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Hematopathology
Peripheral T-cell lymphomas
Prof. Pier Paolo Piccaluga
Department of Experimental, Diagnostic and Specialty Medicine, Bologna University
Department of Pathology JKUAT, Nairobi
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
University of Bologna
HTLV1-related ATLLEBV-related NK/T cell lymphoma, nasal type
EATCL (HLA haplotypes favouring gliadin allergy & GSE)
PTCL endemic areas
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
PTCL diagnosis
Cytology and Architecture
PTCL diagnosis
PTCL diagnosis
Peripheral T-cell lymphomas not otherwise specfied (NOS)
▪ 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
Overall survival of PTCLs/NOS & AITL
Armitage J, JCO 2008
Morphology
Heterogeneous
University of BolognaT-zone type
PTCL/NOS: morphologic variants
GC
University of BolognaLympho-epithelioid (Lennert’s) type
1. Epigenetic mediators
Aberrant methylation/ acetylation
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
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
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
Gene expression signatures delineate biological and prognostic subgroups in peripheral T-cell lymphomas
Iqbal J et al , Blood 2014
Classification of PTCLs/NOS according to their cellular counterpart
Piccaluga & Iqbal, in preparation
Angioimmunoblastic T-cell lymphoma (AITL) and
TFH-related PTCLs
WHO 2017 Update
• Nodal TFH-related PTCLs
– Angioimmunoblastic T-cell lymphoma (AITL)
– Follicular T-cell lymphoma (FTCL)
– PTCL/NOS with TFH phenotype
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
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
University of Bologna
Clear cells
University of BolognaCD21
Prominent branching high endothelial venules
University of BolognaCD21
Follicular dendritic cell hyperplasia
AITL – Key morphological features
Clear cellsProminent, branching, high endothelium venules
FDC hyperplasia
University of Bologna
CD3 CD20
EBERCD4 CD8 GM
AITL might derive from T-zone lymphomas
Courtesy of Prof. P. Gaulard
WHO 2017 Update
• Nodal TFH-related PTCLs
– Angioimmunoblastic T-cell lymphoma (AITL)
– Follicular T-cell lymphoma (FTCL)
– PTCL/NOS with TFH phenotype
University of Bologna
University of Bologna
University of BolognaCD3
University of BolognaCD4
CD8
University of BolognaCD10 CXCL13
PD1
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
Anaplastic large cell lymphomas (ALCLs)
38
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
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
41
Undistinguishablemorphologically and
phenotypically
ALK+ ALK-
CD30 CD30
Perforin Perforin
ALCL patients’ survavial according to ALK status
42
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
CD30
CD45
EMA
Phenotype:CD30+
T/nullCD45+/-
BSAP-
EMA+/-
CD15-(+)
Cytotoxic markers+
EBV-
Perforin
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
New genetic findings in ALCL
New genetic findings in ALCL
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
Breast implant associated ALCL is distinct from other ALCLs and
presents STAT3 and TCR deregulation
49Di Napoli et al 2018
CD30/CD30L signaling
From CD30 detection to anti-CD30 treatment
1982 2000s 2010
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
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
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
THANKS YOU
Q/A
55
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