Diffuse large B cell lymphoma: using pathologic and molecular biomarkers to define subgroups for novel therapy

Diffuse large B cell lymphoma (DLBCL) comprises specific subtypes, disease entities, and other not otherwise specified (NOS) lymphomas. This review will focus on DLBCL NOS because of their prevalence and their heterogeneity with respect to morphology, clinical presentation, biology, and response to treatment. Gene expression profiling of DLBCL NOS has identified molecular subgroups that correlate with prognosis and may have relevance for treatment based on signaling pathways. New technologies have revealed that the "activated B cell" subgroup is linked to activation of the nuclear factor kB (NF-kB) pathway, with mutations found in CD79A/B, CARD11, and MYD88, and loss of function mutations in TNFAIP3. The "germinal center B cell-like" subgroup is linked to mutational changes in EZH2 and CREBBP. Biomarkers that are related to pathways promoting tumor cell growth and survival in DLBCL have been recognized, although their predictive role requires clinical validation. Immunohistochemistry for detecting the expression of these biomarkers is a practical technique that could provide a rational for clinical trial design.