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
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
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
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
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
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-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)
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
• 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%)
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)
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
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