peripheral t-cell lymphomas · cd4 cd8 gm eber. aitl might derive from t-zone lymphomas courtesy of...
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1
Hematopathology
Peripheral T-cell lymphomas
Prof. Pier Paolo Piccaluga
Department of Experimental, Diagnostic and Specialty Medicine, Bologna University
Department of Pathology JKUAT, Nairobi
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Peripheral T-cell lymphomas
• Rare tumors (10% NHL)
• Heterogeneous
• No diagnostic markers
(but ALK+)
• Genetics
– RHOA, TET2, IDH2,
DNMT3A/B
– t(2;5), t(5;9), t(6;9) ….
• Poor outcome
PTCL/NOS; 26
AITL; 18,5
ALCL ALK+; 6,6ALCL ALK-; 5,5
NKTCL; 10,4
ATLL; 9,6Enteropathy type;
4,7
Primary cutaneous ALCL;
1,7
Hepatosplenic gd TCL; 1,4
Subcutaneous panniculitis-like;
0,9
Other disorder; 14,7
Piccaluga PP., Int J Hematol Oncol. 2017 Jun;6(1):1-4
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University of Bologna
HTLV1-related ATLLEBV-related NK/T cell lymphoma, nasal type
EATCL (HLA haplotypes favouring gliadin allergy & GSE)
PTCL endemic areas
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International PTCL Project
Study Sites Number Cases %
North America
6 sites 333 25.2
Europe 7 sites 452 34.2
Far East 8 sites 535 40.6
Armitage J, JCO 2008
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PTCL diagnosis
Cytology and Architecture
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PTCL diagnosis
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PTCL diagnosis
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Peripheral T-cell lymphomas not otherwise specfied (NOS)
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▪ Commonest PTCL type 25%
▪ Median age ~ 60 years
▪ Stage IV 60%
▪ IPI 3-5 60%
▪ Presentation
• Nodal 22%
• Extra-nodal 16%
• Nodal + extra-nodal 62%
▪ 5-year RFS 25%
▪ 5-year OS 20%
PTCL/NOS – General features
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Overall survival of PTCLs/NOS & AITL
Armitage J, JCO 2008
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Morphology
Heterogeneous
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University of BolognaT-zone type
PTCL/NOS: morphologic variants
GC
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University of BolognaLympho-epithelioid (Lennert’s) type
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1. Epigenetic mediators
Aberrant methylation/ acetylation
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2. JAK/STAT signaling
PTCL/NOS molecular pathogenesis
JAK1-JAK3 mutations• ALCL• T-PLL• ENKTCL• EATL• MEITL
STAT3-STAT5B mutations• ALCL• T-LGL, NK-LGL• T-PLL• ENKTCL• EATL• MEITL• HSTL• PCgdTCL
Piccaluga PP et al, Leukemia 2014 Aug;28(8):1687-97
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3. TCR signaling
A. Fusions and mutations affecting TCR
ITK/SYK RHOA
VAV1 CARD11
ICOS/CD28 FYN
IRF4/DUSP22 ……
B. Stimuli mimicking TCR
a.ALK
b.Other TK (PDGFRs)
PTCL/NOS molecular pathogenesis
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Targeted therapy for PTCL/NOS
1. Epigenetic mediators → HDACi & Demethylating agents
2. JAK/STAT signaling → JAK/STAT inhibitors?
3. TCR signaling → ALK and TK inhibitors18
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Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphomas
Iqbal J et al , Blood 2014
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Classification of PTCLs/NOS according to their cellular counterpart
Piccaluga & Iqbal, in preparation
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Angioimmunoblastic T-cell lymphoma (AITL) and
TFH-related PTCLs
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WHO 2017 Update
• Nodal TFH-related PTCLs
– Angioimmunoblastic T-cell lymphoma (AITL)
– Follicular T-cell lymphoma (FTCL)
– PTCL/NOS with TFH phenotype
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A group of PTCLs, including AITL, derive T follicular helper cells
DOI: 10.1084/jem.20120994
Piccaluga PP et al. Ca Res, 2007
De Leval L et al. Blood, 2007
Rudiger T et al. J Pathology, 2006
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15-20% of PTCL cases
1-2% NHLs
Clinical features
• Generalized lymphadenopathy
• Hepatosplenomegaly
• Skin rash
• BM commonly involved
• Usually advanced clinical stage
• Systemic symptoms
• Polyclonal hypergammaglobulinemia
• Clinical course aggressive
• Median survival: < 3 yrs
Low cellular density
Angioimmunoblastic T cell lymphoma
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University of Bologna
Clear cells
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University of BolognaCD21
Prominent branching high endothelial venules
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University of BolognaCD21
Follicular dendritic cell hyperplasia
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AITL – Key morphological features
Clear cellsProminent, branching, high endothelium venules
FDC hyperplasia
