What is the pathophysiology of diffuse large B-cell lymphoma (DLBCL)?

Updated: Aug 20, 2020
  • Author: Shipra Gandhi, MBBS; Chief Editor: Emmanuel C Besa, MD  more...
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Answer

B-cell lymphomas arise at various stages of B-cell development. Under normal circumstances, a pro-B cell undergoes various stages of maturation that include the following:

  1. The recombination of the V, D, and J gene segments necessary for assembling of the immunoglobulins’ heavy and light chains
  2. Somatic hypermutation
  3. Immunoglobulin-class switching

During the process of V(D)J recombination (regulated by the recombination activating genes 1 [RAG1] and 2 [RAG2] enzymes) and somatic hypermutation/immunoglobulin-class switching (regulated by the activation-induced cytidine deaminase [AID] enzyme) phases, multiple DNA alterations occur and normal B cells are susceptible to the development of undesirable chromosomal translocations or gene mutations, leading to  the selective growth advantage of a malignant clone and the development of B-cell lymphoma. [6]

The type of mutation(s) and the stage of lymphoid maturation at the time of genetic aberration(s) play a role in the type of lymphoma that may develop in a given patient. [7]  Subtypes of diffuse large B-cell lymphoma (DLBCL) arise from genetic alterations occurring during the process of B-cell differentiation/maturation and, in general, are characterized by a blockage of the programmed cell death process (ie, up-regulation of Bcl-2, loss of Bcl-6 function, p53 deletion/mutation), an increase in cell proliferation (eg. increase in nuclear factor kappa B [NFkB], up-regulation of c-Myc), or impaired terminal differentiation (ie, defective Blimp-1 function). Specific genetic alteration(s) or protein expression/function deregulation varies depending on the subtype of DLBCL.

Several oncogenic pathways have been identified in DLBCL (B-cell receptor [BCR] signaling pathway, constitutive activation of NFkB activity pathways, and deregulation of the Bcl-6/apoptosis pathway); however, only one pathway appears to play a pivotal role in the biology of distinct types of DLBCL (ie, germinal center B-cell [GCB] versus activated B-cell [ABC] DLBCL). [6]

On DNA microarray studies, most DLBCLs exhibit gene expression patterns indicative of either of two different stages of B-cell differentiation, which allows classification by cell of origin. [8]  GCB DLBCL expresses genes characteristic of germinal center B-cells, while ABC DLBCL expresses genes normally induced during in vitro activation of peripheral blood B-cells. [9]  A third heterogeneous subtype of DLBCL does not express genes characteristic of either ABC- or GCB-type cells and is labeled unclassifiable.

GCB DLBCL is associated with recurrent gene translocations involving BCL-2 and C-REL amplification, whereas the ABC subtype has frequent amplifications of the oncogene SPIB, recurrent trisomy for chromosome 3, and activation of the antiapoptotic nuclear factor (NF)-κB signaling pathway. [8]


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