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International PTCL StudyInternational PTCL StudyStudy Sites Number Cases %Study Sites Number Cases %
North North AmericaAmerica
6 sites6 sites 333333 25.225.2
EuropeEurope 7 sites7 sites 452452 34.234.2
Far EastFar East 8 sites8 sites 535535 40.640.6
Presented by D.D. Weisenburger at the Meeting Presented by D.D. Weisenburger at the Meeting ““ItIt’’s time to takes time to takecare of Tcare of T--cell lymphomascell lymphomas””, held in Bologna, October 22, held in Bologna, October 22--24, 200624, 2006
Median ageMedian age
Stage IVStage IV
IPI 3IPI 3--55
PresentationPresentation•• NodalNodal
•• ExtraExtra--nodalnodal
•• Nodal + extraNodal + extra--nodalnodal
55--year RFSyear RFS
55--year OSyear OS
PTCL/NOS PTCL/NOS -- Clinical FeaturesClinical Features
~ ~ 60 years60 years
60%60%
60%60%
22%22%16%16%62%62%26%26%20%20%
DiagnosisDiagnosis CENSORCENSOR FAILFAIL TOTALTOTAL MEDIANMEDIAN
Angioimmunoblastic TAngioimmunoblastic T--cell lymphomacell lymphoma 8787 154154 241241 2.262.26
Peripheral TPeripheral T--cell lymphomacell lymphoma--NOSNOS 112112 218218 330330 2.012.01
Test: p=0.89Test: p=0.89
Overall SurvivalOverall SurvivalPeripheral TPeripheral T--cell Lymphomacell Lymphoma--NOS, andNOS, and
Disease subDisease sub--group: Angioimmunoblastic Tgroup: Angioimmunoblastic T--cell lymphoma cell lymphoma
Prop
orti
onPr
opor
tion
0.00.0
0.10.1
0.20.2
0.30.3
0.40.4
0.50.5
0.60.6
0.70.7
0.80.8
0.90.9
1.01.0
TimeTime
00 11 22 33 44 55 66 77 88 99 1010 1111 1212 1313 1414 1515 1616 1717 1818 1919
International peripheralInternational peripheralTT--cell lymphoma projectcell lymphoma project
Morphologic spectrumMorphologic spectrum
T zone typeT zone type
PTCLnos: peculiar morphologic patternsPTCLnos: peculiar morphologic patterns
GCGC
Low magnification: Hodgkin like patternLow magnification: Hodgkin like pattern
LymphoLympho--epithelioid cell type (Lennertepithelioid cell type (Lennert’’s lymphoma)s lymphoma)
No marked pleomorphism of tumoural cellsNo marked pleomorphism of tumoural cells
Macon WR et al. Am J Surg Pathol 1995, 19:297-303 Rudiger T et al. AM J Surg Pathol 2000, 24:117-22de Leval L et al. Am J Surg Pathol 2001, 25:395-400Jiang L et al. Am J Clin Pathol 2005, 123:448-55Ikonomou IM et al. Virchows Archiv 2006, 449:78-87Streubel B et al. Leukemia 2006, 20:313-18Bacon CM et al. Br J Haematol 2008, 143:439-50Qubaja M et al. Hum Pathol 2009, 40:264-69Huang Y et al. Am J Surg Pathol 2009, 33:682-90Ortiz-Muchotrigo N et al. Histopathol 2009, 54:901-3 Le Tourneau A et al. Histopathol 2010, 56:548-51.
CD3CD3
CD4CD4
CD8CD8
CD10CD10 CXCL13CXCL13
PD1PD1
CD21CD21
DRDR-- PTCL/NOSPTCL/NOSDRDR++
Supervised analysisSupervised analysisgenes=185genes=185
Supervised analysisSupervised analysisgenes=70 genes=70
CD4CD4 CD8CD8 PTCL/NOSPTCL/NOS
Most PTCL/NOS are related to activated Most PTCL/NOS are related to activated central memorycentral memoryTT--cells; a small minority shows cytotoxic profile. cells; a small minority shows cytotoxic profile.
de Leval L. et al. Blood 2007; 109:4952-63.
