OfficialreprintfromUpToDate

www.uptodate.com2016UpToDate

ErdheimChesterdisease

Author: EricJacobsen,MD
SectionEditor: ArnoldSFreedman,MD
DeputyEditor: AlanGRosmarin,MD

Alltopicsareupdatedasnewevidencebecomesavailableandourpeerreviewprocessiscomplete.
Literaturereviewcurrentthrough:Oct2016.|Thistopiclastupdated:Oct28,2016.

INTRODUCTIONErdheimChesterdisease(ECD)isararenonLangerhanshistiocyticdisordermost
commonlycharacterizedbymultifocalosteoscleroticlesionsofthelongbonesdemonstratingsheetsoffoamy
histiocytesonbiopsywithorwithouthistiocyticinfiltrationofextraskeletaltissues.ECDwasfirstdescribedby
ErdheimandChesterin1930[1].Onlyseveralhundredcaseshavebeenreportedinthemedicalliterature
sincethattime.

Histocyticdisordersarethoughttobederivedfrommononuclearphagocyticcells(macrophagesanddendritic
cells)orhistiocytes.ThisgrouphasgenerallybeendividedintoLangerhanscellhistiocytosisandnon
Langerhanshistiocytosis.Langerhanscellhistiocytosisissonamedforitspresumedderivationfromthe
Langerhanscells,whicharespecializeddendriticcellsfoundintheskinandmucosa.Incontrast,non
Langerhanshistiocytosesarethoughttobederivedfromthemonocytemacrophagelineage.

Theepidemiology,clinicalmanifestations,pathologicfeatures,diagnosis,andmanagementofECDwillbe
presentedhere.ThediagnosisandmanagementofLangerhanscellhistiocytosisispresentedseparately.
(See"Clinicalmanifestations,pathologicfeatures,anddiagnosisofLangerhanscellhistiocytosis"and
"PulmonaryLangerhanscellhistiocytosis"and"Langerhanscellhistiocytosis(eosinophilicgranuloma)of
boneinchildrenandadolescents".)

EPIDEMIOLOGYECDisararehistiocyticdisorderandtheincidenceisunknown.Fewerthan500cases
havebeenreportedinthepublishedliterature[2].ECDhasbeendiagnosedinallagegroups,butismost
commoninadults.Themeanageatdiagnosisis53years[2].Thereisaslightmalepredominance.Although
thereisspeculationthatECDandotherhistiocytedisordersmayrepresentanaberrantresponsetoinfection,
noinfectiousetiologyhasbeenidentified.ThereisnoevidencethatECDisaninheritablegeneticdisorder.

PATHOGENESISThepathogenesisofECDispoorlyunderstood.Attemptstoestablishclonalityhave
producedvariedresults,andalthoughoccasionalclonalcytogeneticaberrationshavebeenidentified,none
arecharacteristicordiagnostic[35].Astudyoftissuefromasinglepatientdemonstratedinducible
productionoftumornecrosisfactor(TNF)aswellasspontaneoussecretionofinterleukin(IL)6andCXC
chemokineligand8/IL8(CXCL8/IL8),whichisknowntoattractmonocytesandpolymorphonuclearcells
[6,7].DatafromalargerseriesofpatientsdemonstratedthatthecellularinfiltrateofECDcontainsa
significantnumberofTcellhelper1(Th1)lymphocytes,andtheinfiltratinghistiocytesexpresstheinterferon
gammainducedchemokineCXCL10/IP10aswellasIL1[8].Subsequentstudiesdemonstratedasignificant
increaseintheserumlevelsofIFNbutnotinterferongammainuntreatedECDpatientscomparedwith
controls.

Plasmacytoiddendriticcellsareacommonsourceofinterferonalpha,butinsituimmunohistochemical
studiesofECDlesionsdidnotdemonstrateplasmacytoiddendriticcells,arguingthatthesecellsarenotthe
primarysourceofIFNproductioninECD[9].Thesesameinvestigatorsdemonstratedincreasedserum
levelsofIL12,acytokinethatfavorstheTh1pathwayandasignificantdecreaseinIL4,amajorTcell
helper2cytokineinbothtreatedanduntreatedpatients.Theyalsodevelopeda5cytokinesignature(IFN,
IL12,MCP1,IL4,andIL7)thatcoulddistinguishECDpatientsfromcontrolsandfrompatientswithother
inflammatorydiseasessuchasrheumatoidarthritis,systemicsclerosis,andsepsis.

BRAFisamemberoftheserinethreoninekinasefamily,whichplaysapartintheRAS/RAF/MEK/MAPK
signalingpathwayleadingtoenhancedcellproliferationandsurvival.Anactivatingpointmutationofthe
BRAFisoformofRAF(BRAFV600E)isidentifiedinapproximately50percentofcasesofECDandsmall
caseserieshavereportedclinicalresponsestotheBRAFinhibitorvemurafenib[1012].Furtherstudiesare
neededtoinvestigatethispotentialroleofBRAFinthepathogenesisofECD.(See'BRAFinhibition'below.)

CLINICALMANIFESTATIONSTheclinicalpresentationofpatientswithECDvariesdependinguponthe
sitesofinvolvement.MostpatientswithECDwillhaveosseousinvolvementatthetimeofdiagnosisandthe
vastmajoritywillalsohaveatleastonenonosseoussiteofinvolvement.Asubsetofpatientsis
asymptomaticwithboneinvolvementdetectedatthetimeofradiographyforunrelatedconditions.

