Original contributionFrequent expression of multiple myeloma 1/interferon regulatory factor 4 in Burkitt lymphoma☆
Introduction
Burkitt lymphoma (BL) is a highly aggressive non-Hodgkin lymphoma with endemic, sporadic, and immunodeficiency-associated clinical variants composed of monomorphic medium-sized B cells with a high proliferation rate [1]. Morphologically, in addition to classic BL, there are 2 cytologic variants: BL with plasmacytoid differentiation and atypical BL (aBL), the latter showing greater pleomorphism in nuclear size and shape than the classic type. Immunophenotypically, all types are similar, expressing CD20, CD10, bcl-6, and membranous immunoglobulin (Ig) M but not IgD, bcl-2, or terminal deoxynucleotidyl transferase (TdT). The Ki-67 proliferation index is nearly 100%. Cytogenetically, all cases have a translocation involving the C-MYC gene at 8q24 with the immunoglobulin heavy chain (IGH) gene on 14q32, or less commonly, with the κ light chain locus (IGK) at 2q11 or the λ light chain locus (IGL) at 22q11 [2].
MUM1/IRF4, or multiple myeloma 1/interferon regulatory factor 4 protein, is a lymphocyte-specific member of the interferon regulatory factor family of transcription factors [3] and is encoded by the MUM1/IRF4 gene, which has been identified as a myeloma-associated oncogene activated at the transcriptional level as a result of t(6;14) (p25;q32) [4]. MUM1 is induced by antigen receptor-mediated stimuli and plays a crucial role in cell proliferation, differentiation, and survival [5]. Loss of MUM1 function results in the absence of activated lymphoid cells and Ig-secreting plasma cells. Tsuboi et al [6] demonstrated MUM1 expression in plasma cells and in a small fraction of B cells located in the light zone of germinal centers (GCs) corresponding to the final step of intra-GC B-cell differentiation, and in activated T cells. Therefore, MUM1 expression may denote the final step of intra-GC B-cell differentiation at the centrocyte stage, as well as subsequent steps of B-cell maturation toward plasma cells. Inside the GC, the centrocytes are the first cells to express MUM1, and this expression is maintained during post-GC maturation, in contrast to bcl-6 expression, which is observed immediately after the B cell enters the GC and is maintained only until GC exit. Thus, MUM1 is considered to be a histogenetic marker of the late-GC and post-GC B cell [7], [8], and the morphologic spectrum of positive cells ranges from that of a centrocyte to that of a plasmablast/plasma cell. In a polymerase chain reaction analysis of single MUM1-positive cells from GC, Falini et al [9] demonstrated that they contained rearranged immunoglobulin heavy chain genes with a varying number of VH somatic mutations, suggesting that MUM1 cells represent surviving centrocytes whose progeny is committed to exit the GC and to differentiate into plasma cells. Unlike most normal GC B cells, in which the expression of MUM1 and bcl-6 are mutually exclusive, the tumor cells in approximately 50% of MUM1-positive DLBCL show coexpression of bcl-6, suggesting that the expression of these proteins may be deregulated [9], [10]. One of the first well-characterized transcription factors found to be involved in regulating cell proliferation and growth was c-myc; its repression is required for normal plasma cell differentiation [11]. Deregulation of C-MYC prevents B-cell differentiation and it is an oncogenic hallmark in BL [12], [13].
Among neoplastic B-cell lymphoproliferations, MUM1 expression is observed in multiple myeloma and lymphoplasmacytic lymphoma, many cases of DLBCL (75%), some cases of chronic lymphocytic leukemia and marginal zone lymphomas, most cases of classic Hodgkin lymphoma, also in the setting of the acquired immunodeficiency syndrome, and in posttransplant lymphoproliferative disorders. In most reports, there are limited numbers of BL cases included, and all cases of BL are reported to be MUM1-negative [6], [9], [14], [15]. Carbone et al [16] studied 19 BL cases associated with HIV; 2 of these cases showed occasional MUM1-positive cells, less than their 20% cutoff for positivity. Among Burkitt cell lines, MUM1 expression has been observed in the Ramos but not in the Daudi line, both lines being bcl-6–positive [10]. Chuang et al [2] described MUM1 expression in 5 of 28 cases of BL, without specifying the criteria and cutoff for considering a case positive.
In the present study, we analyzed the expression pattern of MUM1, bcl-6, and CD138 (syndecan-1) along with the association of Epstein-Barr virus (EBV) in 222 well-characterized cases of BL.
Section snippets
Case material and clinical data
A total of 222 cases of BL, all showing C-MYC translocation by fluorescence in situ hybridization (FISH), were included in the present study. These cases were part of 595 cases with tentative diagnosis of BL obtained retrospectively from the files of Consultoria em Patologia, a large reference consultation service in anatomic pathology located in Botucatu, Sao Paulo State, Brazil, between June 1997 and December 2007. The study group cases (222 cases) had the diagnosis of BL confirmed by
Results
Of the 222 BL cases, 165 (74%) were male and 57 (26%) female. One hundred thirty-four cases (60%) were children 16 years or younger and 82 cases (37%) were adults. In 6 cases the age was unknown. The median age was 19 years (range, 1-81 years). Extranodal BLs were 69% of the cases (148 cases), primary lymph node involvement was observed in 31% of the cases (66 cases), and in 8 cases it was not possible to determine nodal versus extranodal presentation. In the pediatric population, primary
Discussion
Our BL cases showed a male and pediatric predominance, a high frequency of extranodal presentation, with lymph node involvement more common among adults than among children, in concordance with the literature [1], [18], [19], [20].
From a morphologic point of view, most of the cases were classic BL (91%), with the 2 variants, plasmacytoid and atypical, found in 3% and 6% of cases, respectively [18]. BL is a B-cell lymphoma that shows clonally rearranged immunoglobulin genes and carries a high
Acknowledgments
We acknowledge the outstanding service of Consultoria em Patologia staff for skillful technical assistance.
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This study was partially supported by NCI 5R01CA121935 (W.H.), 5R01CA112217 (W.H.), and the (NCI) AIDS Malignancy Consortium (5U01CA121947).