amphi 1 faculté de médecine bichat - ovh

LaurencedeLevalIns.tuteofPathology,Lausanne,Switzerland

Paris,January13,2017-DESEnseignementsurleslymphomesTAmphi1FacultédeMédecineBichat

ClassificaGonanatomo-pathologiqueetmoléculairedeslymphomesT

EpidemiologyofmatureT/NK-cellneoplasms

GeographicandracialvariaGons,viralassociaGons

5-10%5-10%15-20%

HTLV1EBV+NK/T

HTLV1

EBV+NK/T

Enteropathy

GisselbrechtCetal.,Blood1998;IntT-cellLymphomaProject,JClinOncol2008;MakVetal.,JCO2013

PTCLs:challengesinclinicalmanagement

2008

Relapsed/refractory

1970 1980 1990 2000 2010

REAL1994

Histology

WHO200120082016

Theevolu.onoflymphomaclassifica.on

Kiel1974

Clinicalfeatures

Immunohistochemistry

PCR

Microarrays

SequencingFISH

Immunology Gene.cs Molecular HighthroughputMorphology

NCIWF1982

Kiel1988

Rappaport19561966

Morphology ClinicalgroupingSurvival

MulGpleparametersCellularorigin

Nodallymphomas

AdaptedfromJaffeES,HarrisNL,CampoE,Hematopathology2010

Thefirstinterna.onallyacceptedconsensusclassifica.on

Lymphoma

Neoplas.ctransforma.onPathogenicmechanisms

Normallymphocyte

Celloforigin MorphologyImmunophenotype

GeneGc&molecularfeatures

EGologicagent(s)VirusesEBVHTLV1

ClinicalfeaturesDiseaselocaGon

Clinico-pathologicen..esMul.parametricdefini.on<–>Diagnos.ccriteria

Naturalhistory,prognosis,responsetotherapy

PrinciplesoftheWHOclassifica.on

ANTIGEN

CD8+αβ CD8+

CD8+αβ

CD4+αβ CD4+

LYMPHNODE BLOODTISSUES

CD8+αβ

CD4+αβ

γδ(αβ)

BLOOD MUCOSAESKIN,SPLEEN

CD8+αβ

CD4+αβ

CD4+αβ

EXTRANODALNK/TCL,NASALTYPE

HEPATOSPLENICTCLENTEROPATHY-ASSOCIATEDTCLCUTANEOUSγδTCL

ALCL

MYCOSISFUNGOIDES

INNATE

TFH Treg

AITLHTLV1+ATLL

NK NK

Treg GERMINALCENTER

γδ(αβ)

EATL

SPTCL

Adapted from de Leval L, Gaulard P, Histopathology 2011

BLOOD

ChronicNK-LPD

T-LGL

T-PLL

AggressiveNKleukemia

PTCLNOS

ADAPTIVE

MatureT/NK-cellneoplasms

•  T-cellPLL•  T-cellLGLleukemia•  ChronicLPDsofNKcells•  AggressiveNK-cellleukemia•  ATLL•  SystemicEBV+T-celllymphoma

ofchildhood•  Hydroavacciniforme-like

lymphoprolifera.vedisorder

•  PTCL-NOS•  AITL(angioimmunoblas.c)•  FollicularT-celllymphoma•  NodalPTCLwithTFHphenotype•  ALCL,ALK-posi.ve•  ALCL,ALK-nega.ve

•  ExtranodalNK/TCL,nasaltype•  Enteropathy-associatedTCL•  Monomorphicepitheliotropic

intes.nalT-celllymphoma•  IndolentT-cellprolifera?vedisorder

oftheGItract•  HepatosplenicTCL•  Subcutaneouspanniculi.s-likeTCL•  MF/SezarySyndrome•  PrimarycutaneousCD30+LPD•  LyP,pcALCL•  Breastimplant-associatedALCL•  PrimarycutaneousγδTCL•  PrimarycutaneousCD8+aggressive

epidermotropiccytotoxicTCL•  PrimarycutaneousacralCD8+TCL•  PrimarycutaneousCD4+small/