Inaliteraturereviewthatincludeddatafrom259patientswithhistologicallyprovenECD,themostcommon
clinicalpresentationswerebonepain(26percent),neurologicfeatures(23percent),diabetesinsipidus(22
percent),andconstitutionalsymptoms(20percent)[2].

Aretrospectivecaseseriesof37patientsreportedinvolvementofthefollowingsites,inorderofdecreasing
frequency[9]:

Longbones(95percent)
Maxillarysinus,largevessels,andretroperitoneum(59percenteach)
Heart(57percent)
Lungs(46percent)
Centralnervoussystem(41percent)
Skin(27percent)
Pituitaryglandandorbit(22percenteach)

Othercaseserieshavereportedasimilarpatternofinvolvement[13].

BoneBoneinvolvementoccursinthemajorityofECDpatients.Thismostcommonlymanifestsclinically
asmildbutpersistentjuxtaarticularpain,particularlyinthelowerextremities.However,asubsetofpatientsis
asymptomaticandboneinvolvementisdetectedatthetimeofradiographyforunrelatedconditions.Bilateral
andsymmetricosteosclerosisofthediaphysisofthelongbonesisnearlyuniversal(image1andimage2).
Osteosclerosisoftheskullbones,particularlythefacialbones,isalsowelldescribed[14].Bonelesionscan
bemissedonplainradiographs.Ifthereisahighclinicalsuspicionofosseousinvolvementandaplain
radiographisnormal,computedtomography(CT)ormagneticresonanceimaging(MRI)shouldbe
performed.

Aretrospectiveseriesof11patientswithbiopsyprovenECDwhohadundergoneconventionalradiography
andbonescintigraphyreportedbilateralandsymmetricosteosclerosisofthediaphysisofthelongbonesin
98percentofbonelesionsvisibleonconventionalradiographs[15].Theosteosclerosiswasheterogeneousin
65percentofthepatientsandhomogeneousin35percent.Thediaphysiswasinvolvedinallpatients,and83
percentofthelesionsalsoinvolvedthemetaphysis.Partialepiphysealinvolvementwithsparingofthe
subchondralbonewasalsocommon,aswereperiostitisandendosteitis.Bonescintigraphydepictedtracer
uptakeinallbonelesionsvisibleonradiographs(image3).MRIdetectedallabnormalitiesnotedbyplain
radiographandscintigraphy,andalsodepictedreplacementofthenormalfattybonemarrowby
heterogeneoussignalintensityonT1andT2weightedspinechoimages(image4).

CardiacCardiacinvolvementwithECDisseeninthemajorityofpatientsandisasignificantsourceof
morbidityandmortality.Cardiovascularinvolvementcanrangefromvalveabnormalitiestoconductiondefects
toperiaorticfibrosisalongtheentirecourseofthevessel.
Inaseriesof37patientssystematicallyscreenedwithelectrocardiogram(ECG)andimaging(cardiacMRI
and/orcomputedtomography),70percenthadabnormalheartimaging,and12of32hadanabnormalECG
[16].Themostcommonfindingwasinfiltrationoftherightheart(includingpseudotumor)inhalfofthe
patients.Periaorticfibrosis,periarterialinfiltrationofthecoronaryarteries,andpericardialthickening/effusion
werealsocommon.Inanotherseries,31percentofECDrelateddeathsweredeemedtobesecondaryto
cardiacinvolvement[17].Thecausesofdeathincludedmyocardialinfarction,cardiomyopathy,and
symptomaticvalvedisease.

PulmonaryOnequartertoonehalfofpatientswillhavepulmonaryinvolvement,eitherofthepleura,the
lungparenchyma,orboth[18].Pulmonaryinvolvementmaybeasymptomaticormanifestasdyspneaand/or
cough[19].Spirometrymayshowrestrictivefeaturesanddecreaseddiffusecapacity.Plainfilmsareoften
normal.Findingsoncomputedtomographyofthechestincludemediastinalinfiltration,pleural
thickening/effusion,centrilobularnodularopacities,groundglassopacities,orlungcysts[20].Ifperformed,
fluidfrombronchoalveolarlavagemaycontainmacrophagesandfoamyhistiocytes[19].Openlungbiopsies
havedemonstratedhistiocyticinfiltratesinalymphangiticpatternwithassociatedfibrosisand
lymphoplasmacyticinflammatoryinfiltrates.Althoughdyspneaandprogressivefibrosisleadingtorespiratory
failurecanoccur,inonelargeseriespulmonaryinvolvementwasnotanindependentpredictorofdecreased
survival[21].

RetroperitoneumRetroperitonealinvolvementwithECDcanmanifestasamasslikeinfiltrativelesionor
asarindlikelesionsurroundingthekidneys[22].Thiscanleadtoacuteor,morecommonly,slowly
progressiverenalinsufficiency.Percutaneousnephrostomytubesareoftenrequiredtoalleviateureteral
obstruction.(See"Clinicalmanifestationsanddiagnosisofurinarytractobstructionandhydronephrosis".)

CentralnervoussystemNeurologicinvolvementisseenin40to50percentofcases[2,9].Periorbital
involvementismostcommonandcanmanifestasexophthalmoswithorwithoutvisionchanges.Xanthomas
oftheeyelidarefrequentlyreported.Symptomsconcerningforneurologicinvolvementincludevision
changes,excessivethirstorurination,ataxia,headache,weakness,cordcompression,andlossoflibido[23].

