ptld for san diego - sdhematopathology.org · ptld, t/nk‐cell type swerdlow s and craig f (in)...

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Post‐TransplantLymphoproliferativeDisorders(PTLD)withEmphasisonEBV‐PositiveMucocutaneousUlcer

RobertMcKenna,M.D.

IllustrationsandTablesareProvidedbyBeenuThakral,M.D.

PTLDwithEmphasisonEBV‐PositiveMucocutaneousUlcer

•  ReviewofPTLD– Riskfactors– Epidemiologyandincidence– Classificationandpathology

•  RoleofEBVinPTLD•  EBVviralloadmonitoringasasurveillancetool

•  EBV‐positivemucocutaneousulcer(EBVMCU)

•  EBVMCUinorgantransplantrecipients

Post‐transplantlymphoproliferativedisorders

•  Lymphoidorplasmacyticproliferationsasaconsequenceofimmunosuppressioninorganorstem‐celltransplantrecipients

•  Insolidorgantransplantrecipientsmostareofhostorigin– donororiginisseeninliverandlungallografts

•  InBMtransplantrecipientsPTLDismostlyofdonororigin

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RiskFactorsforDevelopingPTLD

•  Children>adults•  EBVorCMVseronegativerecipientwithEBVseropositivedonor

LorenAWetal.BMT2003;31:145‐155


•  Solidorgantransplant– Typeoftransplant

• Heart,heart‐lungandGI– Timefromtransplant

• Medianintervalaftertransplantis6months

– Typeandintensityofimmunosuppression

• OKT3(21.5%),ATG(4.9%),IL‐2receptorantagonist(7.8%),Campath(noassociation)

•  Intensity(triplevs.quadruple),andduration


•  Allogeneicstemcelltransplant– T‐celldepletion– HLAmismatchandsomeHLAtypes

• Relatedvs.unrelated (synergisticwithT‐celldepletion)

• HLAtype:A25,B38vs.A1,8andDR3– Timefromtransplant

• MediantimeintervalafterHSCTis2‐3months

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•  Allogeneicstemcelltransplant(cont.)•  17%riskofEBV‐associatedPTLDwithumbilicalcordbloodtransplantsandATGorspecificanti‐lymphocytetherapy

• Primaryimmunodeficiencyasanindicationoftransplantation

LorenAWetal.BMT2003;31:145‐155

Epidemiology

PTLDdevelopsin~2%oftransplantrecipients

OrganTx Incidence% References

Kidney 0.3‐1.4 Caillardetal,2006

Liver 2‐5 Jainetal,2002

Heart 0.7‐6.8 Swerdlowetal,2000

Lung 3.3‐10.0 Reamsetal,2003

Heart‐lung 4.6‐12.5 Swerdlowetal,2000

GI/multi 10toupto25 Holmanetal,2012

Pancreas 2.1 Paraskevasetal,2005

Bonemarrow 0.5‐6.9 Holmanetal,2012

LocationandfrequencyofPTLDinSOT

IncidenceofPTLDinthetransplantedorganitselfishighforallSOTexceptheart,thereby,raisingthedifferentialofPTLDvs.rejection

Muchaetal.NephrolDialTransplant2010;25:2089‐2098

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WHOClassificationofPTLD

Category

•  Earlylesions

•  PolymorphicPTLD

•  MonomorphicPTLD(classifyaccordingtothelymphomatheyresemble)

•  ClassicalHodgkinlymphoma‐typePTLD

Sub‐type•  Plasmacytichyperplasia•  Infectiousmononucleosis‐like

lesion

•  Bcellneoplasms–  DiffuselargeBcelllymphoma–  Burkittlymphoma–  Plasmacellmyeloma–  Plasmacytoma‐likelesion–  other

•  Tcellneoplasms–  PeripheralTcellLymphoma,NOS–  HepatosplenicTcelllymphoma–  Other

Architecture Preserved,butoftenamasslesion

Clinical YoungerageSolidorganrecipientswithoutpriorEBVLN,tonsilsandadenoids,stage1E

Majorfindings

Hyperplasticfollicles&paracorticalexpansionSmalllymphocytes,plasmacells,±immunoblasts

Immuno‐phenotype

PolyclonalB‐cells,T‐cells&plasmacellsOftenEBV+

Genetics Polyclonaloroligoclonal

Earlylesion

SwerdlowSandCraigF(In)JaffeEetal.Hematopathology.1sted.2011.