mediumT-cellLPD

Nodal

Leukemic

Extra-Nodal

% AITL PTCL-NOS

ALK+ALCL

ALK-ALCL NKTCL EATL ATLL HSTL Others

World 21.7 30.4 7.7 6.5 12.2 5.5 11.3 1.6 2.9

Europe 29.1 34.8 6.5 9.5 4.4 9.2 1 2.3 3.3

France 36.1 26.9 8.6 7.9 5.2 3.8 2.5 3.3 8

InternaGonalPTCLstudy-World

InternaGonalPTCLstudy-Europe

Lymphopath-France

Non-cutaneousT-celllymphomasinFrance-epidemiology

de Leval L, Parrens M et al. Haematologica 2015

Nodal Extranodal










mediumT-cellLPD

Nodal

Leukemic

Extra-Nodal

Transcrip.onfactorsBCL6MAFothers

SolublefactorsIL21CXCL13

CellsurfacereceptorsCXCR5ICOSPD1CD40L

ICOS

Tangye SG et al, Nature Rev Immunol 2013

NodallymphomasofTFHorigin

AITL : angioimmunoblastic T-cell lymphoma F-TCL: follicular T-cell lymphoma

PTCL-TFH: nodal PTCL with TFH phenotype

Angioimmunoblas.cT-celllymphoma-WHO2016AneoplasmofmatureTFHcellscharacterizedbysystemicdisease,apolymorphousinfiltrateinvolvinglymphnodeswithaprominentproliferaGonofhighendothelialvenulesandfolliculardendri.c

cells,andfrequentexpansionofEBV+Bcells

•  Elderly,disseminateddisease,Bsymptoms

•  Lymphadenopathies,spleenandliverinvolvement,skinrash,effusions

•  Anemia(CoombsposiGve),cytopenias,hypereosinophilia,hyperγglobulinemia

AITL–sinussign

Diffusepakern–vascularprolifera.on

Polymorphousinfiltrate

CD20CD21 CD3 CD4 CD8

CD30

EBERs

TFHcellmarkersfordiagnos.cuse

Dorfman D et al. AJSP 2006; Krenacs L et al. Blood 2006; Ortonne N AJSP 2007; Roncador G et al. Haematologica 2007; Marafioti T et al. Haematologica 2009; Bisig B et al. Histopathology 2012

Sensi.vity

Specificity

ICOSPD1c-MAF

BCL6

CXCL13CD10

CD20 EBER

Epithelioid cell rich

CD3 CXCL13

Tumor cell rich

AITLpakern1withhyperplas.cfollicles

GCGC

CD10 CD21

GCGC

CD3CD20

AITL F-TCL TFH-PTCLEpidemiology Firstorsecondmost

commonPTCLVeryrare 20%ofPTCL-NOS

Pakern Diffuse(perifollicular) FL-likeorPTCG-like Diffuse(T-zone)

Neoplas.ccells Smalltomedium,clearcells

Variable Mediumtolarge

Polymorphousinfiltrate

Abundant Absentorminimal Absentorminimal

FDC DiffuseproliferaGon Restrictedtofollicules Minimalorabsent

Vascularprolifera.on

Abundant Absentorminimal Absentorminimal

EBV+blasts Typicallypresent Maybepresent Maybepresent

TFHphenotype SeveralTFHmarkers,heterogeneous

SeveralTFHmarkers,strong

Atleast2TFHmarkers

Gene Altera.on Freq.TET2LemonnierFBlood2012

InacGvaGngmut. 50-75%

DNMT3 InacGvaGngmut. 30%

IDH2*CairnsRBlood2012

R172(R140)Targetableinhibitor

25%AITL

RHOAPalomeroTSakataMNatGenet2014

G17V 60-70%

t(5;9)(q33;q22)StreubelBLeukemia2006

ITK-SYKfusion 20%FTCL(AITL)

CD28RohrJLeukemia2016;LeeSHHaematologica2015PLCG1,CARD11,FYN…ValloisDetal.Blood2016

AcGvaGngmut.@residues124195AcGvaGngmut.

