MYC nei Linfomi B Diffusi a Grandi Cellule

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1 Padova, 9 novembre 2012 MYC nei Linfomi B Diffusi a Grandi Cellule Analisi FISH e immunoistochimica Fabio Facchetti Anatomia Patologica Spedali Civili-Università Brescia

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3 Kramer, Blood 1998 Macpherson, JCOl 1999 Kawasaki, Leuk&Lymph 2001 Nakamura, Mod Pathol 2002 AU, Leukemia 2004 Kusumoto, AJSP 2004 Haralambieva, AJSP 2005 Kanungo, Mod Pathol 2006 McClure, AJSP 2005 Bertrand, Leukemia 2007 Le Gouill, Haematologica 2007 Salaverria, Haematologica 2008 Yoon, Histopathology 2008 Klapper, Leukemia 2008 Mead, Blood 2008 Copie-Bergman, JCO 2009 Niitsu, Leukemia 2009 Tomita, Haematologica 2009 Stasik, Haematologica 2009 Johnson, Blood 2009 Shustik, Haematologica 2010 Snuderl, Am J Surg Pathol 2010 Cuccuini, Blood 2012 Shaoying, Mod Pathol 2012 Studies on MYC, BCL2 and BCL6 genetic anomalies in DLBCL The occurrence of any anomaly, but especially translocations of MYC, especially MYC+BCL2 (double hit) pinpoints high risk DLBCL Common DLBCL High risk DLBCL IPI as prognosticator No favorable prognostic factors Effective treatment: R-CHOP or high doses CT if high IPI Cure: ~50% No effective therapy (variety of regimens) Cure: very unlikely Median OS: years

4 Review of 303 patients with de novo DLBCL, treated with R-CHOP MYC-r: 35 (14%) (74% double-hit MYC+BCL2) Survival at 2 yrs: 35% vs. 61%

5 Klapper, Leukemia 2008 OS EFS Niitsu, Leukemia 2009

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7 Casistiche non selezionate di DLBCL con n casi >100 Tecnica prevalentemente utilizzata: FISH Single Hit Double Hit SH/DH/TH Myc+ Ref. totale casi Klapper, 2008 Yoon, 2008 Savage, 2009 Niitsu, 2009 Obermann, Barrans, 2010 Pedersen, 2010 Akyurek, 2011 Cuccuini, 2012 TOTALE % ,40 5,04 Myc+ BCL2+ BCL ,52 24,53 Triple Hit BCL2+ Myc+ BCL6+ Myc+ BCL2+ BCL6+ Myc ,51 1,08 1,62 1 0,6 1 0, % 8.3% Brescia % ,3 7 4, , ,9 4 2,5

8 Caratteri prevalenti dei DLBCL con anomalie di MYC ± BCL2 Cliniche Età media: anni (rarissimi in < 18 anni) Pregresso LNH low-grade: raro Frequenti: LDH++, stadio avanzato, sedi extranodali (BM, SNC, pleura) IPI prevalente: 3-4/5 Morfologiche DLBCL-NOS BCL-Unclass-Interm-DLBCL-BL BL-like Casistica Brescia (Myc+) n DLBCL, nos BCL-Unclass-Interm-DLBCL-BL BL-like 9 3 1

9 Caratteri prevalenti dei DLBCL con anomalie di MYC ± BCL2 Cliniche Morfologiche DLBCL-NOS BCL-Unclass-Interm-DLBCL-BL BL-like Fenotipiche CD10+: 88% BCL6+: 75% MUM1/IRF4+: 17% Molecolari Età media: anni (rarissimi in < 18 anni) Pregresso LNH low-grade: raro Frequenti: LDH++, stadio avanzato, sedi extranodali (BM, SNC, pleura) IPI prevalente: 3-4/5 Different from classical BL and DLBCL Hummel, NEJM 2006 Dave, NEJM 2006

10 BCL2 MYC MIB1

11 BCL2 MIB1 Myc BC2

12 BCL2 MYC MIB1 BCL2

13 GC MYC BL (# ) Rb-Mab Y69 (Epitomics) Mantle

14 F, 37 DLBCL # FISH: BCL2- Myc- BCL6- F, 54 DLBCL # FISH: BCL2+ Myc- BCL6- MYC protein expression in FFPE tissue 15/77 high MYC protein (nuclear staining in >50% tumor cells) 11 MYC+/IIC and MYC+/FISH 4 MYC+/IIC and MYC-/FISH All MYC+/IIC had poor outcome similar to MYC+/FISH (R-CHOP) MYC+/IIC confirmed increased MYC transcriptional activity by gene-set enrichment analysis (regardless of underlying MYC translocation status) M, 68 DLBCL # FISH: BCL2+ Myc+ BCL6-

15 Myc+: > 30% pos.

16 Myc+: 40% pos. Bcl2+: 50% pos. Myc+: 40% pos. Bcl2+: 70% pos.

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19 1. The poor outcome in DLBCL observed with MYC+/IIC is largely the result of double-hit biology, and it is the concurrent expression of BCL2 and cmyc that is important for outcome 2. DH-IIC is significantly more frequent than DH-FISH: 20%-30% of DLBCL 3. DH MYCIIC/BCL2IIC is present in both GCB and ABC DLBCL (defined with IIC or GEP), suggesting heterogeneous molecular pathways may be responsible for MYC deregulation 4. Double-hit lymphomas determined by IIC occur among the elderly in the majority of cases (median age: 67 and 69 years)

20 MYC+ e/o Double hit (MIC+BCL2+) hanno scarsa/nulla risposta a R-CHOP Scarsa predittività dei caratteri clinici, fenotipici e istologici per MYC+ e DH Possible utilità della valutazione immunoistochimica della proteina MYC associata a BCL2, con alta correlazione con traslocazione, superiore sensibilità nell individuare DH-biologia e simile predittività pognostica PROPOSTA 1.Revisione IIC (MYC e BCL2) di casistica retrospettiva consecutiva (Commissione Clinica Linfomi Aggressivi e Commissione Patologi) 2.Validazione FISH (Commissione Patologi) 3.Correlazione outcome clinico e risultati IIC e FISH