1. Principles of pathology and microscopic. The paradigm of diffuse large B cell lymphoma Luca Mazzucchelli Istituto cantonale di patologia, Locarno ESO Course, Leukaemia and Lymphoma, Ascona, June 12-14, 2011

2. Lymphoma subtype frequencies Histopathology 2011, 58:4-14 DLBCL

8. Diffuse large B-cell lymphoma A Alizadeh AA et al.: Distinct type of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 2000, 403:503

9. Decision tree for classification of DLBCL based on immunohistochemistry CD10 MUM1 bcl6 GCB GCB Non-GCB Non-GCB + + + - - - Hans et al. Blood 2004

11. Gene expression-based distinction of DLBCL in subgroups Gene expression-based distinction between GCB and ABC DLBCL carried a prognostic impact in the CHOP and R-CHOP treatment era Lenz G et al. N Engl J Med 2008; 359:2313

12. Clin Cancer Res 2009; 15:5494 Concordance rate with GEP of 93% versus 86%

13. CHOP R-CHOP GEP New Algorithm Overall Srvival Overall Srvival Clin Cancer Res 2009; 15:5494

14. Immunoblastic morphology but not the immunohistochemical GCB/non-GCB classifier predicts outcome in diffuse large B-cell lymphoma in the RICOVER-60 trial of the DSHNHL. G Ott et al. Blood 2010, prepublished online August 24 Extension of the study published in Heamatologica 2009; 15:5494 Immunoblastic lymphoma Immunoblastic lymphoma with plasmablastic features

15. G Ott et al. Blood 2010, prepublished online August 24

16. G Ott et al. Blood 2010, prepublished online August 24

21. J Clin Oncol 2010; 28:3360 Univariate Kaplan-Maier analysis of overall survival in the MYC-R versus non rearranged patients

25. Aukema SM et al Blood feb. 2011, 117:2319-2331

27. Timing and synergy of translocation in DH lymphomas Follicular Lymphoma Mantle cell lymphoma BCL2+/MYC+ DH Lymphoma CCND1/MYC+ DH Lymphoma

29. Aukema SM et al Blood feb. 2011, 117:2319-2331

31. DLBCL BL Burkit-like lymphoma Atypical Burkitt lymphoma Gray-zone lymphoma B-cell lymphoma unclassifiable Borderline lymphoma Intermediate between DLBCL and BL (WHO 2008) This is a heterogeneous category that is not considered a distinct disease entity, but is useful in allowing the classification of cases not meeting criteria for classical BL or DLBCL

32. Adv Anat Pathol 2011, 18:219-228 Lymphoma MYC Rearrangement BL Present in >90% of cases; Primary genetic event. Translocations involve Ig partner genes only: 85% t(8;14), 15% t(2;8) or t(8;22). Not associated with “double hit” lymphoma DLBCL Present in 7-14% of de novo cases. Usually a secondary genetic event. Translocations involve IG (70%) and non-IG (30%) partner genes. Associated with “double hit” lymphoma BCLU Present in 35-50% of cases. Translocations rarely involve IGH as a partner gene. Translocations involve IGk , IG  or non-IG partner genes. Associated with “double hit” lymphoma PBL Present in approximately 50% of cases. Translocations involve IG partner genes in the majority of cases, usually IGH . Not associated with “double hit” lymphoma

33. Proposed algorithm for highly aggressive lymphomas Cogliatti S et al. Br J Heamatol 2006; 134:294 (modified) Burkitt lymphoma MYC+ DLBCL Intermediate lymphoma Intermediate lymphoma

35. Thank you