10%AITL50%

Epigene.csHypermethyla.on

TCRsignaling

Gene.caltera.onsinAITLandPTCLofTFHorigin

Mul.stepmodelofTFHlymphomagenesis

Sakata-Yanagimoto et al., Nat Genetics 2014; Int J Haematol 2015

TCRmutaGons

PTCL,NOS AITLF-PTCL

Follicular helper T cell

TFH

TFH phenotype

TET2IDH2DNMT3RHOA

TFH-PTCL

NodallymphomasofTFHorigin

WHO2016

HallmarkCD30

Anaplas.clargecelllymphomas

ALK-posi.veALCL

•  Childrenandyoungadults,M>F•  Lymphadenopathy,extranodalinvolvementfrequent(skin,

bone,sogGssues,liver…)•  Goodresponsetochemotherapies(70-90%5yOS)•  EMA+,acGvatedcytotoxicimmunophenotype•  Lossofpan-TcellanGgens,«nullcell«phenotype

•  CD3-/+CD4+/-CD8-,CD43+,CD2CD5CD7variable,CD25+•  MonoclonalTCRrearrangementinmostcases

WHOdefini.on:aT-celllymphoma(1)composedofcellsusuallylarge,withabundantcytoplasm,pleomorphichorseshoe-shapednuclei,(2)translocaGonoftheALKgeneandexpressionofALKprotein,(3)expressionofCD30

Inv(2)ATIC-ALKt(2;5)NPM-ALK t(2;17)CLTC-ALK

Noimpactonclinicalfeatures,esssen.allynocorrela.onwithmorphologicalvariants

ALKTransloca.ont(2;5)(p23;q35)

t(1;2)(q25;p23)

t(2;3)(p23;q11)

inv(2)(p23q35)

t(2;17)(p23;q23)

t(2;22)(p23;q11.2)

t(2;17)(p23;q23)

t(2;19)(p23;p13.1)

t(2;X)(p23;q11-12)

t(2;9)(p23;q33)…

STAT3:keyeffectorofALK:requiredformaintenanceoftheneoplasGcphenotype,twothirdsofALK-regulatedgenesaredependentonSTAT3

•  Smallcell/LymphohisGocyGc:–  moreadvancedstage,morefrequent

relapses–  adverseprognosis

VariantpakernsinALK+ALCL

Lamant L et al. J Clin Oncol 2011

ALKSmallcell Lymphohis.ocy.c

•  Morphologicallyindis.nguishablefromALK+ALCL

•  Required:hallmarkcells,cohesiveness,stronghomogeneousCD30+

•  Desirable:reducedT-cellAg,cytotoxic+,EMA+,sinusoidalgrowth

•  Olderpa.ents•  Worseprognosis

ALK-nega.veALCL:defini.veen.ty

SYSTEMIC

CUTANEOUS

ALK+

ALK-

sALCL ALK+

sALCL ALK-

cALCL

BREAST IMPLANT biALCL

SYSTEMIC

Rearrangements: IRF4/DUSP22, TP63, VAV1, tyrosine kinases,

Overexpresssion:ERBB4 Mutations: JAK1/STAT3

100% ALK rearr. STAT3 key effector

ALCL CD30+

Adapted from Philippe Gaulard, and Laurence de Leval Blood 2016;127:175-177

FISHIRF4BA

CD30

ALK

TIA-1 GzyB

EMA

CD3

ALK-negALCLwith6p25rearr.

Recurrenttransloca.onsinALK-negALCL •  [email protected](30%)->downregulaGonDUSP22:dual

specificphosphatase,inhibitsTCRsignalling,cytotoxnegEMAneg•  TP63rearrangements(<10%)->fusionproteinscontainingN-

truncatedp63,havingoncogenicproperGes,p63+•  VAV1rearrangements(10%)->acGvaGng

FeldmanALetal.Leukemia2009,Blood2011;ParillaCastellarEetal.Blood2014;BoddickerRLetal.Blood2006

Parilla Castellar E et al. Blood 2014

SurvivalofALCLpa.entsbygene.csubtype

8%ofthecases

73 ALK-negative 32 ALK-positive

30%ofthecases

CD30proteinexpressioninPTCLs(n=374)

N=97

50%96% 28.5% 11%5% 0%23%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

ALCL PTCLNOS

AITL ENKTL EATL ATLL HSTL

score4(>75%)score3(50-75%)score2(25-49%)score1(5-24%)score0

Bossard C, et al. Blood. 2014.