Pituitaryinvolvementcommonlymanifestsascentraldiabetesinsipidusandotherendocrinopathies.Pre
existingdiabetesinsipidusandendocrinopathiestypicallypersist,evenwithradiographicregressionof
disease,andrequirespecificmanagement.Incontrast,diabetesinsipidusrarelydevelopslateinthe
diseasecourse[2].(See"Clinicalmanifestationsofhypopituitarism"and"Diagnosisofpolyuriaand
diabetesinsipidus".)

Cerebellarinvolvementandmasslesionsofotherpartsofthecentralnervoussystemoccurfrequently
andareoftenmultifocal.

ECDcaninfiltratethedura,inwhichcaseitmaybeconfusedwithameningioma[24].

LesionstypicallyenhancewithgadoliniumonMRI[19].

SkinUnlikeLangerhanshistiocytosis,whichfrequentlyaffectstheskin,cutaneousinvolvementwithECD
islesscommon,affectingapproximatelyonequarterofcases[25].Approximatelyonethirdofpatientshave
yellowplaquesunderneaththeskin(xanthelasma),mostcommonlyontheeyelids[19].Otherskinlesionsare
generallymultifocal,reddishbrown,andpapulonodularinappearance,buthavefewotherdistinguishing
characteristics.Prurituscanoccur,butisnotauniversalfeature.

OtherorgansInvolvementofotherstructures(breast,thyroid,testis,gingiva,kidneys,andspleen)israre.
Breastinvolvementusuallypresentsasapalpablemassornoduleinoneorbothbreasts[26].Liver
involvementmaybedetectedonradiographicstagingormanifestwithabnormalitiesintransaminases,
bilirubin,and/oralkalinephosphatase[27].Renalinvolvementmaymanifestasrenalfailure,renovascular
hypertension,orhydronephrosis[2].
PATHOLOGICFEATURESBiopsiesofinvolvedtissuesarecharacterizedbytissueinfiltrationbysheetsof
foamy(xanthomatous)histiocyteswithinterspersedinflammatorycellsandmultinucleategiantcells(Touton
cells)withadmixedorsurroundingfibrosis(picture1andpicture2andpicture3)[28,29].ECDcellsexpress
thehistiocytemarkerCD68andexpressCD163andFactorXIIIa,butunlikeLangerhanscellhistiocytosis,do
notexpressCD1aorS100(picture4andpicture1)[6].Birbeckgranules(anultrastructuralfindingonelectron
microscopyinLangerhanscellhistiocytosis)areabsent.Attemptstoestablishclonalityhaveproducedvaried
results,andarenotusedroutinelyfordiagnosis,andalthoughoccasionalclonalcytogeneticaberrationshave
beenidentified,nonearecharacteristicordiagnostic[35].

DIAGNOSISANDDIFFERENTIALDIAGNOSISECDisdiagnosedbaseduponthepathologicevaluation
ofinvolvedtissueinterpretedwithintheclinicalcontext[2830].ECDcanbedifficulttodiagnosesinceitisa
veryrarediseasethatcanaffectmanyorgansystems.Abiopsyofanosteoscleroticbonelesionisgenerally
preferred,whenpossible.Decalcificationofbonebiopsysamplesinpreparationforhistologicexamination
rendersthemunsuitableforgeneticanalysis.Biopsyshouldaimtoattainenoughtissuetoallowforhistologic
reviewandreserveadditionalsamplesforgenetictesting(ie,BRAFV600E).

ECDmustbedistinguishedhistologicallyandimmunophenotypicallyfromotherhistiocyticanddendriticcell
disorders,metastaticsolidorhematopoieticneoplasms,andhemophagocyticlymphohistiocyticand
macrophageactivationsyndromes.

LangerhanscellhistiocytosisLangerhanscellhistiocytosis(LCH)andECDarebothhistiocytic
diseasesthatcaninvolvemultiplesites,mostcommonlybones.Skininvolvementismorecommonin
LCH.Thetwoentitiescanusuallybedistinguishedbymorphologicandimmunohistochemicalevaluation.
ECDtumorcellslackcentralnucleargroovesandBirbeckgranulestypicalofLCHcells,andunlike
Langerhanscellhistiocytosis,theydonotexpressCD1aorS100[6].CasesofconcomitantLCHand
ECD(ie,mixedhistiocytosis)havebeendescribed[31].(See"Clinicalmanifestations,pathologic
features,anddiagnosisofLangerhanscellhistiocytosis".)

PagetsdiseaseandPOEMSsyndromeTheosteoscleroticlesionsofboneinECDcanbeconfusedfor
avarietyofmetabolicbonedisorders,includingPagetsdiseaseandthePOEMSsyndrome,thelatterof
whichalsocausesendocrineabnormalities,thusaddingtotheconfusion.Whiletheboneabnormalities
ofECDoftenareconfinedtobilateralandsymmetricosteosclerosisofthediaphysisofthelongbones,
PagetsdiseaseandPOEMSsyndromegenerallycauselesssymmetricboneabnormalitieswithless
specificlocalization.ECDcanreadilybedistinguishedfromPagetsdiseaseandPOEMSsyndromeby
histologicandimmunophenotypicfindingsonbiopsy.(See"POEMSsyndrome"and"Clinical
manifestationsanddiagnosisofPagetdiseaseofbone".)