Architecture Effaced,destructiveextranodalmasses

Clinical 20‐80%,MCinchildren,usuallyafterEBV‐infection,lung,GI,LN,tonsils,stage1E‐IV

Majorfindings

Fullspectrumoflymphoidmaturation,+/‐geographicnecrosis,scatteredatypicalimmunoblastswithRS‐likecells

Immuno‐phenotype

PolyormonoclonalB‐cells,admixedT‐cells,RS‐likecells:CD30+,CD20+,CD15‐EBER‐positive

Genetics Clonallyrearranged:monoclonalB‐cells(75%),non‐clonalT,somewithBCL‐6somatichypermutation(43%)

PolymorphicPTLD

SwerdlowSandCraigF(In)JaffeEetal.Hematopathology.1stedn2011.

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Architecture Effaced

Clinical Extranodalmasses,olderage(56years);LN,BM,skin,softtissue,IIIE,IV

Majorfindings

MonomorphicSomehavebizarreormultinucleatedcells~RScells

Immuno‐phenotype

ClonalB‐cells(CD20,CD79a,CD19),mostarenon‐GCtype(CD10‐,BCL6‐,MUM+,CD138‐)EBVpositivein70%

Genetics ClonalB‐cellsand/orT‐cells,somaticallymutatedIGH,p53,RAS,MYCrearrangements,BCL6somatichypermutationcommon(90%),multiplegains(trisomies2,7,9,11,22,X),losses,breaks(1qregion),lackp16expression

MonomorphicPTLD

Monomorphic PTLD, Burkitt lymphoma

Monomorphic PTLD, plasma cell myeloma

JaffeEetal.Hematopathology.1stedn2011.


Clinical <1%ofallPTLD;Mostcommoninrenaltransplant,m=32years(6‐54years)and63monthspostTX,30M:1F,stage1‐2,nodal,donotregresswithreductionofISand75%alive

Majorfindings

FulfillscriteriaforCHL(MC>NS>LD)

Immuno‐phenotype

~100%EBER‐positive(latenttypeII)likeinCHL

Genetics IgHclonalityisnoteasytodemonstrateandnoothergeneticabnormalities

PTLD,classicalHodgkinlymphoma

JaffeEetal.Hematopathology.1stedn2011.

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Clinical <15%allPTLD,usuallyextranodal,pooroutcome,60%deadat2monthsofDx

Majorfindings

PeripheralT‐celllymphoma,NOS;hepatosplenicT‐celllymphoma,aggressiveNK/Tcelllymphoma

Immuno‐phenotype

LossofsomeT‐cellantigens,1/3EBER‐positive

Genetics ClonalTCRrearrangementi7(q10,+8(HSTL)P53andotheroncogenemutationscommon

PTLD,T/NK‐celltype

SwerdlowSandCraigF(In)JaffeEetal.Hematopathology.1sted.,2011.

EBVnegativePTLD

•  25‐30%ofPTLD•  2/3rdofT‐cellPTLDareEBVnegative

Characteristics EBV+PTLD EBV‐PTLD

Age 40years 50years

TimefromTx 10months 50months

Morphology(monomorphic)

43% 65%

Immunophenotype(GCtype)

15% 60%

Prognosis(died) 20% 40%

EBVMLP‐1

EBVviralloadmonitoring:Surveillancetool

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•  EBVDNAwasmeasuredinsolidorgan(SOT)andhematopoieticcelltransplants(HCT)usingreal‐timeTaqManEBVPCR

•  TheproportionofpatientswhohadEBVDNAviremiapost‐transplantwassignificantlyhigherinSOTvs.HCT(p<0.001)

•  SOTrecipientsdevelopedPTLDsignificantlylaterthanHCTrecipients(median,2.8yearsvs.121days;p<0.001)

•  PTLDriskinviremicpatientsincreasedwiththepeakquantityofEBVDNAemia(p<0.001)

•  EBVPCRwaspredictivein29(78%)of37patientstestedwithinthreeweekspriortotissuediagnosisofPTLD,andthus,theauthorsconcludedthatEBVPCRwithcarefulattentionpaidtochangesinEBVDNAemiacouldleadtoearlierdiagnosisandtreatmentofPTLD

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AmJClinPathol2014;141:268‐274