50%100% 46% 55.5%63% 0%58%

N=78 N=141 N=9 N=7N=14N=28N=97

96%ofALCLstronglyexpressCD30(cfsmallcellvariants)58%ofotherPTCLsexpressCD30in>5%cells20%ofotherPTCLsstronglyexpressCD30(>50%cells)

LyP

pcALCL

scALCL

CD30+MF

LyP

CutaneousCD30+lymphoprolifera.onsPrimarycutaneousversussystemic

Overlappingclinicalandpathologicalfeatures

BreastimplantassociatedALCL

•  Firstcasereportedin1997,manyotherssincethen•  withsalineorsiliconeimplants•  cosmeGcorreconstrucGveplasty•  variableintervalspostimplantaGon,meanabout10years

•  Raredisease:1/500’000-3’000’000womenwithbreastimplants•  Largeandpleomorphichallmarkcells•  CD30+,ALK-negaGve,EMA+,cytotoxicmolecules+,T-cell

anGgens+/-,norearrangementofDUSP22

WHO2016–provisionalen.ty:T-celllymphomawithmorphologicandimmunophenotypicfeaturesindisGnguishablefromALCL,ALK-,arisingprimarilyinassociaGonwithabreastimplant.

C. Laurent et al. Ann Oncol 2016;27:306-314

Effusionwithoutamass->insituMassadjacenttoprosthesis+/-effusion->infiltra.veALCL

•  MOSTCOMMON•  insituproliferaGonoftumorcells•  excellentoutcome•  implantremovalalone?

•  LESSCOMMON•  infiltraGvegrowthintocapsule•  lessfavorableormanifestaGonof

systemicdisease

-  Large,pleomorphic,hallmarkcells-  CD30+,ALK-negaGve,EMA+,

cytotoxicmolecules+,T-cellanGgens+/-,noDUSP22rearr

-  STAT3JAK1mutaGons

BreastimplantassociatedALCL

PeripheralT-celllymphoma,nototherwisespecified

PeripheralT-celllymphomanototherwisespecified(PTCLNOS)

• AheterogeneouscategoryofnodalandextranodalmatureT-celllymphomaswhichdonotcorrespondtoanyofthespecificen..es

• Exclusiondiagnosis(incltes.ngforTFHmarkers)• Aggressivetumors,adults,nodaland/orextranodal• Variablecytomorphologyandmicroenvironment

Small,monomorphic Large,polymorphous Eosinophilia

PTCL-NOS• Commonimmunophenotypicfeatures

• MostcasesTCRαβ,onlyrarecasesarederivedfromTCRγδ• CD4>CD8(CD4+CD8+,CD4-CD8-)• FrequentlossofT-cellanGgenexpression(CD5CD7)• AberrantB-cellanGgenexpression• EBVposiGvityinTorbystanderBcells

•  Immunophenotypic/gene.csubgroups• Cytotoxicimmunophenotype

• Usuallyadverseprognosis,withthepossibleexcepGonofLennertlymphoma

• CD30expressioninasubsetofcases,+/-CD15• RaretranslocaGons,VAV1• Molecularsignatures

TwosubgroupsofPTCLNOSwithdifferencesinbiologyandsurvival

Iqbal J et al. Blood 2014; Wang T et al. Blood 2014

GATA3subgroup(Th2)(mTorMYCPIK3Kinase)TBX21subgroup(Th1)(IFNCD8NFkBsignatures)










mediumT-cellLPD

Nodal

Leukemic

Extra-Nodal

• ApredominantlyextranodallymphomacharacterizedbyvasculardamageanddestrucGon,prominentnecrosis,cytotoxicphenotypeandassociaGonwithEBVinfec.on.• NK/T:manycasesarederivedfromNKcells,whileasubsethaveacytotoxicT-cellphenotypeofαβorγδderivaGon• FrequentinAsiaandSouthAmerica• Youngadults,malepredominance

