabove,patientswith
symptomsreferabletotheGItractshouldbeconsideredforendoscopytoevaluateforvisceralmucosal
involvement.
StagingIncontrasttoAIDSrelatedKS,thereisnocommonlyusedoruniversallyagreeduponstaging
systemforCKS.TheAmericanJointCommitteeonCancer(AJCC)TNMstagingsystemforsofttissue
sarcomasspecificallyexcludesKS.(See"AIDSrelatedKaposisarcoma:Stagingandtreatment",sectionon
'Stagingandevaluation'.)
GiventhevariablenaturalhistoryofCKS,onegroupofinvestigatorsusedtheirexperiencewith300CKS
patientstoderiveaproposedstagingsystem,basedupondiseasedistributionandtheclinicalpaceof
progression[24]:
StageI(maculonodularstage)Smallmaculesandnodulesprimarilyconfinedtothelower
extremities
StageII(infiltrativestage)Plaquesmainlyinvolvinglowerextremities,sometimesassociatedwitha
fewnodules
StageIII(floridstage)Multipleangiomatousplaquesandnodulesinvolvingthelowerextremitiesthat
areoftenulcerated
StageIV(disseminatedstage)Multipleangiomatousnodulesandplaquesextendingbeyondthe
lowerextremities
StageItoIIIdiseasewasfurthersubdividedintoslow(groupA)orrapiddiseaseprogression(groupB,
definedasanincreaseinthetotalnumberofplaques/nodulesorinthetotalareaofplaquesinthethree
monthsfollowinganexamination)allpatientswithstageIVdiseasewereconsideredtohaverapidly
progressivedisease.
Intheoriginalseriesof300patients,thoseclassifiedashavingstagesIorIIdiseasehadaslowerrateof
progression,fewercomplications,andaloweroccurrenceofGItract/visceralinvolvement.Incontrast,
patientswithstageIIIorIVdiseasehadmorerapiddiseaseprogressionandagreaterlikelihoodofGI
tract/visceralinvolvement,localcomplications,andfunctionalimpairment.Rapidevolutionwasprevalentin
thefloridanddisseminatedstages(92and100percent,respectively),andlessfrequentintheinfiltrativeand
maculonodularstages(42and21percent,respectively).Visceralinvolvementoccurredonlyinpatientswith
stageIIIBandIVdisease(1.2and24percent,respectively).Survivalforthefourgroupswasnotreported.
Theauthorsproposedusingthisclassificationschemetoselectpatientswiththemostaggressivenatural
history(ie,thosewithstagesIIB,III,andIVdisease)forsystemictherapy.However,thisstagingsystemis
notinwidespreaduse.Itisbaseduponsubjectiveratherthanobjectiveclassificationoftheextentof
disease,anditsprognosticvaluehasnotbeenindependentlyvalidated.Furthermore,itspredictivevaluefor
responsetosystemictherapyhasnotbeenaddressed.
TREATMENTGiventheabsenceoftreatmentscapableoferadicatinglatentHHV8infection,onecan
questionwhetheranyformofKaposisarcoma,includingClassicKaposisarcoma(CKS),canbeconsidered
"curable".Nonetheless,anumberofstrategieshavebeenusedtomanageCKS,withthemajortherapeutic
goalsofachievingsymptompalliation,alleviatinglymphedema,improvingfunction,decreasingthesizeof
cutaneousorviscerallesions,anddelayingorpreventingdiseaseprogression.
Withrelativelyfewexceptions,thepublishedliteratureontreatmentofCKSconsistsofretrospectiveseries
andcasereports.ProspectivelydesignedphaseIItrialsarescarce,usuallyincluderelativelyfewpatients,
anddonotusestandardizedobjectivemethodstodocumentresponse.Furthermore,withasingleexception
[25],therearenoprospectivelyrandomizedtrialsthatcomparedifferenttreatmentsforCKS,makingit
impossibletoidentifythe"best"approach.Thisisnotsurprisinggiventherelativescarcityofthedisease,the
advancedageofmanyaffectedindividuals,andthefrequentpresenceofcomorbiditiesthatmaylimit
treatmentoptionsandtheabilitytoparticipateinclinicaltrails.
Despitetheselimitations,somegeneralprincipleshaveemergedaboutCKStreatmentbasedonempirical
evidence:
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Observationwithoutspecifictreatmentisanoptionforpatientswhohavealimitednumberof
asymptomaticlesionsthatdonotimpairfunction,althoughdiseaseprogressioneventuallyoccursin
mostpatients.Inastudyof39patientswithasymptomaticlesionswhowereobservedwithoutspecific