HemophagocyticlymphohistiocytosisHemophagocyticlymphohistiocytosisandtherelated
macrophageactivationsyndromearesystemicdisordersthatdemonstratetissueinfiltrationbynon
neoplastichistiocytes.UnlikeECD,thesedisordersdemonstrateprominenthemophagocyticactivityin
thebiopsy,andarealsocharacterizedbyanumberofotherfindingsincludingfever,hypertriglyceridemia,
hypofibrinogenemia,hyperferritinemia,andbicytopenia.(See"Treatmentandprognosisof
hemophagocyticlymphohistiocytosis".)

Juvenilexanthogranuloma(JXG)JXGisabenignproliferativedisorderofhistiocyticcellsofthedermal
dendrocytephenotype.JXGbelongstothebroadgroupofnonLangerhanscellhistiocytosesandis
typicallyadisorderofearlychildhood.JXGpresentsinthefirsttwoyearsoflifeasasolitaryreddishor
yellowishskinpapuleornodule(picture5),mostoftenonthehead,neck,anduppertrunk.Histologically
andimmunophenotypically,JXGisindistinguishablefromECD.JXGgenerallyfollowsabenigncourse
withspontaneousresolutionoveraperiodofafewyears.Lesscommonly,skinlesionscanbemultiple
(picture6).Extracutaneousorsystemicforms(brain,lung,kidney,spleen,liver,bonemarrow,andretro
orbitaltumors)areexceedinglyrareandcanbeassociatedwithconsiderablemorbidity.(See"Juvenile
xanthogranuloma(JXG)".)
 RosaiDorfmandisease(RDD,sinushistiocytosiswithmassivelymphadenopathy)RDDisa
macrophagerelateddisorderthatmostoftenpresentsasasystemicdisorderinvolvinglymphnodesand
otherorgans[3234],orrarelycanbelimitedtotheskin[35,36].UnlikeECD,skinlesionsarefirm,
induratedpapules.AlthoughthepathologiccellsinRDDarethemacrophages(CD14+,CD1a,S100+/,
CD68+),RDDishistologicallydistinctfromtheotherhistiocyticdiseasesbecausethemacrophageshave
normalappearinglymphocytesresidinginthemacrophagecytoplasm(emperipolesis)[37].(See
"Peripherallymphadenopathyinchildren:Etiology",sectionon'RosaiDorfmandisease'.)

ECDofthecentralnervoussystem(CNS)canbeconfusedformetastaticsolidorhematopoieticneoplasms
orprimaryCNStumorsincludingmeningioma.Cutaneousinvolvementisuncommon,butcanmimic
vasculitis,cutaneouslymphoma,orcutaneousinvolvementwithLCH.Abdominalinvolvementisfrequently
confusingwithprimaryorsecondaryretroperitonealfibrosis,sclerosingmesenteritis,oravarietyof
retroperitonealneoplasmsincludinglymphomaandgermcelltumor.Cardiacinvolvementcanmimicother
infiltrativecardiovascularprocesses,includingsarcoidosis,andpulmonaryinvolvementcanhavetheclinical
appearanceofanynumberofinterstitiallungdiseases.

STAGINGTobesttreatpatientswithECD,theinitialevaluationmustconfirmthehistologicdiagnosis,the
extentandsitesofdisease,andtheperformancestatusofthepatient.Inadditiontoahistoryandphysical
examination,itisourpracticetoperformthefollowingpretreatmentstudiesinpatientswithECD:

Laboratorystudiesincludeacompletebloodcountwithdifferential,serumelectrolytes,chemistrieswith
liverandrenalfunctionandelectrolytes,vitaminB12andthiaminelevels,Creactiveprotein(CRP),and
erythrocytesedimentationrate(ESR).Ifdiabetesinsipidusissuspected,urineelectrolytesandurine
osmolalityshouldbemeasured.Patientssuspectedofhavingdiabetesinsipidusshouldalsobe
evaluatedforothermanifestationsofhypopituitarism,includingassessmentsofthyroid,sex,growth,and
adrenocorticalhormones.(See"Clinicalmanifestationsofhypopituitarism"and"Diagnosisofpolyuriaand
diabetesinsipidus".)

Inadditiontostandardhistologicanalysis,biopsyspecimensshouldundergogenetictestingforBRAF
V600E.

Imagingstudiesincludemagneticresonanceimaging(MRI)ofthebrain,acomputedtomography(CT)
scanoranMRIoftheentireaorta,acardiacMRI,combinedpositronemissiontomography(PET)/CT
scanofthechest,abdomen,andpelvis(whichcanalsobeusedtoimagetheentireaorta)includingall
distalextremities,andatransthoracicechocardiography[19,38,39].AnMRIofthespinalcordisonly
necessaryifthepatienthassignsorsymptomsofspinalcordinvolvement.Bonescanisacceptable
alternativeifPETisunavailable.Theutilityofpositronemissiontomography(FDGPET)scanningis
unclearandnotroutinelyrecommendedatpresent[38,39].

Electrocardiogram(ECG)shouldbeperformedtoevaluateforconductionabnormalities.

MANAGEMENT

OurapproachNotallpatientswithECDrequiretreatmentatthetimeofdiagnosis.Activetreatmentis
typicallyreservedforpatientswithsymptomaticdisease,symptomaticorasymptomaticcentralnervous
system(CNS)involvement,evidenceoforgandysfunction,orimpendingorgandysfunction.Treatmentis
suggestedforpatientswithasymptomaticCNSinvolvementbecauseitisanindependentpredictorofaworse
outcome[40].

