Overall the morphologic, in conjunction with the immunohistochemical, flow cytometry and genetic studies, are consistent with a diffuse large B-cell lymphoma (DLBCL).
DLBCL is clinically and genetically heterogeneous. Its pathogenesis represents a multistep process that involves accumulation of multiple genetic and molecular abnormalities, including distinct chromosomal translocations, which lead to the selection of a malignant clone. The presence of BCL2 gene rearrangement, as was seen in this case, is consistent with transformation from follicular lymphoma. The most common, t(14; 18)(q32;q21), is present in 20-30% of the cases places the BCL2 gene on18q21 in close proximity to the IGH gene on 14q32 leading to a constitutive expression of the BCL2 protein, an integral outer mitochondrial membrane protein that blocks the apoptotic death of lymphocytes. The translocations likely arise from abnormal recombination occurring during variable diversity joining (VDJ) and class switch recombination and somatic hypermutation of the Ig genes.
Although not observed in this case, chromosomal translocations of 3q27, the locus of the BCL6 gene, are the most characteristic and common genetic abnormalities detected in 30% to 40% of DLBCL tumors. The partners of the BCL6 chromosomal translocations most often involve the Ig genes on chromosome bands 14q32, 2p12 and 22q11. BCL6 gene expression is tightly regulated during B-cell differentiation, being restricted to B cells in the germinal center. The role of BCL6 in the pathogenesis of DLBCL has only recently been elucidated. BCL6 represses the expression of PRDM1, whose product is necessary for plasma cell differentiation, and the expression of factors which control the cell cycle, apoptosis, DNA repair and maintenance of genomic stability. In addition, BCL6 downregulates TP53 allowing DLBCL cells to escape apoptosis in response to DNA damage and thus allowing continued tumor cell growth.
MYC gene rearrangements, the hallmark aberration in Burkitt lymphoma, are uncommon in DLBCL. This case had t(8; 22) a rearrangement that brings the MYC gene located on the q24 band of chromosome 8 under the regulation of the immunoglobulin lambda light chain. MYC is a protooncogene that encodes a protein capable of activating the cell cycle machinery and its safeguards via mechanisms that include the activation and maintenance of glycolysis. In DLBCLThe combination of MYC and BCL2 rearrangements is unusual, but has been reported to be associated with very poor prognosis. Another gene mutation/deletions associated with a more aggressive clinical course involves TP53 and is reported in up to 20% of DLBCL most of which are in tumors without BCL6 translocations.
ACKNOWLEDEMENTS: The authors would like to acknowledge the input of Sathanoori, Malini.
Contributed by Kudakwashe Chikwava, MD and Urvashi Surti, PhD