treatment,only34percentremainedprogressionfreeattwoyears[18].
Symptomsrelatedtolimitedlowerextremityedemacanbealleviatedinmanypatientswithelastic
compressionstockings[26].
Whentreatmentisindicated,thereareavarietyoflocalandsystemictumordirectedtherapyoptions,
thechoiceofwhichdependsontheextent,location,andpaceofdisease.
Thepresenceofregionalnodaldiseasedoesnotnecessarilyinfluencethechoiceoflocalversus
systemictreatment.Unlessthenodaldiseaseislargeandsymptomatic(anuncommonscenario),we
treatthesepatientsbaseduponthevolumeandextentoftheirlocalskindisease.
LocaltreatmentsThesearetreatmentsdirectedatspecificlesionsorgroupsoflesions.
SurgeryInsomecases,ifthereisasinglesymptomaticlesion(eg,bleedingorchafingagainst
clothing),excisionalonemayprovidesustainedlocaltumorcontrol[18,19,27],butnewlesionscommonly
developatothersites.
RadiationtherapyAllformsofKS,includingCKS,areverysensitivetoradiotherapy(RT).However,
becauseofthemultifocalnatureofthedisease,thepersistenceofHHV8evenwithsuccessfullocallesion
control,andthetendencyfornewlesionstodevelopinnonirradiatedareas,thereisnoconsensusastothe
placeofRTinthetherapeuticarmamentarium(particularlywhentochooseRToversystemictherapy)orthe
optimalradiationtechnique.
Severalsuccessfulstrategieshavebeendescribed[18,2838].Highratesoftumorregressionarereported
usingdifferentenergysources(Cobalt60,lowenergyelectrons,superficialXrays)todeliverlocal(or,
occasionallyextendedfield)RT.ThereismarkedvariationintotalRTdoses(6to60Gy)andinthe
fractionationregimens,whichrangefromdosesof6to12Gyinasinglefractiontolargertotaldoses
administeredinsmallerfractionsoverseveralweeks[18,28,29,3135,38].Oneofthemostcommonly
prescribedregimensis30Gyin15daily2Gyfractions[36,37].
Althoughdurablelocallesioncontrolandsymptomreliefcanbeachievedinover90percentofcases,most
publicationsdonotclearlyaddressthefrequencyofoutoffieldrecurrencesandtheeventualneedfor
additionallocalorsystemictherapy.Treatmentofsolitarylesionsastheyarisemayrequireirradiationof
numerousadjacentfieldsandcanleadtodosimetricproblemsatjunctionpoints.Forthisreason,although
overallresponseratesaresimilar,someauthorspreferastrategyofonceweeklytotalorsubtotalskin
electronbeamtherapy(forthreetofoursessions)overlocalinvolvedfieldradiotherapy,becauseofthe
loweroutoffieldrecurrencerates[30].Oneotherfrequentlyemployedtechniqueistreatmentoftheinvolved
portion(s)ofthefeetandlowerextremitieswhenextensivelyinvolvedusingawaterbathtechnique,which
allowshomogeneousradiationofacomplextarget.Inoneseriesusingasplitcoursetechniquedelivering30
Gyin10fractions,disappearanceoflesionswasseenin89percentofpatients,althoughlimbedemaonly
regressedin57percent[39].
CryotherapyandlasertherapyAswithAIDSrelatedKS[40],liquidnitrogencryotherapyis
sometimesused(mainlybydermatologists)forlocalcontrolofsmallCKSlesions[41,42].However,the
effectismainlycosmetic,andthereisnoinformationontheimpactofthisformoflocaltherapyonlongterm
diseasecontrol.
Lasertherapymayalsobeusefulforselectedcases[43,44].
IntralesionaltherapyIntralesionalinjectionofchemotherapy(mostoftenvinblastine,butsometimes
bleomycin)leadstolocalregressionofcutaneousKSlesions[45,46].Inourexperience,suchinjections,
whilecapableoferadicatinginjectedtumors,canbepainfulandleadtolocalscarring.(See"AIDSrelated
Kaposisarcoma:Stagingandtreatment",sectionon'Localsymptomatictherapy'.)Onereporthasalso
describedahighresponserateinsinglenodularCKSlesionstreatedwithintralesionalvincristine[46].
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Intralesionalinjectionofinterferonalfa,aloneorincombinationwithinterleukin2,hasalsobeenreportedto
induceregressionofclassicalKSlesions[47,48].Thestudiescitedevaluatedtheeffectsoftwiceorthrice