ForpatientswhoareasymptomaticwithoutevidenceofCNSinvolvementororgandysfunction,wesuggesta
periodofobservationratherthanimmediatetreatment.Thisisprimarilybecausethereisnoknowncurefor
ECDandsomecasesfollowanindolentclinicalcourse.Duringthisobservationperiod,weperformserial
examinationssimilartothoseusedforthefollowupforpatientsundergoingactivetreatment.(See'Patient
followup'below.)
ThereisnostandardtreatmentregimenforpatientswithsymptomaticECD,andpatientsshouldbe
encouragedtoenrollinaclinicaltrial.Outsideofaclinicaltrial,treatmentoptionsincludeinterferonalpha,
systemicchemotherapy,corticosteroids,andradiationtherapy.Surgeryhasnoclearroleinthemanagement
ofECDexcepttoaddressmechanicalcomplications,suchasureteralobstruction.Dataregardingthese
treatmentoptionscomeprimarilyfromretrospectivecaseseries.Interferonalphaisthepreferredtherapydue
toasuggestionofasurvivalbenefitinthelargestretrospectiveanalysis[40].

FormostpatientswithECD,werecommendtheuseofconventionalorpegylatedinterferonalpharatherthan
systemicchemotherapyorglucocorticoids.TheBRAFinhibitorvemurafenibisareasonableoptionfor
patientswithaBRAFV600Emutationwhofailtorespondtoorcannottolerateinterferonalpha.Systemic
chemotherapycanbeconsideredforpatientswhoeitherfailtorespondtointerferonalphaordevelop
intolerablesideeffects.Glucocorticoidsaregenerallyreservedforpatientswhocannottoleratemore
aggressivesystemictherapiesorforpatientswhohaveverymildsymptomsandwishtoavoidthepotential
sideeffectsassociatedwithmoreaggressivetherapies.Radiotherapymaybeusedforlocalpalliation.The
followingsectionsdescribethesetreatmentapproaches.Ourapproachisgenerallyconsistentwiththat
proposedbyaninternationalpanelofphysicianswithexpertiseinECD[19].

InterferonalphaConventionalorpegylatedinterferonalphaisourpreferredtreatmentoptionforpatients
withnewlydiagnosed,symptomaticECDoutsideofaclinicaltrial.Theoptimaldurationoftreatmentis
unclear,butpatientsareusuallytreateduntildiseaseprogressionorintolerablesideeffectsoccur.Therisk
benefitratioofinterferonshouldberevisitedperiodicallyinpatientswhoareontreatmentformorethantwo
years.Patientsoninterferonshouldbemonitoredforinfection,liverfunctionabnormalities,thyroid
abnormalities,anddepression.(See"Neuropsychiatricsideeffectsassociatedwithinterferonalfaplus
ribavirintherapy:Treatmentandprevention".)

Pegylatedinterferonalphaisstartedat135microgramsweeklyandthedoseistitratedupwardsas
toleratedifpatientsarenotrespondingtotheinitialdosetoamaximumdoseof200microgramsweekly.

Conventionalinterferonalphaisstartedat3millioninternationalunits(MIU)threetimesaweekandthe
doseistitratedupwardsastoleratedifpatientsarenotrespondingtotheinitialdosetoamaximumdose
of9MIUthreetimesaweek.

Inthelargestandmostcomprehensiveseriesof53patientswithECD,87percentweretreatedwith
interferonalphaforamedianof19months[40].Dosesrangedfrom3MIUto9MIUthreetimesweeklywith
conventionalinterferon,or135to200microgramsweeklywithpegylatedinterferon.Fourteenpatients(26
percent)diedafteramedianfollowupof56months(range,14to198months)fromsymptomonset,and27
months(range,0.7to165months)fromdiagnosis.Theoneyearandfiveyearsurvivalrateswere96and68
percent,respectively.Treatmentwithinterferonalphawasanindependentpredictorofimprovedsurvival
(hazardratio0.3295%CI0.140.70).CNSinvolvementwasanindependentpredictorofinferiorsurvival.
Therearesomereportsthatinterferonalphamaybelesseffectiveinpatientswithmultisysteminvolvement
andCNSand/orcardiacinvolvement[41],butthepreponderanceofevidencestillsuggeststhatinterferon
alphaorpegylatedinterferonalphashouldbeconsideredthestandardtherapyforECD.

BRAFinhibitionVemurafenibisapotentinhibitorofthekinasedomaininmutantBRAFusedinthe
treatmentofmetastaticorunresectablemelanoma.Initialreportshavedemonstratedactivityinpatientswith
ECDandactivatingpointmutationsinBRAF[1012,42,43].ForpatientswithBRAFV600Emutationwhofail
torespondtoorcannottolerateinterferonalpha,wesuggestvemurafenibasasecondlineoption,ideallyas
partofaclinicaltrial.

Inonereport,allthreepatientswithmultisystemicandrefractoryECDcarryingtheBRAFV600Egene
mutationdemonstratedpartialclinicalresponsesfollowingtreatmentwiththeBRAFinhibitorvemurafenib
[11].

AnothercasereportdescribedpartialresponsestovemurafenibineightpatientswithrefractoryBRAF
V600Epositivedisease[42].Cutaneoustoxicitywascommonandsevereandatleastonepatient
 developedacutaneousmalignancy.