ExtranodalNK/T-celllymphoma(ENKTCL),nasaltype

EBER

• Presenta.onintheupperaerodiges.vetract•  nasalcavity,sinuses,nasopahrynx•  chronicobstrucGon,bleeding,destrucGvelesions

• Extranasalpresenta.on:skin,intesGnes,lung…•  ulceratedandnecroGctumors,intesGnalperforaGon

• DisseminaGontootherorgans,rarelytotheBM• HemophagocyGcsyndromemayoccur• Pooroutcome(45%5yOS)

•  worseforextranasalcases(AuWYBlood2009)

ExtranodalNK/T-celllymphoma(ENKTCL),nasaltype

• Cytology:variable• CD2+cCD3+CD5-CD56+CD57-• CD4-CD8-/+CD7-/+CD30-/+• TIA1+GzB+Perforin+• EBV+:EBER+LMP1-/+• Clonality:TCRusuallypolyclonal,monoclonalindicaGveofT-cellorigin

ENKTCL

pPDGFRa

HuangY,deLevalL,GaulardPBestPrac\ceResearchClinHaematol2013

Muta.onsandPathwaysinENKTCL

JAK3ac.va.ngmuta.ons

0to35%ofcases

STAT3ac.va.ngmuta.ons:6to26%ofcases

STAT5Bac.va.ngmuta.ons:6%ofcases

CoppoPetal.Leukemia2009;Kücüketal,PNAS2011;Kücüketal.AJP2012;HuangYetal.Blood2010;PiccalugaPP.etal.LancetOncol2005,JClinInvest2007;KooGCetal.CancerDiscovery2012;Bouchekiouaetal.Leukemia2013;KucukCetal.

NatureComm2015;LeeSetal.Oncotarget2015;JiangLetal.NatGenet2015;DobashiAetal.GCC2016

Del6q:candidatetumorsuppressorgenes

HACE1PRDM1FOXO3

DDX3Xmuta.ons(20%)BCORmuta.ons(33%)

TCRγ

CD8+CD56+

monomorphic epitheliotropic

EATLII->MEITL

CD30

EATLI->EATL

CD3

Enteropathy-associatedT-celllymphomatypeI

(80-90%)

EATLtypeII(10-20%)Monomorphic

epitheliotropicintes.nalT-celllymphoma

Epidemiology NorthernEurope,associaGonwithceliacdisease(CD)HLA-DQ2/-DQ8:>90%

CeliacdiseaseuncommonHLA-DQ2/-DQ8:nlfrequency

Morphology Pleomorphic,mediumtolargesize,somecasesanaplasGcInflammaGon,necrosiscommon

Monomorphic,smalltomedium,epitheliotropicNoinflammaGon,nonecrosis

Distantmucosa Enteropathy IncreasedIEL,noatrophy

Immunophenotype CD3+,CD5-,CD8-/+,CD56-frequentlyCD30+CytotoxicacGvatedMATK+<40%oftumorcells

CD3+,CD5-,CD8+/-,CD56+/-CD30-CytotoxicacGvatedMATK+>80%tumorcells.