Prof. Dr. Dr. h.c. Karl Lennert Prof. Dr. Dr. h.c. Karl Lennert -- Kiel, 2009Kiel, 2009
Agostinelli C, Hartmann S, Klapper W, Agostinelli C, Hartmann S, Klapper W, KorkolopolouKorkolopolou P, P, RighiRighi S, Marafioti T, S, Marafioti T, Piccaluga PP, Piccaluga PP, PatsourisPatsouris E, E, HansmannHansmann MM--L, Lennert K and Pileri SA. L, Lennert K and Pileri SA.
Peripheral TPeripheral T--cell lymphomas with follicular Tcell lymphomas with follicular T--helper phenotype: a new basket helper phenotype: a new basket or a distinct entity? Revising Karl Lennertor a distinct entity? Revising Karl Lennert’’s personal archive. s personal archive.
Histopathology, 2011, 59:1173Histopathology, 2011, 59:1173--82. 82.
A road to a new category of TFHA road to a new category of TFH--PTCLs?PTCLs?
Training setTraining set Test setTest set CD4CD4--CD8CD8--DR+DR+
00
PTCL/NOSPTCL/NOS
Normal lymphocytesNormal lymphocytes
Genes differentially expressed in PTCL/NOS Genes differentially expressed in PTCL/NOS and normal Tand normal T--cells (training set + test set)cells (training set + test set)
Supervised analysis 155 genes: 91 downSupervised analysis 155 genes: 91 down--regulated and 64 upregulated and 64 up--regulatedregulated
Cellular programs deCellular programs de--regulated in PTCL/NOSregulated in PTCL/NOS
AdhesionAdhesionApoptosisApoptosis
MatrixMatrix
ProliferationProliferationSignal transductionSignal transduction
CytoskeletonCytoskeleton TranscriptionTranscriptionPER1PER1CBX4CBX4CHD2CHD2COPEBCOPEBCREMCREMEPC1EPC1JMJD1CJMJD1CMAFMAFNR4A2NR4A2NR4A3NR4A3SERTAD1SERTAD1ZBTB10ZBTB10ZBTB24ZBTB24ZNF198ZNF198ZNF331ZNF331BCL10BCL10
GJA1GJA1TNSTNSVCAM1VCAM1LIFRLIFR
PTCL/NOSPTCL/NOS CD4CD4--CD8CD8--DR+DR+
CD69CD69DUSP2DUSP2DUSP8DUSP8GADD45AGADD45AGADD45BGADD45BING3ING3JUNDJUNDMOAP1MOAP1PPP1R15APPP1R15A
FN1FN1COL12A1COL12A1COL1A2COL1A2COL3A1COL3A1COL4A1COL4A1COL4A2COL4A2FBN1FBN1LAMB1LAMB1SPARCSPARCCDH11CDH11
AXUD1AXUD1FOXP1FOXP1RHOBTB3RHOBTB3CAV2CAV2PLEKHC1PLEKHC1BTG1BTG1CLK1CLK1HECAHECAJUNJUNRGC32RGC32TOB1TOB1
PTCL/NOSPTCL/NOS CD4CD4--CD8CD8--DR+DR+
CALD1CALD1STK17BSTK17BMKNK2MKNK2HIPK1HIPK1PTP4A1PTP4A1PDE4DPDE4DMAP3K8MAP3K8ITPKBITPKBSEPT10SEPT10TJP1TJP1IRS2IRS2
PTCL/NOSPTCL/NOS CD4CD4--CD8CD8--DR+DR+
TPM1TPM1Dlc2Dlc2MGAT4AMGAT4AMYLIPMYLIPNFIBNFIBWASPIPWASPIP
PTCL/NOSPTCL/NOS CD4CD4--CD8CD8--DR+DR+
PTCL/NOSPTCL/NOS CD4CD4--CD8CD8--DR+DR+