weeklyinjectionsoveraperiodoffourtosixweeks,whichisunlikelytobepracticalforroutinetreatmentof
individualswithmultiplecutaneouslesions.
Electrochemotherapyusesasmallelectriccurrent(electroporation,aformofelectromotivedrug
administration)toincreasedrugdeliveryintothetumorthisapproachhasbeenusedprimarilywith
bleomycin.Inoneseriesof23patientswithclassicalKStreatedwiththisapproach,allpatientsshowed
tumorregression,whichwascompletein65percent[46].Itshouldbenoted,however,thatgeneralorspinal
anaesthesiawasrequiredtoadministerthetreatment.
Topicaltherapy
CisretinoicacidAlitretinoin(9cisretinoicacid)gel0.1percentisanFDAapprovedtopical
treatmentforcutaneousAIDSassociatedKSbutpublishedexperienceinCKSislimited.(See"AIDS
relatedKaposisarcoma:Stagingandtreatment",sectionon'Localsymptomatictherapy'.)
AsinglecasereportofanelderlypatientwithCKSnotedagoodlocalresponsewithpartialorcomplete
resolutionofmultipletreatedcutaneouslesions,althoughthepatientcontinuedtodevelopnewlesions
inuntreatedskin[49].Ofnote,anothercasereportdescribedthefailureofalitretinoingelinapatient
withCKS[50].
ImiquimodAprospectiveclinicaltrialoftopicalimiquimoddemonstratedanobjectiveresponse
(completeorpartial)in47percentof17patientswithnonAIDSrelatedKS[51].Responsewas
assessedatonlyonepoint(36weeks),andthedurationofdiseasecontrolwasnotreported.There
wasaninverseassociationbetweenlesionareaandresponse.Asinglecasereportdescribed
completeregressionofextensiveCKSusingtopicalimiquimodwithocclusivedressings[52].
NicotinepatchesBasedupontheobservationthatsmokingwasassociatedwithareducedriskof
CKS,andthepotentialeffectsofnicotinebothonimmunefunctionandvasoconstriction,arandomized,
placebocontrolledtrialofdermalnicotinepatcheswasconductedinCKS[53].Treatmentwaswell
tolerated,buttherewerenosignificanteffectsonCKSlesionsoronHHV8antibodytitersorDNA
levelsinPBMCs[53].(See"ClassicKaposisarcoma:Epidemiology,riskfactors,pathology,and
molecularpathogenesis",sectionon'Smoking'.)
SystemictreatmentsThesearetreatmentswiththepotentialtocauseregressionatalldiseasesites.
ChemotherapyWidespread,bulky,orrapidlyprogressiveCKS,particularlywhenitinterfereswith
functionorisassociatedwithmoderatetoseveresymptomaticedemaorvisceralorganinvolvement,isan
indicationforsystemicchemotherapy.Althoughnocytotoxicchemotherapeuticagentshavebeenapproved
intheUSorelsewherespecificallyfortreatmentofCKS,anumberofdrugsapprovedfortreatmentofAIDS
associatedKSorotherneoplasmshaveactivityagainstCKSeitherasinitialchemotherapyor,insome
cases,afterfailureofpriortherapy.Theseincludepegylatedliposomaldoxorubicin,vinblastine(aloneorin
combinationwithbleomycin),paclitaxel,oraletoposide,vinorelbine,andgemcitabine[18,20,25,5467].
Overallresponseratesforallofthesedrugsordrugcombinationshavebeenquitehigh(60toover90
percent),andthetreatmentsaregenerallywelltolerated,evenintheelderlypopulationatgreatestriskfor
CKS.Medianresponsedurationsrangefromfourmonthstoovertwoyears.
Intheabsenceofuniformprospectivelydefinedobjectivecriteriaforinclusionorforresponseand
progression,andintheabsenceofrandomizedtrials,itisdifficulttomakerecommendationsforpreferred
treatmentsonthebasisofresponserates,durationofbenefit,oradverseeffects[68].
Onlyonerandomizedtrialhasbeenconductedinwhichtwodifferentsystemictherapieswerecompared
[25].SixtyfivepatientswithCKSwererandomlyassignedtooraletoposide(60mg/m2dailyforthreedays
forthefirstcycle,fourdaysforthesecondcycle,andfivedaysforthethirdcycle,astolerated,withcourses
repeatedeverythreeweeks)orintravenousvinblastine(3mg/m2weeklyforthreeweeks,then6mg/m2
everythreeweeks).
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Therewerenosignificantdifferencesbetweenthetwotreatmentswithregardtoresponserate(74versus58
percentwithetoposideandvinblastine,respectively),durationofresponse,orsurvival(mediannotreached