TCRexpression UsuallyαβTCR γδTCR(Vδ1)>αβTCR

Gene.cs +1q32.2-q41,+5q34-q35.2+9q-16q21.1

+8q24(MYC)+9q-16q21.1

IEL IEL

EATL

CD refractory to gluten-free diet Ulcerative jejunitis

Celiac disease gluten

RCDIRCDII

Intraepitheliallymphoma

IL-15

Lymphoma

ProgressionfromCeliacDiseasetoEATL-1

CD

CD RCD1 RCD2 EATLLymphs IEL:sCD3+,cCD3+,

CD5-,CD8+,CD103+

IEL:sCD3+,cCD3+,CD5-,CD8+,CD103+

IEL:sCD3-,cCD3+,CD5-,CD8-,CD103+,CD30-

AtypicalinfiltraGng:CD3+,CD5-,CD8-,Ki67+,CD30+

Gene.cs PolyclonalTCR PolyclonalTCR MonoclonalTCRParGaltrisomyof1q

MonoclonalTCR+9q31-16q12…

Clinicalcourse

Indolent Ratherindolent5-yOS:~90%

Aggressive5-yOS:~50%

Highlyaggressive5-ysurvival:~20%

RiskofEATL 0.7%in5years 14%in5-y 33-52%in5-y

His2514

17 22 20 24 25 15 12 26 4 21 14 2 3 13 1

CSMD3DLGAP3FNDC1MYO18BPTCHD4RYR2

SMCHD1NFKB1RASA2KRASBRAFTP53AKT1JAK1SH2B3JAK3

STAT5BCREBBPSETD2

17 22 20 24 25 15 12 26 4 21 14 2 3 13 1

SETD2_cgh

SETD2_mut

SETD2altera.onsintypeIIEATL(MEITL)

Roberti AL et al. Nat Comm 2016

SETD2 mut 3p21 del

FISH3p21

Dis.nctmuta.onalpakernandfrequentJAK-STATaltera.onsinEATLandMEITL

Roberti AL et al. Nat Comm 2016; Nairismagi ML et al Leukemia 2016; Nicolae A et al. Leukemia 2016

EATL–differen.aldiagnosis

•  EATLversusMEITL–  Emphasisonepitheliotropismandmonomorphicfeatures–  LackofassociaGonwithCD

•  Notallintes.nalT-celllymphomasrepresentEATLs–  OtherspecificPTCLenGGes–  PTCLNOS

•  Indolentlymphoprolifera.vedisordersoftheGItract–  Mucosallesions,paucysmptomaGcindividuals,clinicalcorrelaGon!

–  IndolentT-celllymphoprolifera.vediseaseoftheGItract• Blandcytology,CD4orCD8(cytotoxic),clonalTCR

–  NK-cellenteropathy(Lymphomatoidgastropathy)• Moreaggressivehistology,CD56+CD8-,EBV-,polyclonalTCR

CD8 CD3 MIB

YoungadultmalepaGentwhopresentedwithdiarrheaandhadpersistentdigesGvediseasefor3years.Clonalbutindolent;importanttorecognizeshouldnotbediagnosedaslymphomaanddonotrequireaggressivetherapy.CourtesyCCopie

•  IndolentT-cellprolifera?vedisorderofthegastro-intes?naltract*

•  PrimarycutaneousacralCD8+TCL*•  PrimarycutaneousCD4+small/mediumT-cellLPD*

IndolentT-celllymphoprolifera.ons

PD-1WHO2016

WHO2016

HepatosplenicT-celllymphoma(HSTL)

•  Veryraredisease,youngadults(medianage34y),M>F

•  Bsymptoms,splenomegaly,hepatomegaly,noLNThrombocytopenia,anemia+/-leucopenia,monocytosis

•  ImmunedyregulaGonorchronicanGgensGmulaGon(posttransplant,..)

•  Verypoorprognosis,noefficienttherapy

•  Sinusal/sinusoidalinfiltrateinliverspleen&BM

•  Medium-sizedcellscells,roundnuclei

K Belhad et al. Blood 2003 redpulpinvolvementsinusoids>cords

51

HSTL:spleen:monotonoustumorcells,medium-sized,roundnuclei,moderatelyabundantcytoplasm;somecasesblas.cormoreatypical

CD3

HSTL:constantBMinvolvement:hypercellularmarrow,sinusoidallymphoidinfiltrate

TCRγ

CD3

•  Immunophenotype–  CD2+CD3+,CD5-,CD7+CD56+(CD57-),CD4-/CD8-(orCD8+)–  Non-acGvatedcytotoxic:TIA1+,GrB-,perforin-–  Mostcases:TCRβF1-TCRγδ+