PTCL/NOSPTCL/NOS CD4CD4--CD8CD8--DR+DR+
PTCL/NOSPTCL/NOS CD4CD4--CD8CD8--DR+DR+
CaldesmonCaldesmon ((⇑⇑))
LIFR (LIFR (⇑⇑))
BCL10 (BCL10 (⇓⇓))
pp--PDGFRPDGFRαα
p27 (p27 (⇑⇑))
IGFBP7 (IGFBP7 (⇑⇑))
PDGFRPDGFRαα ((⇑⇑))
CYR61 (CYR61 (⇑⇑))
Piccaluga PP, et al The Lancet Oncology, 2005; 6: 440Piccaluga PP, et al The Lancet Oncology, 2005; 6: 440
Expression of plateletExpression of platelet--derived growth factor derived growth factor receptor in PTCL/NOSreceptor in PTCL/NOS
Training setTraining set Test setTest set CD4CD4--CD8CD8--DR+DR+
PDGFRaPDGFRa
PDGFRAPDGFRA
PTCL/NOSPTCL/NOS
TK TK inhibitorsinhibitors
Imatinib reduces cell viability, by inducing cell cycle Imatinib reduces cell viability, by inducing cell cycle arrest and apoptosis in PTCL/NOS primary cellsarrest and apoptosis in PTCL/NOS primary cells
0
20
40
60
80
100
120
0 6 12 18 24 30 36 42 48 54 60 66 72
Control Sugen 0,3 mM Sugen 1 mM
0
20
40
60
80
100
120
0 6 12 18 24 30 36 42 48 54 60 66 72
Control Sugen 0,3 mM Sugen 1 mM
AnnexinAnnexin V: t48hV: t48h
MediumMedium
Medium +Medium +Imatinib 1 Imatinib 1 mMmM
BrdUrdBrdUrd proliferationproliferation assayassay; 48 h; 48 h
00101020203030404050506060707080809090
100100
ControlControl ImatinibImatinib
G1G1SSG2G2--MM
Imatinib is more effective than daunorubicin Imatinib is more effective than daunorubicin and gemcitabine against and gemcitabine against PTCLnosPTCLnos primary primary
cellscells
0
20
40
60
80
100
120
0 8 16 24 32 40 48 56 64 72
Control Dauno 5mM Imatinib 1 mM
0
20
40
60
80
100
120
0 24 48 72
Control Dauno 5 mM Imatinib 1 mM
020406080
100120
0 24 48 72
ControlGemcitabine 0,5 mMGemcitabine 0,5 mM + Imatinib 1 mMImatinib 1 mM
0
20
40
60
80
100
120
0 24 48 72
Control Sugen 0,3 mMSugen 1 mM Gemcitabine 0,5 mM
HDACiHDACi
CD69CD69DUSP2DUSP2DUSP8DUSP8GADD45AGADD45AGADD45BGADD45BING3ING3JUNDJUNDMOAP1MOAP1PPP1R15APPP1R15A
Histone deacetylase Histone deacetylase inhibitorsinhibitors
HDACi is dramatically effective against HDACi is dramatically effective against PTCLnosPTCLnosprimary cellsprimary cells
0102030405060708090
100
0 24 48
Control ITF 0.5 mM ITF 1 mM ITF 5 mM
BrdUrdBrdUrd proliferationproliferation assayassay; 48 h; 48 h
AnnexinAnnexin V V assayassay; 48 h; 48 h
00
5050
100100
ControlControl +HDACi+HDACi
G1G1SS
Peripheral T-cell lymphomas(leukaemic and extranodal)
Alma MaterStudiorum
1088 d.C.
