IX. Is it only about MYC? How to approach the diagnosis of diffuse large B-cell lymphomas.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL), representing around 30% to 40% of all newly diagnosed lymphomas [1]. DLBCL is clinically, morphologically and biologically a heterogeneous disease reflected in the highly variable clinical course. The 2008 World Health Organization (WHO) classification of lymphoid malignancies recognizes within the group of DLBCL, not otherwise specified (NOS) several subtypes characterized by unique clinical and pathological features including primary DLBCL of the central nervous system (CNS), primary cutaneous DLBCL, leg type, T-cell histiocyte-rich large cell lymphoma and EBV positive DLBCL of the elderly (Table 1). Nevertheless, most cases of DLBCL fall into the ‘NOS’ category. In the last 15 years our understanding of the genetic changes and biology of DLBCL has increased tremendously [2]. Gene expression profiling (GEP) studies have revealed that DLBCL comprises several molecular subgroups that reflect either the stage in B cell development from which the disease originates or the activity of different biological programs [3,4]. The standard initial treatment for DLBCL is combined immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) [5]. While durable remissions can be achieved in the majority of cases with this combined regimen, over 30% of patients will not respond or will relapse with resistant disease. A possible explanation for such differences in therapeutic success is the considerable biological heterogeneity of DLBCL. Therefore, there is an ongoing effort to tailor therapy based on specific subtypes of DLBCL, and to identify prognostic markers like BCL2 and MYC. The diagnosis of DLBCL needs to integrate, in addition to classic morphology and immunophenotype, all the new genetic and molecular diagnostic tools. This report attempts to review