  RetrospectivereviewofEBVDNAquantitationdataof9,779bloodsamplesfrom740transplantpatients(233SOTand507HSCT)andtheirassociationswithPTLD

  6.5%(48/740)werediagnosedwithPTLD,8.6%(20/233)inSOTand5.5%(28/507)inHSCTpatients.PTLDdiagnosiswasbiopsyprovenin82.3%ofpatients

•  41.8%(306/740patients)hadEBVviremia

•  13.4%(41/306)ofviremicpatientsdevelopedPTLDascomparedto1.6%(7/306)innon‐viremicpatients

•  EBVviremiaoccurredmorefrequentlyinpatientswithPTLD(85.4%)incomparisontopatientswithoutPTLD(38.3%;P<.0001)

•  WholebloodEBVDNAviremia:103‐105:6.9%developedPTLDand>105:40%developPTLD

PatientswithPTLDdemonstratedsignificantlyhigherfirstpositiveresults,higherpeaklevels,andahigherrateofincreaseinEBVviralloadcomparedwithpatientswithoutPTLD(P=.002)

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EBVviralloadmonitoring:Surveillancetool

•  IdentifiespatientsatriskforEBV‐associatedPTLD–  Nointernationalreference,?optimalsample

–  Thresholdsdefiningriskandspecifictriggerpointsforpreemptiveinterventionarenotwelldefined

–  Comparisonbetweencentersisdifficult

–  EBVnegativePTLDwillnotbedetected•  IntransplantrecipientsathighriskofearlyEBV‐associatedPTLD,EBVviralloadmonitoringhas:–  Goodnegativepredictivevalue(>90%)–  Poorpositivepredictivevalue(25‐65%)

MonomorphicB‐cellPTLD:TreatedassystemicpolymorphicPTLD

•  Recentlydescribedentitycharacterizedbyisolatedwell‐circumscribed,ulcersthatoccurinthemucocutaneouslocations

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•  Majorityoflesionsoccurredinoralcavity(16),theskin(6)orgastrointestinaltract(4)inpatientswith:•  Iatrogenicimmunosuppression(MTXorAZA,CYAinduced):n=8

•  Agerelatedimmunosuppression(63‐101years):n=17

•  Hematopoieticstemcelltransplantpatient:n=1

60 year female with RA, on standard methotrexate therapy

Presentation

4 weeks

2 weeks

8 weeks

MorphologicandIHCcharacteristicsofEBVMCU

•  Polymorphousinfiltrate•  Lymphocytesandimmunoblasts•  Scatteredplasmacells,histiocytes,eosinophils,anddispersed“plasmacytoid”apoptoticcells

•  ScatteredlargepleomorphiccellsreminiscentofHodgkincells,oftenReedSternberg‐likecells

•  R‐S‐likecellsco‐expressB‐cellantigensCD20(88.5%),CD30(100%)andsomeCD15expression(43%)

•  Backgroundnecrosisandulceration

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IHCCharacteristicsofEBVMCU

•  ProminentrimofT‐lymphocytesattheulcerbaseinallcaseswithabundantCD8positiveT‐cells

•  EBVpositivityinboththelargeandsmallcells

CD3 CD8

DiseaseCourseandFollow‐up•  Alliatrogenicimmunosuppressedpatientsachievedcomplete

remissionwithreductioninimmunosuppression

•  30%ofagerelatedEBV‐MCUreceivedaggressivetherapy(CT+/‐RT)

•  Nodiseaseassociateddeathoveramedianfollow‐upof22months(3‐72months)

•  Recommendation:EBVMCUisanewlyrecognizedclinicopathologicentitywithHodgkinlikefeaturesandaselflimitedindolentcourserespondingwelltoconservativemanagement

EBV-Positive Mucocutaneous Ulcer in Organ Transplant Recipients

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CaseSelection

•  RetrospectivereviewofallPTLDsurgicalexcisionorbiopsyspecimensfrom12/03to4/13

•  IdentifedlocalizedMCUshistologicallycompatiblewithEBVMCU

•  Patientswereexcludedifphysicalexamination,imagingstudies(includingCT/PETscans)orstagingbonemarrowbiopsieswerepositiveorsuspiciousforotherlesionsadjacenttoordistantfromtheMCU

