Diffuse Large B-Cell Lymphoma (DLBCL): Still a pandora’s box?

Abstract

DLBCL is the most common lymphoid malignancy worldwide. It includes tumors that cannot be morphologically classified (NOS) and clinic-pathologic variants characterized by specific features (e.g., age, primary site, immunodeficiency, and/or relationship with infectious agents). Nowadays, the cell of origin and complex cytogenetic alterations deserve great attention by affecting the disease behavior and therapeutic decisions. Gene expression profiling (GEP) studies have subdivided DLBCL/NOS into two main categories, related to germinal center and activated blood B-lymphocytes. The former has a more favorable course also in thepresent immunochemotherapy era. The attempts to surrogate GEP by immunohistochemistry ensued in algorithms, none of which as effective as GEP. More recently, an approach based on 15 genes and Nanostring technology has revealed excellent accuracy, inter-lab reproducibility and affordable costs. Equally important is the search for double/triple hits involving BCL2, MYC and BCL6, which can be detected by FISH and confer protection against apoptosis and high proliferative activity. The search for the corresponding proteins does not represent an absolute surrogate of cytogenetics. However, BCL2/MYC double expression heralds a poor prognosis. Further relevant parameters are CD30 expression and EBV infection. Finally, next generation sequencing has highlighted a series of mutations that might represent the rationale for innovative-targeted therapies.