PTCL: morphology and pathobiology Anaplastic large cell lymphoma
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1 PTCL: morphology and pathobiology Anaplastic large cell lymphoma Stefano A. Pileri Director Haematopathology European Institute of Oncology - Milan Alma Mater Professor of Pathology Bologna University
2 Systemic!
3 Anaplastic large cell lymphoma ALK-positive ALK-negative CD45+/- EMA +/- TCM -/+ CD43 + CM + PAX5 (*) TCR/R CD30 hallmark cells Indistinguishable morphologically and phenotypically CD45 CD30 Benharroch EMA D et al. Blood 1998 Perforin Perforin (*) Feldman et a., Mod Pathol 2010, 23:
4 Inflammatory cells Inflammatory cells Morphologic spectrum of ALK + ALCL ALK + hallmark cells Benharroch D et al. Blood 1998 ALK + small cells (reservoir?) ALCL - CT - mixed - SCV - HL (perivascular) - LH
5 Translocations and fusion proteins involving the ALK gene in ALK+ ALCL Anaplastic large-cell lymphoma. Inghirami G and Pileri SA. Sem Diagn Pathol 2011; 28:
6 Translocations and fusion proteins involving the ALK gene in ALK+ ALCL The oncogenic role of ALK fusion proteins Translocations involving ALK produce fusion proteins with constitutive tyrosine kinase activity in most cases deriving from spontaneous dimerization induced by the different fusion partners Transforming ability in vitro Tumorigenic role in transgenic mouse models Engagement of intracellular pathways ALK, anaplastic lymphoma kinase. Chiarle R, et al. Nat Rev Cancer 2008;8:11 23.
7 ALK + ALCL AP-1 PDGFR
8
9 ALCL: ALK-positive and ALK-negative status ALK-positive: most frequent in the first three decades of life 1 Overall survival of systemic ALK according to ALK status 2 % ALCL: overall survival ALK-positive ALK-negative months
10 Influence on neoplastic cells and microenvironment
11 ALCL: ALK-negative (provisional entity) ALK-positive T/null ALCL 1,2 ALK-negative T/null ALCL 1,2 PTCL/NOS 1 1. Mason D, et al. In: Swerdlow SH, et al. World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissues, Fourth edition. Lyon, France: IARC Press; 2008, pp. 317; 2. Jaobsen E, The Oncologist 2006, 11:
12
13 de Leval L and Gaulard P. Haematologica 2013; 95:
14
15 JCI, 117:823-34, 2007 JCO, 2010; 28: Blood, 2012;120:
16
17
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19 Training set Test set FFPE GEP effective in discriminating PTCL subtypes Enriched Biological Processes according to Gene Ontology AITL PTCL/NOS membrane lipid metabolism cell cycle DNA metabolism DNA replication S phase of mitotic cell cycle RNA metabolism RNA processing cell sphingolipid proliferation metabolism regulation of cell cycle sodium ion transport DNA replication and chromosome cycle DNA recombination nucleobase\, nucleoside\, nucleotide and nucleic acid metabolism mitotic cell cycle protein kinase cascade membrane lipid metabolism cell cycle DNA metabolism DNA replication S phase of mitotic cell cycle RNA metabolism RNA processing cell proliferation sphingolipid metabolism regulation of cell cycle sodium ion transport DNA replication and chromosome cycle DNA recombination nucleobase\, nucleoside\, nucleotide and nucleic acid metabolism mitotic cell cycle protein kinase cascade Cell cycle, RNA metabolism, kinase cascade. DNA metabolism DNA replication S phase of mitotic cell cycle cell cycle sodium ion transport protein kinase cascade cell proliferation membrane lipid metabolism DNA replication and chromosome cycle RNA metabolism ALCL/ALK- PTCL/NOS DNA metabolism DNA replication S phase of mitotic cell cycle cell cycle sodium ion transport protein kinase cascade cell proliferation membrane lipid metabolism DNA replication and chromosome cycle RNA metabolism Discriminant analysis PTCL/NOS vs. AITL PTCL/NOS vs. ALK - /ALCL 38 genes 53 genes
20 CD30-positive PTCL/NOS cases were classified as PTCL/NOS No ALCL morphology; CD30 >75% CD30-positive PTCL/NOS cases No criteria for ALKnegative ALCL diagnosis 16 cases Molecular classifier 16/16 PTCL/NOS
21 ALK- ALCL vs. CD30+ PTCL/NOS P=0.62 P=0.011 P=0.02 Conventional Histopathology Molecular Classifier Molecular Classifier
22
23
24
25
26 DUSP22-IRF4 locus
27
28 17p13 (TP53) 6q21 (PRDM1)*
29 Gains of 9p24.1 (JAK) and 13q31.3 (MIR17HG)
30
31
32 Clinical Advisory Committee Meeting WHO Classification Update Chicago March 31 April 1, 2014
33 In the updated WHO Classification ALK - ALCL Distinct entity!
34
35 Thank you very much for your attention!
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