ALCL was firstly described by Stein et al. (Blood, 66:848-58) in 1985.

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2 ALCL was firstly described by Stein et al. (Blood, 66:848-58) in The tumour previously often misdiagnosed as malignant histiocytosis or metastatic involvement by occult carcinoma was characterised by distinctive morphology, cohesive growth pattern, frequent intra-sinusoidal diffusion, and regular expression of the lymphoid activation molecule Ki-1/CD30 1/CD30. At that time, no distinction was made among anaplastic large cell lymphoid tumours carrying T, null or B-cell B phenotype.

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4 Thanks to two Intercontinental Workshops held in Berlin in 1987 and 1988 ALCL primary: systemic: common (CT) giant-cell rich (GCR) lympho-histiocytic histiocytic (LH) small cells (SC) Hodgkin-related (HR) of the skin ALCL secondary: after HL, PTCL, etc.

5 CT GCR LH LH-CD30 Sheet of tumoural cells

6 HR HR SC

7 Further histological variants: signet-ring cell 1, sarcomatoid 2-3, eosinophil-rich 4, epithelioid cell-rich 5. CD30 ALK c References: 1) Falini et al, Histopathol, 1997; 2) Bueso-Ramos et al, Mod Pathol, 1994; 3) Pereira et al, Arch Pathol Lab Med 2002; 4) McCluggage et al, Histopathol, 1998; 5) Piccaluga et al, Haematologica, 2000.

8 t(2;5) (p23;q35) It is characteristic of most ALCLs (T-cell) 1. It causes the fusion of the ALCL kinase (ALK) and nucleophosmin (NPM) genes, by producing the hybrid gene NPM/ALK 2, which encodes for a chimeric 80 kd protein (NPM/ALK or p80) 3,4. ALK protein over-expression expression is thought to play a role in the lymphomagenesis process 5,6. References: 1) Mason et al, Br J Haematol, 1990; 2) Morris et al, Science, 1994; 3) Fujimoto et al, PNAS, 1996; 4) Ladany,, Cancer Surveys, 1997; 5) Bischof et al, Mol Cell Biol, 1997; 6) Chiarle et al, 2003.

9 REAL Classification (Harris NL et al, Blood, 1994): DLBCL, anaplastic variant; ALCL T/null (CT, LH, SC, GCR) (primary systemic, cutaneous) = accepted entity; ALCL Hodgkin s-like (ex-hr) = provisional entity.

10 WHO Blue Book (2001): DLBCL, anaplastic variant; ALCL, T/null (about 3% of all lymphomas), primary, systemic; CD30 + lymphoid proliferations of the skin: a. lymphomatoid papulosis A and B; b. Lymphomatoid papulasis C; c. primary CD30 + ALCL of the skin.

11 ALCL HL CHL Not specifically recognised because of the lack of conclusive data.

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13 Translocations and fusion proteins involving the ALK gene in ALCL Translocation Frequency Localization t(2;5)( p23 ;q35 ) t(1;2)( q25 ;p23 ) 70-80% Cytoplasmic/Nuclear nucleolar 10-20% Cytoplasmic t(2;3)( p23 ;q21 ) 2-5% 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 ;q )? - or inv (2)( p23 ;q )? - Nuclear membrane t(x;2)( q ;p23) - Membranous

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15 Cutaneous presentation of ALK-positive anaplastic large cell lymphoma following insect bites: evidence for an association in 5 cases. L Lamant,, S Pileri, E Sabattini, L Brugières res,, ES Jaffe and G Delsol Haematologica 2010, 95:

16 AP-1 ALK + ALCL

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18 Nature Medicine 2005, 11: Nature Medicine 2008, 16: Nature Reviews, in press Anaplastic Lymphoma Kinase (ALK) in cancer pathogenesis. Antonella Barreca 1, Elena Lasorsa 1, Ludovica Riera 1, Rodolfo Machiorlatti 1, Roberto Piva 1,2, Maurilio Punzoni 3, Ivo Kwee 4, Francesco Bertoni 4, Pier Paolo Piccaluga 5, Stefano A. Pileri 5, Giorgio Inghirami 1,2 & the European T-Cell Lymphoma Study Group.