ineithergroupwithamedianfollowupof38months).Sideeffectswereinfrequentandmildinbothgroups,
althoughalopeciaandnauseaandvomiting(allgrade1or2)weremoreprominentwithetoposideand
myelosuppressionwasmoreevidentwithvinblastine(grade1in7,grade3in2).
Despitethelackofrandomizedtrialsdemonstratingsuperiority,mostcliniciansconsiderpegylatedliposomal
doxorubicin(PLD,adrugapprovedintheUSforAIDSrelatedKS)tobethefirstlinetherapyofchoice
unlessthereisacardiaccontraindication.ThebenefitoffirstlinePLD(20mg/m2everythreeweeks)was
addressedinaretrospectivemultiinstitutionalseriesof55patientswithCKS[20].Acomplete(absenceof
detectablelesionsforatleasteightweeks)ormajorresponse(50percentdecreaseinthenumberof
measurablelesions,andabsenceofnewcutaneouslesionsforatleasteightweeks)wasnotedin71
percent.Themediantimetoresponsewasfourmonths,andthemedianresponsedurationwas25months.
Theoptimaldurationofchemotherapyhasnotbeensystematicallystudied.Weusuallytreatwithoneortwo
coursesbeyondastablemaximalresponseandgraduallystretchouttheintervalsbetweentreatments.If
thereisnoevidenceofprogression,weattempttodiscontinuetherapy,andcloselymonitor,offering
retreatmentwiththesameregimenatthetimeofprogression.
ForpatientswhodonotrespondtoPLD(orwhoinitiallyrespondbutthenbecomerefractorytothedrug),the
choiceofasecondlineagent(vinblastinealoneorincombinationwithbleomycin,paclitaxel,oraletoposide,
orgemcitabine)mustbeindividualized,takingintoaccountage,comorbidity,andpersonalpreference.
ImmunomodulatorsRecombinantinterferonalfa(IFNa)isapprovedfortreatmentofAIDSassociated
KSintheUS.WhilethemechanismofantitumoractionofIFNainKSisnotknown,itmayinvolvedirect
antiproliferativeeffects,antiviraleffects,inhibitionofangiogenesis,andmodulationofhostcellularand
humoralimmuneresponses[69].(See"AIDSrelatedKaposisarcoma:Stagingandtreatment",sectionon
'Otheragents'.)
ThereislimitedexperiencewiththisdruginCKS.InaprospectivelydesignedphaseIIclinicaltrial,16
patients(13withCKS,threewithendemicAfricanKS),nineofwhomwererefractorytochemotherapyand/or
radiotherapy,weretreatedwithIFNa(5millionunitssubcutaneouslythreetimesaweek)foraminimumof
sixmonths[70].Major(completeorpartial)tumorregressionswereobservedin10patients,andfourother
patientsshowedminorresponseorstabledisease.However,sideeffects,especiallyfatigue,lowgrade
fever,myalgias,anddepression,canbeprominent.
LowerdosesofIFNa(1to3millionunits,fivedaysaweek)inducedcompleteregressionofCKSinthree
patientsandapartialregressioninafourth[71].Inanothersmallcaseserieshowever,onlyoneofsixCKS
patientstreatedatanIFNadoseof3millionunits,threetimesaweek,showedamajorresponse,whilefour
othersshowedminor(<50percent)tumorregression[56].
LikeIFNa,thalidomidehasantiangiogenicandimmunomodulatoryeffects,andthedrugisactiveinAIDS
relatedKS[72].ExperiencewiththalidomideislimitedinCKS[73,74].Onereportnotedactivityinthree
patientswithCKSwhoreceivedthalidomide100mgdaily[73].Twoofthethreehadacompleteclinical
responseafter12monthsoftreatment.Inthesecondseries,3of11patientswithCKShadapartial
responsetothesamedoseofthalidomide[74].Threepatientsdiscontinueddrugtherapyprematurelydueto
sensoryneuropathyorvertigo.ThalidomideisnotanFDAapprovedtreatmentforanyformofKS.
InvestigationaltherapiesApproachesunderinvestigationforAIDSassociatedKS,manyofwhichtarget
angiogenesis,arealsobeingtestedagainstCKS[7577].SeveralphaseIIprotocolsstudyingnew
approachesareopenforpatientswitheitherHIVrelatedornonHIVrelatedKS[78].Thereisnoreasonto
believeapriorithatanyoftheseapproaches(withtheexceptionofthosespecificallytargetingHIVinfection),
ifprovensuccessful,wouldnotalsoapplytotreatmentofCKS.
OnestudyattemptedtoexploitthefindingthatHIVproteaseinhibitorsexertantiangiogenicandantitumor
propertiesthataredistinctfromtheirantiretroviraleffects[79].Sixteenof28patientswithCKSwhowere