TT--cell prolymphocytic leukemiacell prolymphocytic leukemia
2% of cases of mature lymphocytic leukaemia2% of cases of mature lymphocytic leukaemia
Clinical featuresClinical features
Median ageMedian age (range) (range) 65 years65 years (30 (30 -- 94)94)M : F ratioM : F ratio 1. 31. 3HepatosplenomegalyHepatosplenomegaly 79%79%LymphadenopathyLymphadenopathy 46%46%Skin lesionsSkin lesions 23%23%EffusionsEffusions 12%12%WBC x 10WBC x 1099/L/L > 100> 100Hb < 10 g/dlHb < 10 g/dl 25%25%Platelets < 100 x 10Platelets < 100 x 1099/L/L 44%44%
Morphology: PMorphology: Prolymphocytic rolymphocytic 75%75%
Peripheral bloodPeripheral blood
Cytoplasmic protrusions or blebsCytoplasmic protrusions or blebs
Small cell Small cell 20%20%
Lymph nodeLymph node
Cerebriform 5Cerebriform 5%%
TT--PLL hairy cell leukaemiaPLL hairy cell leukaemia--likelike CD3CD3
Peripheral bloodPeripheral blood
ImmunophenotypeImmunophenotype
AntigenAntigen % of cases% of cases++
CD3CD3 8484
CD4+/CD8CD4+/CD8-- 6060
CD4+/CD8CD4+/CD8++ 2525
CD4CD4--/CD8/CD8++ 1010
TCL1TCL1 7171
All: All: CD52CD52++, CD2, CD2++, CD5, CD5++, CD7, CD7++, TdT, TdT--, CD1a, CD1a--, NK markers, NK markers--. .
Cytotoxic markes: negative.Cytotoxic markes: negative.
CD3CD3+ + BM infiltrateBM infiltrate
Complex karyotypeComplex karyotype
80%80%7070--80%80%
TCL1TCL1
ATMATM
p53 delp53 del
Prognosis and predictive factorsPrognosis and predictive factors
•• Median survival less than 1 yearMedian survival less than 1 year
•• Cases with a more chronic course: accelerated Cases with a more chronic course: accelerated phase after 2phase after 2--3 years3 years
•• AlemtuzumabAlemtuzumab
•• Autologous or allogeneic stem cell transplantationAutologous or allogeneic stem cell transplantation
•• High expression of TCLHigh expression of TCL--1 and AKT: poor outcome1 and AKT: poor outcome
TT--cell LGL leukaemiacell LGL leukaemia(2(2--3% of mature lymphocytic leukaemias)3% of mature lymphocytic leukaemias)
Definition: Definition: increased number of circulating LGLs (2increased number of circulating LGLs (2--20x1020x1099/L) lasting at least 6 /L) lasting at least 6 months and without a clearly identified cause, often arising in months and without a clearly identified cause, often arising in a setting a setting of immune stimulation of immune stimulation
Clinical features:Clinical features:-- No clearNo clear--cut sex and age prevalence (45cut sex and age prevalence (45--75 years)75 years)-- involvement of the peripheral blood, bone marrow, liver and spleinvolvement of the peripheral blood, bone marrow, liver and spleen en -- severe neutropeniasevere neutropenia with/without anaemiawith/without anaemia-- possible recurrent bacterial infectionspossible recurrent bacterial infections-- moderate splenomegalymoderate splenomegaly-- frequent association with rheumatoid arthritis, autofrequent association with rheumatoid arthritis, auto--antibodiesantibodies-- circulating immune complexes and hypergammaglobulinemiacirculating immune complexes and hypergammaglobulinemia-- TT--LGL clonal expansions following allogeneic BMT LGL clonal expansions following allogeneic BMT -- typically typically indolentindolent clinical courseclinical course
Azurophilic granulesAzurophilic granulese.me.m.: parallel tubular arrays; .: parallel tubular arrays;
cytotoxic proteins.cytotoxic proteins.