Withinaphase2trial,vemurafenibdemonstratedanatleastpartialresponsein6of18patientswith
BRAFV600EpositiveECDorLangerhanscellhistiocytosis[43].Theremainderhadstabledisease.The
mediandurationofresponsewassixmonths(range0.6to19months).Fourpatientsdiscontinued
therapyduetotoxicity.Themostcommonsideeffectswererash(78percent),fatigue(61percent),and
arthralgia(61percent).Withamedianfollowuplessthanoneyear,progressionfreeandsurvivaldata
werenotmature.

Clinicallysignificantcutaneoussideeffectsarecommonwithvemurafenibandincludesquamouscell
carcinomasandkeratoacanthomas.(See"Molecularlytargetedtherapyformetastaticmelanoma",sectionon
'Vemurafenib'.)

SystemicchemotherapySystemicchemotherapyregimenshavebeenstudiedinotherhistiocytic
disorders,suchaLangerhanscellhistiocytosis.Weconsidersystemicchemotherapyforpatientswhofailto
respondtointerferonalphaorwhodevelopintolerablesideeffectsoninterferonalpha.Themostcommonly
usedregimenisa24weektreatmentconsistingofweeklyvinblastineandetoposideforsixweeksfollowedby
vinblastineandetoposideeverythreeweeksuntilweek24[44].Prednisoneisincorporatedintothisregimen,
asisdaily6mercaptopurine(startingatweeknine).Thisregimenhasdemonstratedactivityinother
histiocyticdisordershowever,patientswithECDwerenotincludedinthepublishedreportsofthisregimen,
andassuchtheresponseratesareunknown.

AvarietyofothertherapieshavebeenutilizedinECD,thoughreportsoftheirefficacyarelargelyrestrictedto
singlepatientcasereportsorverysmallcaseseries:

IL1RaproductionisstimulatedbyinterferonalphaandtherearecasereportsofrecombinantIL1RA
(anakinra,canakinumab)inducingresponsesinasmallgroupofpatientswhocouldnottolerate
interferonalpha[4551].Furtherstudiesofthisagentarecertainlywarranted,butasofyetwehavenot
utilizedrecombinantIL1RAroutinelytotreatECD.

SeveralcasereportshavedemonstratedactivityofimatinibinECD,thoughtheexactroleofimatinibin
thetreatmentparadigmremainsundefined[52,53].Weconsiderimatinibtherapyforpatientswhofailto
respondtoorareintolerantofinterferonalphaandvinblastinebasedregimens.

MethotrexatemayhaveactivityinECDandhasbeenusedforotherhistiocytedisorders[54].Highdose
systemicmethotrexatewithleucovorinrescuemaybeusefulinECDwithCNSinvolvementgiventhe
abilityofmethotrexatetocrossthebloodbrainbarrier,althoughthisapproachhasnotbeenstudied.

Inanopenlabeltrialofsirolimusplusprednisonein10patientswithECD,sixpatientshadapartial
response,twohadstabledisease,andtwohadprogressivedisease[55].

Cladribineandcyclophosphamidemayalsobeactive[56,57].

AreportfromoneinstitutiondescribedclinicalresponsesintwocasesofECDwithcardiacinvolvement
treatedwithinfliximab[7].

GlucocorticoidsGlucocorticoidshavedemonstratedclinicalactivityinECD,buthavenotdemonstrateda
survivalbenefit[40].Glucocorticoidsaregenerallyreservedforpatientswhocannottoleratemoreaggressive
systemictherapiesorwhohaveverymildsymptoms.Forsuchpatientsweconsiderprednisone60mgdaily
fortwotofourweeksfollowedbyaslowtaperoverthreetosixmonths.Patientsonlongtermglucocorticoids
shouldreceiveprophylaxisforPneumocystisjiroveci(previouslyPneumocystiscarinii)infectionandmay
benefitfromprophylaxisforgastrointestinalulcers.(See"TreatmentandpreventionofPneumocystis
pneumoniainHIVuninfectedpatients",sectionon'Prophylaxis'and"Majorsideeffectsofsystemic
glucocorticoids",sectionon'Gastrointestinaltract'.)
RadiotherapyRadiotherapyhasbeenusedforlocalpalliation,thoughECDseemstobemuchless
responsivetoradiotherapythanLangerhanshistiocytosis,andlackofresponseorinfieldrecurrenceisfairly
common[58].Theoptimaldoseandfieldareunknown.Wegenerallyusedosesappropriateforaggressive
lymphomas(40to50Gy)whenfeasibleratherthanthemuchlowerdosesutilizedforLCH.

PATIENTFOLLOWUPPatientsshouldbeclinicallyassessedaminimumofeverythreetosixmonthsor
morefrequentlyassymptomsandorgandysfunctionrequire.Thefrequencyofimagingisdictatedby
baselinediseasestatus,organinvolvement,andrequirementforongoingtreatment.Affectedorgansshould
beimagedeverythreetosixmonthsuntilstabilityisdocumented.Evenifthereisnobaselinecardiovascular
involvement,patientsshouldundergoanelectrocardiogramandechocardiogramatleastannually.Our
experienceisthatchangesinradiographicimagingareoftendiscordantwithsymptomsandthatsymptoms
arethebestindicatoroftheneedfortreatmentandresponsetotreatment.