treatedwithindinavirweredescribedashavingbenefitsthatincludedacompleteresponse(n=1),partial
response(n=2),"improveddisease"(n=5)andstabilizationofprogressivedisease(n=8).Theauthors
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describedanassociationbetweenafavorableclinicalcourseandhigherplasmaindinavirlevels,reduced
levelsofbasicfibroblastgrowthfactor,lowernumbersofcirculatingendothelialcells(acelltypereportedto
beincreasedinCKS[80]),andareductioninHHV8antibodytiters.
CasereportsdescribingregressionofCKSinpatientstreatedwiththemTORinhibitor,rapamycin(sirolimus)
[77,81]suggestthatthisapproach,whichhasproveneffectiveinsomecasesoftransplantassociatedKS,
maybemoregenerallyapplicable.
INFORMATIONFORPATIENTSUpToDateofferstwotypesofpatienteducationmaterials,TheBasics
andBeyondtheBasics.TheBasicspatienteducationpiecesarewritteninplainlanguage,atthe5thto6th
gradereadinglevel,andtheyanswerthefourorfivekeyquestionsapatientmighthaveaboutagiven
condition.Thesearticlesarebestforpatientswhowantageneraloverviewandwhoprefershort,easyto
readmaterials.BeyondtheBasicspatienteducationpiecesarelonger,moresophisticated,andmore
detailed.Thesearticlesarewrittenatthe10thto12thgradereadinglevelandarebestforpatientswhowant
indepthinformationandarecomfortablewithsomemedicaljargon.
Herearethepatienteducationarticlesthatarerelevanttothistopic.Weencourageyoutoprintoremail
thesetopicstoyourpatients.(Youcanalsolocatepatienteducationarticlesonavarietyofsubjectsby
searchingonpatientinfoandthekeyword(s)ofinterest.)
Basicstopics(see"Patientinformation:Kaposisarcoma(TheBasics)")
SUMMARYANDRECOMMENDATIONS
ClassicKaposisarcoma(CKS)isaneoplasmcharacterizedbyabnormalangiogenesisthatrequires
infectionwithahumanherpesvirus,HHV8,alongwithothercofactors.(See'Introduction'above.)
CKSarisesmostcommonlyinelderlymenofMediterraneanandCentral/EasternEuropeandescent,
butitcanalsooccurinyoungerindividuals,inwomen,andinothergeographicareas.(See"Classic
Kaposisarcoma:Epidemiology,riskfactors,pathology,andmolecularpathogenesis",sectionon
'Epidemiology'.)
Themostcommonpresentationisthatofpurplish,reddishblue,ordarkbrown/blackskinlesions
(macules,nodules,plaques)onthelowerextremities,oftenwithlymphedema.(See'Clinicalfeatures'
above.)
CKSisfrequentlydescribedasslowgrowing,localizedandindolent,butitcanbecomedisseminated
and/orgrowrapidly,andcausesignificantmorbidityandmortality.(See'Naturalhistory'above.)
ThediagnosisofCKSrequiresabiopsy.Involvementofmucousmembranes,lymphnodes,and
visceralorgansisrelativelyinfrequentradiographicstagingevaluationandendoscopicscreeningare
notroutinelyindicatedinasymptomaticpatients.(See'Extracutaneousinvolvement'aboveand
'Radiographicevaluation'above.)
TreatmentThereisnoconsensusontheoptimaltumordirectedtherapyfordifferentCKSmanifestations.
Becausemanyactivetreatmentshavebeendescribed,therapeuticchoicesareoftenmadebaseduponthe
experienceandmedicaldisciplineofthetreatingclinician,butalsoincludeconsiderationofpatient
preferencesandcomorbidconditions.
Thefollowingrepresentsourgeneralapproach:
Wesuggestobservationratherthanspecifictreatmentforpatientswhohavealimitednumberof
asymptomaticlesionsthatdonotimpairfunction(Grade2C).Symptomsrelatedtolimitedlower
extremityedemacanbealleviatedinmanypatientswithelasticcompressionstockings.(See
'Treatment'above.)
Forpatientswhohavelimitedvolumediseasecausingsymptoms(eg,bleedingorchafingagainst
clothes)orcosmeticdisfigurement,wesuggestlocaltreatmentratherthanobservationorsystemic
chemotherapy(Grade2C).Thechoiceofmodality(radiationtherapy,excision,cryotherapy,laser
ablation)dependsonanumberoffactors,includingthesiteandextentofthediseaseinvolvementas
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Classic Kaposi sarcoma: Clinical features, staging, diagnosis, and treatment