DisDis--maturation of the haematopoietic series!maturation of the haematopoietic series!MildMild fibrosisfibrosis
50%: hypercellular50%: hypercellular50%: 50%: normonormo//hypohypo--
cellularcellular
SpleenSpleen
CD3CD3
CD57CD57
Phenotype:Phenotype:
TIATIA--11++, Granzyme B, Granzyme B++, Granzyme M, Granzyme M++, , perforinperforin++, CD57, CD57+v+v
High expression of High expression of FAS and FASFAS and FAS--LL
80%: CD380%: CD3++, , TCRTCRαα//ββ++, CD4, CD4--, CD8, CD8++
variants: CD3variants: CD3++, , TCRTCRαα//ββ++, CD4, CD4++, CD8, CD8--
CD3CD3++, , TCRTCRαα//ββ++, CD4, CD4++, CD8, CD8++
CD3CD3++, , TCRTCRγγ//δδ++, CD4, CD4vv, CD8, CD8vv
CD5 and CD7 expression: weak or CD5 and CD7 expression: weak or absentabsent
Genotype:Genotype:
TCR TCR γγ (+(+ββ) clonal rearrangement) clonal rearrangement
BM biopsy misleading without IHCBM biopsy misleading without IHC
CD4CD4
CD8CD8
Reactive nodulesReactive noduleswith mixedwith mixed
composition (3+,composition (3+,4+>8+, CD20+)4+>8+, CD20+)
CD20CD20CD4CD4
Chronic NK-cell LPD
• Morphologically LGL (blood and BM involvement)
• Phenotypically abnormal NK-cells (CD3εε+, CD16+, CD56+w, cytotoxic markers+, CD2-, CD7-, CD57-, CD5+, CD8+, EBV-)
• Blood LGL count ≥ 2x109/L
• Without obvious cause for the elevation
• Persists for > 6 months
• Associated with solid and haematological tumours, vasculitis, splenectomy, neuropathy and autoimmune disorders
• No worsening of the lympho-proliferation or clinical condition
• Exceptional transformation to an aggressive NK-cell disorder
Granzyme BGranzyme B
Phenotype & genotypePhenotype & genotype
CD2CD2++
CD3CD3--
CD3CD3εε++
CD56CD56++
CD16CD16+/+/--
CD57 usuallyCD57 usually--
cytotoxic moleculescytotoxic molecules++ (TIA(TIA--1; GB; perforin)1; GB; perforin)
TCR genes: germ line configurationTCR genes: germ line configuration
EBVEBV--
Neither TCR rearrangement nor Neither TCR rearrangement nor karyotype abnormalities, but hints of karyotype abnormalities, but hints of
clonality!clonality!
•• XX--chromosome inactivationchromosome inactivation–– HUMARA HUMARA
•• ImmunophenotypingImmunophenotyping–– Unique profile of markersUnique profile of markers–– Restricted KIR expression patternRestricted KIR expression pattern
KIR (KIR (kkiller cell iller cell IIgg--like like rreceptors)eceptors)•• Located on Located on 19p13.419p13.4•• Polymorphic in the Polymorphic in the KIRKIR genes present and genes present and
in the allele representedin the allele represented•• May have 2 or 3 IgMay have 2 or 3 Ig--like domain (2D,3D).like domain (2D,3D).•• May have a May have a long or short cytoplasmic taillong or short cytoplasmic tail (L (L
or S forms)or S forms)•• Long forms can transduce signals but short Long forms can transduce signals but short
forms need to associate with adaptors for forms need to associate with adaptors for signal transduction eg. DAP12signal transduction eg. DAP12
•• Can be activating or inhibitoryCan be activating or inhibitory but normal but normal NK cells always have one or more inhibitory NK cells always have one or more inhibitory KIRsKIRs
Aggressive NKAggressive NK--cell leukaemia (EBVcell leukaemia (EBV++))
Clinical featuresClinical features rare (higher prevalence among rare (higher prevalence among AsiansAsians))young to middleyoung to middle--aged adults aged adults (mean age: 42 yrs)(mean age: 42 yrs)no sex predilectionno sex predilectionat onset: leukaemic blood picture, fever, Bat onset: leukaemic blood picture, fever, B--symptoms symptoms hepatosplenomegaly: commonhepatosplenomegaly: commonlymphadenopathy: occasionallymphadenopathy: occasionalskin lesions: uncommonskin lesions: uncommonelevated serum soluble elevated serum soluble FASFAS--LL levelslevels