•  Gene.cs:iso7q•  SYKoverexpression:candidatetargetforpharmacologicinhibiGon•  STAT5BandSTAT3muta.ons:acGvaGng,mutuallyexclusive,30%of

thecases,coexistwithiso7qFISH 7q31/CEP7

TCRγ TIA CD56CD3

HepatosplenicT-celllymphoma(HSTL)










mediumT-cellLPD

Nodal

Leukemic

Extra-Nodal

En.ty Cellderiva.on

Cytotoxic Virus Gene.cs

T-cellPLLAggressive

Tαβ (CD4) Non-cytotoxic

No Inv(14)(q11;q32),t(14;14)(TCL1)ort(X;14)(MTCP1)JAK/STAT3mut.(75%)

T-cellLGLleukaemiaIndolent

Tαβ (CD8)(rarelyTγδ)

Cytotoxic(A)

No STAT3mutaGons(30%)STAT5BmutaGons(rare)

ChronicLPDofNKcells*Indolent

NK Cytotoxic(A)

No STAT3mutaGons(30%)

AggressiveNK-cellleukaemiaAggressive

NK Cytotoxic(A)

EBV 6q21-23deleGon

SystemicEBV+T-cellLPDofchildhoodAggressive

Tαβ Cytotoxic(A)

EBV

AdultT-cellleukaemia/lymphomaAggressive

Tαβ Treg HTLV1 CD28-CTLA4(5%)CD28-ICOS(3%)PLCG1(35%),PRKCB,CARD11(25%),VAV1,FYN(5%),RHOA(15%),CD28(rare)

Leukemic/disseminatedmatureT/NK-cellneoplasms:defini.onbymorphology,immunophenotypeandviralassocia.ons

*provisionalenGty

Lymphomatouspresenta.onsofATLL

MimicsotherPTCLsATLLinnon-endemicregionsmaybeunderdiagnosed

SerologicaltestsforHTLV1tobeperformedinanycaseofPTCL

•  Morphologicandcytologicspectrum:smallmediumorlargecell•  ALCL-likeAITL-like•  Prominenteosinophiliamaybeseen•  CasescomprisingEBV-posiGveHRScellspossiblymimickingHL

CD4 CD7 CD25

M47 mesenteric adenopathies - CD3+ CD4+ PTCL NOS -> HTLV1+ -> ATLL

Concludingremarks•  Recentdiscoveriesinthebiologyandgene.csofT-cellneoplasias:

amoleculardimensionisaddedtomanyPTCLen..es–  prognosGc,theranosGcordiagnosGcvalueofmolecularabnormaliGesremains

tobecharacterized•  Diagnosisandclassifica.onofPTCLiscomplexandrequires

–  anadequatespecimen(surgicalbiopsy)–  examinaGonbyanexperiencedhematopathologist

•  Broaddifferen.aldiagnosisofPTCLen..es–  BenigncondiGons–  LymphoblasGcversusmatureTCL–  PTCLversusB-NHL/HL–  InterpretaGonofclonalityresults!IndolentclonalT-celllymphoproliferaGons

•  Correla.onwithclinicalinforma.on–  Clinicalhistory,diseasestaging,siteofinvolvement–  RuleoutdisseminaGonofprimarycutaneouslymphoma–  TestforHTLV1serology

CD4+CD8+Activated T cell

sALCL,ALK-

sALCL,ALK+

AITL

F-TCL

Follicular helper T cell

TFH

?

CD30+ PTCLs Nodal lymphomas of TFH origin

TET2IDH2DNMT3RHOATCRsignallingpathway(50%)PLCG1(15%)CD28(10%)

t(5;9)(q33;q22)ITK-SYK

PTCL-TFH

PDGFRAacGvaGonSYKacGvaGon

TP63VAV1rearr.

100%ALKrearr.

Variable TH1/TH2 Cytotoxic

IRF4/DUSP22,TP63,VAV1

rearr.STAT3act.

PTCL,NOS

cytotox

TbetTH1 GATA3

TH2

EBV

WHO2016

Thankyouforyouraken.on

amphi 1 faculté de médecine bichat - ovh

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