wellasclinicianandpatientpreference.(See'Localtreatments'above.)
Thereisnoconsensusastotheindicationsforsystemictherapy.Weconsiderthisapproachin(butnot
limitedto)thefollowingsituations:
Symptomaticvisceralormucosalinvolvement(althoughrare)
Diffusesymptomaticlesionsonmultiplebodypartsthatarenoteasilyencompassedinasingleor
alimitednumberofradiationfields
Extensivenodulardiseaseordiffuseinvolvementofalargeportionofanextremity
Bulkydiseaseinalocalizedareaofonelimbthatcannotbeencompassedwithinasingle
radiationtherapyport
Moderatetosevereassociatedlymphedemabeyondwhatcanbecontrolledwithelasticstockings
Whenthereisanindicationforchemotherapywesuggestpegylatedliposomaldoxorubicin(PLD)as
thefirstlineregimen,intheabsenceofacardiaccontraindication(Grade2C).(See'Chemotherapy'
above.)
ForpatientswhohaveprogressedwhilereceivingPLDorforthosewhodonotrespondtoPLD,there
areseveraloptionsforsecondlinetherapyinthosewhoretainanadequateperformancestatus.The
availableoptionsincludeasingleagenttaxane,oraletoposide,vinblastine,orgemcitabine.Noone
regimencanberecommendedoveranyother.Thedecisionmustbeindividualized,takinginto
considerationpatientage,accompanyingcomorbidity,andclinicianandpatientpreference.
Thereisaneedforprospectivelydefinedstudiesthatusewelldefinedresponsecriteriatobetterdefine
optimaltreatment(s)forCKS.
UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.
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GRAPHICS
EpidemiologicandclinicaltypesofKaposisarcoma
Type
Classic(sporadic)