ComplicationsComplications coagulopathycoagulopathyhaemophagocytic syndromehaemophagocytic syndromemultimulti--organ failureorgan failure
Clinical courseClinical course more often more often fulminantfulminant (mean survival: 2 months)(mean survival: 2 months)
MarrowMarrow
SpleenSpleen
TestisTestis
Phenotype & genotypePhenotype & genotype
CD2CD2++
CD3CD3--
CD3CD3εε++
CD56CD56++
CD16CD16+/+/--
CD57 usuallyCD57 usually--
cytotoxic moleculescytotoxic molecules++ (TIA(TIA--1; GB; perforin)1; GB; perforin)
TCR genes: germ line configurationTCR genes: germ line configurationdel(6)(q21;q25)del(6)(q21;q25)EBVEBV++
CD3CD3εε
CD56CD56
Adult TAdult T--cell lymphoma/leukaemiacell lymphoma/leukaemia
-- Discovered by Takatsuki et al. (1976)Discovered by Takatsuki et al. (1976)-- EndemicEndemic in: Southern Japan, Caribbean basin, and in: Southern Japan, Caribbean basin, and
Central AfricaCentral Africa-- The disease is The disease is linked to the prevalence oflinked to the prevalence of HTLVHTLV--1 1 in in
the populationthe population-- Incidence: 2.5% among HTLVIncidence: 2.5% among HTLV--1 carriers1 carriers-- Exposure to the virus in the early life (breast milk, Exposure to the virus in the early life (breast milk,
blood and blood products)blood and blood products)-- Long latencyLong latency-- Adults Adults (20 (20 -- 80 yrs80 yrs--old) old) with M/F = 1.5/1with M/F = 1.5/1-- HTLVHTLV--1 not sufficient to result in neoplastic 1 not sufficient to result in neoplastic
transformationtransformation
Clinical variants:Clinical variants:
acuteacute: leukaemic phase, lymphadenopathy, hepatosplenomegaly, : leukaemic phase, lymphadenopathy, hepatosplenomegaly, skin rash, hypercalcaemia (lytic bone lesions) and associated Tskin rash, hypercalcaemia (lytic bone lesions) and associated T--cell immunodeficiencycell immunodeficiencylymphomatouslymphomatous: prominent lymphadenopathy without PB : prominent lymphadenopathy without PB involvement, cutaneous lesions common, hypercalcaemia less ofteninvolvement, cutaneous lesions common, hypercalcaemia less oftenseenseenchronicchronic: exfoliative skin rush, mild leukaemic component, : exfoliative skin rush, mild leukaemic component, hypercalcaemia absenthypercalcaemia absentsmoulderingsmouldering: >5% circulating neoplastic cells, frequent skin or : >5% circulating neoplastic cells, frequent skin or pulmonary lesionspulmonary lesions
Progression to an acute variant in 25% of chronic or smoulderingProgression to an acute variant in 25% of chronic or smoulderingcasescases
Adult TAdult T--cell lymphoma/leukaemiacell lymphoma/leukaemia
Overall survival of ATLL according to clinical subtypesOverall survival of ATLL according to clinical subtypes
Nagasaki Nagasaki UnvUnv..LeukLeuk Res 1993Res 1993
ShimoyamaShimoyama et alet alBrit J Brit J HaematolHaematol19911991
Diversity of leukaemic cell morphology in ATLLDiversity of leukaemic cell morphology in ATLL
CytomorphologicalCytomorphological AcuteAcute ChronicChronicType (% lymph)Type (% lymph) (n=36) (n=36) (n=14) (n=14) p Valuep Value
PrototypePrototype 49%49% 29%29% 0.0150.015CLLCLL--likelike 17%17% 52%52% <0.0001<0.0001UnusualUnusual 20%20% 3%3% <0.0001<0.0001IntermediateIntermediate 8%8% 10%10% NSNS
AcuteAcute Acute crisisAcute crisis
AcuteAcute
AcuteAcuteChronicChronic
SmolderingSmolderingx1000x1000
x1000x1000
x1000x1000
x1000x1000
x1000x1000
x400x400
CD2/3/5CD2/3/5++, , CD7CD7--, CD4/CD8, CD4/CD8vv, , CD25CD25++, CD30, CD30vv, cytotoxic markers, cytotoxic markers--
frequent expression of frequent expression of CCR4CCR4 and and FoxP3FoxP3 (regulatory T(regulatory T--cells)cells)TCR clonal rearrangement; HTLVTCR clonal rearrangement; HTLV--1 monoclonal1 monoclonal
FoxP3FoxP3
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