19 % ALCL: Overall survival 100 ALK ALK months

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21 Morphologic spectrum of ALK + ALCL Inflammatory cells ALK + hallmark cells Benharroch D et al. Blood 1998 ALK + small cells (reservoir?) Inflammatory cells ALCL - CT - mixed - HL (perivascular) - SCV - LH

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23 CT SCV CD30 ALK C ALK C Onset Relapse

24 CD30 EMA Perforin Phenotype: CD30 + T/null CD45 +/- EMA +/- CD15 -(+) Cytotoxic markers + EBV - CD45

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26 (Provisional entity)

27 ALK + T/null ALCL ALK - T/null ALCL PTCL/NOS

28 ALK + ALK - CD30 Undistinguishable morphologically and phenotypically CD30 Perforin Perforin

29 CD68

30 Histological variants do exist but the small cell one! CD30 ALK c

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32 JCO, 2010; 28:

33 ALK - ALCL Blood, E-pub ahead of print Abstract submitted to ASH Meeting Gene expression signatures that delineate biologic and prognostic subgroups in peripheral T-cell T lymphoma J Iqbal,, G Wright, A Rosenwald,, RD Gascoyne, DD Weisenburger,, C Wang, TC Greiner, P Gaulard,, PP Piccaluga, SA Pileri, L Smith, LM Rimsza,, E Jaffe, E Campo, J Delabie,, RM Braziel,, JR Cook, RR Tubbs, WY Au, S Nakamura, M Seto,, F Berger, J Armitage,, J Vose7, L. Staudt,, and WC Chan for LLMPP and IPTC)

34 ALK - ALCL 8 different genetic lesions detected by RNAseq (2 already reported by the Rochester Group, although at different t rates)

35 ALK - ALCL

36 ALK - ALCL

37 ALK - ALCL

38 ALK - ALCL Wednesday, October 24 th, Key Note Lecture: New genetic findings in T-cell T lymphomas. Andrew Feldman

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41 CD45 ALK + T/null ALCL ALK - T/null ALCL CD15 DLBCL EMA CHL TCRBCL LPHL Cytotoxic markers PAX5/BSAP EBV PCR

42 Innovative therapies Rapamycin - mtor inhibition - mir101 counteraction.

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44 ALK + ALCL

45 TCL subtype cases included in TMA PDGFRα p-pdgfrα PDGF-A PDGF-B PTCL/NOS / /110 74/86 85/92 AITL 45 36/36 21/22 20/23 23/24 ALCL ALK /16 10/12 13/13 9/12 ALCL ALK /10 8/10 6/6 7/9 MF 28 28/28 28/28 5/5 7/8 EATL 5 5/5 ne 3/3 2/2 SPTCL 1 1/1 ne ne 0/1 TCL subtype PDGFRβ PTCL/NOS 4*/38 AITL 0/15 ALCL ALK + 9/9 ALCL AlLK - 15/20

46 ALK + ALCL AP-1 PDGFRβ

47 Conditional deletion of JunB and cjun in transgenic mice in which the human NPM/ALK was put under the control of the murine CD4 promoter Lymphoma development

48 ALK + ALCL

49 ALK + ALCL

50 ALK + ALCL

51 ALK + ALCL Patient suffering from NPM-ALK+, JunB+, cjun+, PDGFRA+, PDGFRB+, c-kitc Kit- ALCL refractory to conventional first line chemotherapy and relapsed after autologous stem cell transplantation. Complete clinical remission with reduced tumor markers and normalized PDGFB levels within days of imatinib therapy. Patient free of ALCL since 24 months after initiation of imatinib.

52 PP Piccaluga, E Sabattini, F Bacci, C Agostinelli, C Sagramoso, F Fuligni,, M Rossi, S Righi, A Gazzola,, T Sista, M Piccioli, MR Sapienza, C Mannu,, F Fuligni,, F Sandri,, P Artioli,, G De Biase,, G Da Pozzo, C Tigrini,, M Monari and D Bignami