Clinicalinformation

•  Ageandgender•  Typeoftransplant• Medicationsandpresentingsymptoms

•  Imagingcharacteristics

•  EBVDNAquantificationresults•  TreatmentforEBVMCUandoutcome

StudiesPerformed

•  Immunohistochemical:CD3,CD20,MUM‐1,BCL2,BCL6,CD15,CD30,CD23andCD10

•  EBV‐encodedRNA(EBER)byin‐situhybridization•  WholebloodEBVDNAquantification•  Pre‐transplantEBVserologicstatusofdonorandpatientincludingIgMandIgGantibodiestoEBVVCAwhenavailable

•  IgHandTCRgenerearrangementstudies

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Results

•  7/70(10%)transplantrecipientswithEBV‐positivePTLDhadisolatedEBVMCU

•  All7wererecipientsofsolidorgans:5renal,1heart,1lung•  NocasesofEBVMCUamongthe14HSCTrecipients

•  Patientsrangedfrom18‐70years(median=61);5weremale

•  4/7hadanoralulcer;theother3wereinesophagus,terminalileumandrectum

•  Themeandurationofimmunosuppressivetherapypriortosymptomswas0.6‐13years(median=6.3years)

Results

•  Diagnosisinthe3mostrecentpatientswasEBVMCU

•  4patientswereoriginallydiagnosedwithmonomorphic(n=3)andpolymorphic(n=1)PTLD–Thediagnosisinthese4caseswaschangedtoEBVMCUonretrospectivereview

•  ReedSternberg‐likecellswerepresentin5/7patients

Esophagealulcer(2X) 20X

20X20X

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CD20 CD30

EBER

EBVMCUresemblingmonomorphicPTLD,largecellsubtype

Lipulcer

EBVMCUresemblingmonomorphicPTLD,largecellsubtype

SmallBowelulcerativelesion

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CD20

CD30EBER

CD15

InallcasesthelargeB‐cellswereCD20,CD30andEBERpositive

MUM‐1+(80%) CD23+(28%)

CD3andCD8immunostain

CD3 CD8

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WholeBloodEBVDNAquantification

•  NoneofthepatientshadEBVDNAdetectableinblood(<1000copies/mL)atdiagnosisorfollow‐upof16.5months

•  ThiscontrastswiththefindingofEBVDNAinbloodspecimensin35of44(80%)solidorgantransplantpatientswithsystemicPTLDreportedfromourinstitutionduringthesameobservationperiod(P<0.001,Fisherexacttest,2‐sided)

EBVserology:Donorandpatient

•  Pre‐transplantrecipientanddonorEBVantibodiesresultswereavailableinfourpatients

•  ThreeEBVnaivepatientsreceivedorgansfromEBVnaivedonorsandlackedEBVantibodiesatthetimeofdiagnosisofEBVMCU

•  OneEBVantibodynegativerecipientreceivedahearttransplantfromanEBVantibodypositivedonorandatthetimeofpresentationwithEBV‐MCUhadseroconvertedwithapositiveEBVVCAIgGantibodybutnegativeVCAIgMresult

Age/Sex

OriginalDiagnosis

EBERISH

EBVserology EBVDNAquantification IgHclonality

BeforeTx(IgM,IgG)

Atulcerpresentation(IgM/IgG)

Atulcerpresentation

Atfollowup

44/M EBVMCU, Positive Unknown ‐/+ Neg Negx4 Clonal

61/M EBVMCU, Positive Unknown NP Neg Negx2 NP

18/M PTLD,polymorphic

Positive Neg ‐/+ Neg Negx5 Equivocal

63/F EBVMCU, Positive Unknown NP Neg NP Polyclonal

70/F PTLD,monomorphiclargeB‐cell

Positive Neg ‐/‐ Neg Neg NP

70/M PTLD,monomorphiclargeB‐cell

Positive Neg ‐/‐ Neg Negx5 Clonal

32/M PTLD,monomorphiclargeB‐cell

Positive Neg ‐/‐ Neg NP Clonal

EBERISH,EBVserology,EBVDNAquantification,andB‐cellclonality

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ClinicalCourse

•  Alllesionsresolvedwith–  Reductionofimmunosuppression(7/7)

–  Changeofimmunosuppressiveagent(2/7)

–  Rituximab(3/7)

•  Fivepatientsareliving–  4healthy–  1awaitingsecondrenaltransplant

•  Twopatientsdied17and60mos.followingresolutionofEBVMCU

•  NopatientsrecurredwithEBVMCUorotherPTLD

Age / Sex

Original Diagnosis

Transplant type

Ulcer site Treatment Resolution (wks)

Follow up duration (mo.)