PROGNOSISThereisnoknowncureforECDandhistoricallytheprognosishasbeenpoor.Caseseries
ofpatientstreatedwithinterferontherapyhavereportedfiveyearoverallsurvivalratesofapproximately70
percent[40].Thismayimproveinthefuturewiththesubsequentdiscoveriesregardingthepresenceof
BRAFV600EmutationsinasignificantfractionofpatientsandtheavailabilityofBRAFinhibitors.

CLINICALTRIALSOftenthereisnobettertherapytoofferapatientthanenrollmentinawelldesigned,
scientificallyvalid,peerreviewedclinicaltrial.Additionalinformationandinstructionsforreferringapatientto
anappropriateresearchcentercanbeobtainedfromtheNationalInstitutesofHealth,NationalCancer
Institute,orfromtheHistiocyteSociety.Areasofactiveinterestincludetheuseoftherapiesdirectedagainst
cytokines(eg,anakinra,infliximab,andtocilizumab[NCT01727206])andserine/threoninekinaseinhibitors
(eg,vemurafenib[NCT01524978]andimatinib).

SUMMARYANDRECOMMENDATIONS

ErdheimChesterdisease(ECD)isararehistiocytedisordermostcommonlycharacterizedbymultifocal
osteoscleroticlesionsofthelongbonesdemonstratingsheetsoffoamyhistiocytesinfiltratesonbiopsy
withorwithouthistiocyticinfiltrationofextraskeletaltissues.(See'Epidemiology'aboveand
'Pathogenesis'above.)

TheclinicalpresentationofpatientswithECDvariesdependinguponthesitesofinvolvement.Most
patientswithECDwillhaveosseousinvolvementatthetimeofdiagnosisandthevastmajoritywillalso
haveatleastonenonosseoussiteofinvolvementwiththemostcommonsitesbeingthemaxillarysinus,
heartandgreatvessels,retroperitoneum,lungs,andcentralnervoussystem(includingthepituitarygland
andorbit).(See'Clinicalmanifestations'above.)

ECDisdiagnosedbaseduponthepathologicevaluationofinvolvedtissueinterpretedwithintheclinical
context.ECDcanbedifficulttodiagnosesinceitisaveryrarediseasethatcanaffectmanyorgan
systems.Abiopsyofanosteoscleroticbonelesionisgenerallypreferred,whenpossible.(See
'Pathologicfeatures'aboveand'Diagnosisanddifferentialdiagnosis'above.)

NotallpatientswithECDrequiretreatmentatthetimeofdiagnosis.Forpatientswhoareasymptomatic
withoutevidenceofcentralnervoussystem(CNS)involvementororgandysfunction,wesuggesta
periodofobservationratherthanimmediatetreatment(Grade2C).

ThereisnostandardtreatmentregimenforpatientswithsymptomaticECDandpatientsshouldbe
encouragedtoenrollinaclinicaltrial.Weusethefollowingapproachforthemanagementofpatients
outsideofaclinicaltrial(see'Clinicaltrials'above):

FormostpatientswithECD,werecommendtheuseofconventionalorpegylatedinterferonalpha
ratherthansystemicchemotherapyorglucocorticoids(Grade1C).

Forpatientswhofailtorespondtoorcannottolerateinterferonalpha,wesuggestvemurafenibasa
secondlineoptioniftheBRAFV600Emutationisdetected(Grade2C).Ifpatientsdonotrespondto
 orareintolerantofvemurafenibordonothavetheBRAFV600Emutation,wesuggesttreatment
withvinblastine,etoposide,prednisone,and6mercaptopurinemodeledafterprotocolsusedfor
Langerhanscellhistiocytosis(Grade2C).Glucocorticoidsaregenerallyreservedforpatientswho
cannottoleratemoreaggressivesystemictherapies.Radiotherapymaybeusedforlocalpalliation.

PatientswithECDareatriskofdevelopingpotentiallylifethreateningcomplicationsduetothe
compressionofnormalstructures.Mechanicalmeasuressuchaspercutaneousnephrostomyand
cardiacvalvereplacementmayalsobecomenecessaryinselectpatients.Inaddition,ahighpercentage
ofpatientswilldevelopdiabetesinsipidusandotherendocrinopathiesduetohypopituitarism.Regardless
ofsystemictherapies,endocrinopathiesincludingdiabetesinsipidusshouldbecorrected.Preexisting
diabetesinsipidusandendocrinopathiestypicallypersist,evenwithradiographicregressionofdisease.
(See"Clinicalmanifestationsofhypopituitarism"and"Diagnosisofpolyuriaanddiabetesinsipidus".)

UseofUpToDateissubjecttotheSubscriptionandLicenseAgreement.

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Topic13942Version22.0
GRAPHICS

OsteosclerosisandosteolysisinErdheimChesterdisease

Xrayofleftfemurrevealeddiffuseosteosclerosiswithfocalosteolysisinthe
diaphysisandmetaphysisoftheleftdistalfemur.

Reproducedwithpermissionfrom:KimMS,KimCH,ChoiSJ,etal.ErdheimChester
disease.AnnDermatol201022:439.Copyright2010KoreanDermatological
Association.