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University of Bologna
CD3 CD20
EBERCD4 CD8 GM
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AITL might derive from T-zone lymphomas
Courtesy of Prof. P. Gaulard
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WHO 2017 Update
• Nodal TFH-related PTCLs
– Angioimmunoblastic T-cell lymphoma (AITL)
– Follicular T-cell lymphoma (FTCL)
– PTCL/NOS with TFH phenotype
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University of Bologna
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University of Bologna
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University of BolognaCD3
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University of BolognaCD4
CD8
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University of BolognaCD10 CXCL13
PD1
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Genetics of TFH-related PTCLs
• ITK/SYK translocation (FTCL)
• RHOA mutations in 70% of AITL and TFH-like
• Mutually exclusive mutations in other TCR-related genes in 49%– PLCG1 (14.1%),
– CD28 (9.4%, mutated exclusively in AITL),
– PI3K elements (7%),
– CTNNB1 (6%),
– GTF21 (6%)
Vallois et al, Blood 2016
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Anaplastic large cell lymphomas (ALCLs)
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WHO 2017 Update
• Anaplastic large cell lymphoma, ALK+
• Anaplastic large cell lymphoma, ALK-
• Cutaneous anaplastic large cell lymphoma
• Breast implant associated Anaplastic large cell lymphoma
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Nodal anaplastic large cell lymphomas
• Anaplastic cytology
– Hallmark cells
• T/null phenotype
– Down regulation of T-cell markers and TCR signaling
• Alternative syrvival signaling:
– ALK – t(2;5) and variants
– STAT3 activation
• ALK+ vs. ALK-40
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41
Undistinguishablemorphologically and
phenotypically
ALK+ ALK-
CD30 CD30
Perforin Perforin
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ALCL patients’ survavial according to ALK status
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ALK+ anaplastic large cells
ALK+ small cells(reservoir?)
ALCL - CT - mixed - SCV- HL (perivascular) - LH
Infl
amm
ato
ry c
ells
Morphologic spectrum of “ALK+ ALCL
Infl
amm
ato
ry c
ells
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CD30
CD45
EMA
Phenotype:CD30+
T/nullCD45+/-
BSAP-
EMA+/-
CD15-(+)
Cytotoxic markers+
EBV-
Perforin
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Translocation Frequency Localization
t(2;5)( p23 ;q35 ) 70-80% Cytoplasmic/Nuclear
nucleolar
t(2;3)( p23 ;q21 ) 2-5% Cytoplasmic
t(1;2)( q25 ;p23 ) 10-20% Cytoplasmic
inv (2)( p23 ;q35 ) 2-5% Cytoplasmic
t(2;17)( p23 ;q23 ) 2-5% Cytoplasmic
t(2;19)( p23 ;q13,1 ) - Cytoplasmic
t(2;2)( p23 ;q11-13 )? - Nuclear
or inv (2)( p23 ;q11-13 )? - membrane
t(X;2)( q11-12 ;p23 ) - Membranous
Translocations and fusion proteins involving the ALK gene in ALCL
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New genetic findings in ALCL
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New genetic findings in ALCL
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Breast implant associated ALCL
• Breast implant-associated anaplastic large cell lymphoma is a rare malignancy that arises around mammary prosthetic implants in patients who have undergone breast augmentation or reconstruction
1. Confined to peri-implant breast seroma
2. With invasion of the fibrous capsule
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Breast implant associated ALCL is distinct from other ALCLs and
presents STAT3 and TCR deregulation
49Di Napoli et al 2018
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CD30/CD30L signaling
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From CD30 detection to anti-CD30 treatment
1982 2000s 2010
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CD30 expression in T-cell lymphomas
PTCL/NOS
AITL
0 no staining; 1+ <25% positive cells; 2+ 25–50% positive cells; 3+ >50–75% positive cells; 4+ >75% positive cells
Sabattini E, et al. Haematologica 2013
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CD30+ PTCLs/NOS is different
from ALCL
• CD30+ PTCL/NOS cases
– No criteria for ALK- ALCL diagnosis
– 16 cases
• Molecular classifier
– 16/16→ PTCL/NOS
P=0.02
Molecular Classifier
No ALCL morphology; CD30 > 75%
Discriminant analysis
PTCL/NOS vs. ALK-/ALCL → 53 genes
Patent N. 61.U2164.12.IT.34
Piccaluga PP et al. J Clin Oncol. 2013 Aug 20;31(24):3019-3025
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Molecular profiling improves classification and prognostication of nodal peripheral T-cell lymphomas:
results of a phase III diagnostic accuracy study.
VS.
P=0.62 P=0.011 P=0.02
Conventional Histopathology Molecular Classifier Molecular Classifier
Piccaluga PP et al, JCO 2013
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THANKS YOU
Q/A
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