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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

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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

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

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