Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma type worldwide, but the treatment still remains challenging because only 60–70% of the patients can be cured with the standard immunochemotherapy (rituximab, cyclophosphamide-doxorubicin-vincristine-prednisone) scheme. In the last twenty years, several molecular-genetic studies showed that DLBCL comprises at least two distinct molecular subtypes: the activated B-cell-like and the germinal centre B-cell-like subtype. The two groups have different genetic mutation landscapes and outcomes following treatment, with the ABC subtype having the worst prognosis. Gene expression profiling seems to be the gold standard method to subdivide DLBCL into ABC and GCB subtypes, but it is difficult to include this technology in clinical practice because it relies on fresh frozen tissue and microarray technology. To facilitate the DLBCL classification in daily clinical practice, other technologies have been developed allowing analysis of formalin-fixed paraffine embedded tissue biopsies. The unique genetic and epigenetic features of both DLBCL subtypes make targeted therapy a promising approach in the future.

(BELG J HEMATOL 2018;9(6):206–13)