Outcome

44 / M EBV MCU, Kidney Tongue Reduction of IS 2 15 No rec.

61 / M EBV MCU, Kidney Esophagus Reduction of IS 4 16.5 No rec.

18 / M PTLD, polymorphic

Heart Right palatine tonsil and left buccal cavity

Reduction of IS, R x 2 doses

4 14 No rec.

63 / F EBV MCU, Kidney Left mandibular mucosa

Reduction of IS 5 8 No rec.

70 / F PTLD, monomorphic large B-cell

Kidney Rectum Reduction of IS, R x 2 doses, and V started

12 17 Dead, renal failure & sepsis

70 / M PTLD, monomorphic large B-cell

Kidney Lip Reduction of IS Lesion excised

111 Norec.

32 / M PTLD, monomorphic large B-cell

Lungs, bilateral

Terminal ileum

Reduction of IS, R x 4 doses

4 60 Dead, lung infection & sepsis, autopsy performed

Clinicalpresentation&followupofEBVMCUpts

Characteristics AJSP2010;34:405‐417 Presentstudy

Patientcharacteristics Agerelated,iatrogenicIS,PBSCT

Organtransplantrecipients

Inclusionandexclusioncriteria

Similar Similar

Morphology Predominantlypolymorphousinfiltratewith30%originallyreportedasDLBCL

PredominantlypolymorphousinfiltratewithRSlikecellsand42%werereportedasmonomorphiclargeB‐cellPTLD

Immunophenotype CD20+(88.5%),CD30+(100%)CD15+(43%)MUM‐1(100%)

CD20+(100%)CD30+(100%)CD15+(0%)MUM‐1(80%)

BloodEBVDNA Notperformed Negative

ComparisonofEBVMCU

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Characteristics AJSP2010;34:405‐417 Presentstudy

Tcellsatthebaseoflesion(CD8>CD4)

Present Present

IgHclonality 38.9% 42.8%

Treatment Conservativemanagement,30%treatedwithchemotherapy

Conservativetreatment,Rituximabin42%

Follow‐up Completeremissioninallpatientswithf/u22months

Completeremissioninallpatientswithf/u111months

ComparisonofEBVMCU

Discussion

•  EBVMCUintransplantrecipientsappearstobeanisolatedmucosalEBV‐drivenlymphoproliferationratherthanaresponsetoageneralizedsystemicinfectionasisusuallyobservedinotherPTLDandimmunodeficiencystates

•  EBVMCUmaydevelopinpatientswithsufficientimmuneresponsetocontrolasystemicinfectionbutalevelofimmunedysregulationthatallowsforalocalizedself‐limitedlymphoproliferativedisorderinresponsetoEBVinfection

•  ItfollowsthatpatientswithEBVMCUcontaintheirEBVinfectionbecausetheyarelessimmunosuppressed,comparedwithpatientswithotherPTLDs,whichhavemoreEBVDNAsheddingduetoagreaterdegreeofimmunosuppression

Discussion

•  EBVMCUappearstobeadistinctiveformofEBV‐drivenPTLDnotassociatedwithincreasedwhole‐bloodEBVDNAandlikelytoresolvewithconservativemanagement

•  AwarenessofEBVMCUintheposttransplantsettingandthevalueofEBVwhole‐bloodquantificationstudiesareimportantforappropriatediagnosisandmanagement.

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Conclusions

•  EBVMCUshouldbeconsideredinthedifferentialdiagnosisofPTLDpresentingasamucosalulceration

•  ClinicopathologiccorrelationandstagingwithmodernimagingareessentialtoexcludesystemicPTLD

•  EBVMCUmaymorphologicallymimicamoreaggressivecategoryofPTLD

•  DifferentiationisimportantbecausechemotherapyseemstobeexcessivetreatmentforEBVMCU

•  EBVMCUmaywarrantconsiderationasadistinctcategoryintheclassificationofPTLD

Acknowledgement

•  BeenuThakral,M.D.•  MelissaHart,M.D.

•  HenryHBalfourJr.,M.D.

•  SophiaYohe,M.D.

•  CharanjeetSingh,M.D.

•  MichaelSpears,M.D.

Thankyou

Questions?

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