Predominant
riskgroups

Cutaneous
presentation

Visceral
involvement

Clinicalcourse

~3:1male:female

Distallower

Uncommon

Usuallyindolent

ratio

extremities

rarelyaggressive&
disseminated

Age>60
Mediterraneanor
Central/Eastern
EuropeanOrigin
MiddleEast
Endemic(African)

Maleadults
Childrenofboth
sexes
EquatorialAfrica

Various(maybe
similartoclassic
ormorelocally
aggressive)

Internalorgans
involvedina
subsetofadult
patients

Indolenttolocally
invasiveinadults

lowerextremity
lymphedemain
adults
cutaneous
diseaseoften
absentin
children

Common
(lymphnodes
andviscera)in
children

visceraldiseasein
adults

Relatively
common

Mayregresswith
modificationof

Iatrogenic
(immunosuppression

Exogenous
immunosuppression,

Distallower
extremitiesmay

related)

esp.solidorgan
transplant

bedisseminated

Occasionalrapid
progressionwith

Aggressivein
children

immunosuppression
Maybeaggressive

Olderpatients(>50)
UseofcyclosporinA
AIDSassociated

Menwhohavesex
withmen(developed
countries)
Heterosexualmen&
women(Africa)

Localizedor
disseminated

Commonwith
poorHIVcontrol

Aggressiveor
indolent
Mayregresswith
effectiveHIV
treatment

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ClassicKaposisarcoma

Multipleredbrownpatchesandplaquesarepresentonthelowerleg.
Reproducedwithpermissionfrom:www.visualdx.com.CopyrightLogicalImages,Inc.
Graphic81468Version4.0

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ClassicKaposisarcoma

Multipleviolaceouspapulesandplaquesarepresentonthedistalupperextremity
ofthispatientwithclassicKaposisarcoma.
Reproducedwithpermissionfrom:www.visualdx.com.CopyrightLogicalImages,Inc.
Graphic69584Version4.0

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Classic Kaposi sarcoma: Clinical features, staging, diagnosis, and treatment

ClassicKaposisarcoma

Multiplepapulesandnodulesarepresentonthelowerleginthispatientwith
classicKaposisarcoma.
Reproducedwithpermissionfrom:www.visualdx.com.CopyrightLogicalImages,Inc.
Graphic54707Version4.0

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