Graphic77396Version2.0
ComputedtomographyimagingoftheleginErdheimChester
disease

Computedtomographyimagingoftheleftlegina48yearoldmalewithErdheimChester
diseaseshowsanexpansilelyticlesioninthedistaltibiawithlobulatedendosteal
scalloping,andmultiplefociofcalcifiedmatrix.Thereismildsubcutaneoussofttissue
strandinganteriorlyandmedially.Withinthefibula,themarrowalsoappearsabnormal,
butthereisnoendostealscalloping.

KindlyprovidedbyGermanPihan,MD,DepartmentofPathology,BethIsraelDeaconessMedical
Center,Boston,MA.

Graphic85923Version1.0
Multipleareasofincreaseduptakeonbonescanin
ErdheimChesterdisease

Bonescanshowedmultipleincreaseduptakesinbothmaxillae,mandible,right
temporalbone,bothradii,bothulnae,bothdistalfemurs,bothproximalanddistal
tibiae,bothcalcanei,leftsecondrib,rightninthrib,bothtenthribs,leftposterior
iliaccrestandrightacetabulum.

Reproducedwithpermissionfrom:KimMS,KimCH,ChoiSJ,etal.ErdheimChester
disease.AnnDermatol201022:439.Copyright2010KoreanDermatological
Association.

Graphic52334Version2.0
MagneticresonanceimagingoftheleginErdheimChester
disease

(A)T1.
(B)T2.
Magneticresonanceimagingoftheleftlegina48yearoldmalewithErdheimChester
diseaseshowsabnormalsignalinginthedistaltibiawithsurroundingsofttissueedema.
ThereisaheterogeneoussignalinthebonemarrowonT1andT2withareasofpatchy
enhancementpostgadolinium.Thebonemarrowsignalabnormalityextendsmore
proximallythanthelesionitself.Thereisamildperiostealreaction,butnoovert
abnormalityoftruetumorextendingoutfromthebone.

KindlyprovidedbyGermanPihan,MD,DepartmentofPathology,BethIsraelDeaconessMedical
Center,Boston,MA.

Graphic85924Version1.0
BonecurettagesamplesinErdheimChesterdisease

Bonecurettagesamples(panelsAandB)fromapatientwithErdheimChesterdisease
demonstratetissueinfiltrationbysheetsoffoamy(xanthomatous)histiocyteswith
interspersedinflammatorycellsandmultinucleategiantcells(Toutoncells).Thehistiocytes
expressthehistiocytemarkersCD68(panelC)andCD163(panelD),butdonotexpress
CD1a(panelE)orLangerin(panelF).

KindlyprovidedbyGermanPihan,MD,DepartmentofPathology,BethIsraelDeaconessMedical
Center,Boston,MA.

Graphic85925Version1.0
ErdheimChesterdiseaselesionbiopsy

Thefiguredemonstratesarepresentativehematoxylin/eosinstainedECDlesion
biopsysamplefromaretroperitoneal,perinephricinfiltrate(400x
magnification).Itshowstheblandhistiocyticinfiltratewithfoamy
(xanthomatous)cytoplasmandinterspersedinflammatorycells.

ReproducedwithpermissionoftheAmericanSocietyofHematology,fromAllenCE,
McClainKL,ErdheimChester:beyondthelesion,Blood2011117:2745,Copyright
2011permissionconveyedthroughCopyrightClearanceCenter,Inc.

Graphic80968Version12.0
SkinbiopsyinErdheimChesterdisease

(A)Lefttemporallesionshoweddermalinfiltrationoffoamyhistiocyteswithgiantcells(H&E,x100).
(B)ScalplesionalsoshowedinfiltratinghistiocytesandmultipleToutontypegiantcellswithdermal
fibrosis(H&E,x100).

Reproducedwithpermissionfrom:KimMS,KimCH,ChoiSJ,etal.ErdheimChesterdisease.AnnDermatol
201022:439.Copyright2010KoreanDermatologicalAssociation.

Graphic65663Version1.0
InfiltrationofCD68positive,S100negativehistiocytesinErdheim
Chesterdisease

(A)Thebiopsyobtainedfromperirenaltissueshowedaninfiltrationofnumeroushistiocytes(H&E,
x100).ThehistiocyteswereCD68positive(B:x100)andS100negative(C:x100).

Reproducedwithpermissionfrom:KimMS,KimCH,ChoiSJ,etal.ErdheimChesterdisease.AnnDermatol
201022:439.Copyright2010KoreanDermatologicalAssociation.

Graphic64303Version1.0
Juvenilexanthogranuloma

Typicalsolitarylesionontheabdomenofaninfant.

Reproducedwithpermissionfrom:www.visualdx.com.CopyrightLogicalImages,Inc.

Graphic69122Version4.0
Juvenilexanthogranuloma

Multiplescalplesionsinayoungchild.

Reproducedwithpermissionfrom:www.visualdx.com.CopyrightLogicalImages,Inc.

Graphic81058Version3.0
Contributor Disclosures
Eric Jacobsen, MD Grant/Research/Clinical Trial Support: Celgene [histiocytoses (lenalidomide)].
Consultant/Advisory Boards: Seattle Genetics [T cell lymphoma (brentuximab)]; Spectrum [T cell lymphoma
(pralatrexate, romidepsin)]. Arnold S Freedman, MD Consultant/Advisory Boards: Kahr Therapeutics [SAB].
Other Financial Interest: Novartis [DMB (Ofatumumab)]; Bayer [DMB (Bayer 17833)]. Alan G Rosmarin,
MD Nothing to disclose

Contributor disclosures are reviewed for conicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
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