Molecular Diagnosis of Primary Mediastinal B Cell Lymphoma Identifies a Clinically Favorable Subgroup of Diffuse Large B Cell Lymphoma Related to Hodgkin Lymphoma

Abstract

Using current diagnostic criteria, primary mediastinal B cell lymphoma (PMBL) cannot be distinguished from other types of diffuse large B cell lymphoma (DLBCL) reliably. We used gene expression profiling to develop a more precise molecular diagnosis of PMBL. PMBL patients were considerably younger than other DLBCL patients, and their lymphomas frequently involved other thoracic structures but not extrathoracic sites typical of other DLBCLs. PMBL patients had a relatively favorable clinical outcome, with a 5-yr survival rate of 64% compared with 46% for other DLBCL patients. Gene expression profiling strongly supported a relationship between PMBL and Hodgkin lymphoma: over one third of the genes that were more highly expressed in PMBL than in other DLBCLs were also characteristically expressed in Hodgkin lymphoma cells. PDL2, which encodes a regulator of T cell activation, was the gene that best discriminated PMBL from other DLBCLs and was also highly expressed in Hodgkin lymphoma cells. The genomic loci for PDL2 and several neighboring genes were amplified in over half of the PMBLs and in Hodgkin lymphoma cell lines. The molecular diagnosis of PMBL should significantly aid in the development of therapies tailored to this clinically and pathogenetically distinctive subgroup of DLBCL.

AIDS and non-AIDS diffuse large B-cell lymphomas express different antigen profiles

“…13,14 Although additional subgroups within the germinal center diffuse large B-cell lymphomas based on the presence or absence of t(14;18)(q32;q21) have been defined, these did not predict survival. 15 Recently, an alternate approach, based on clustering of whole genome arrays has identified three new groups among diffuse large Bcell lymphomas: 'oxidative phosphorylation', 'B-cell receptor/proliferation', and 'host response', but these results were not associated with prognosis.…”

Mutations of the tumor suppressor gene SOCS-1 in classical Hodgkin lymphoma are frequent and associated with nuclear phospho-STAT5 accumulation

“…Despite clear differences in age distribution, sex predominance, lymphoma spread, histology, and immunophenotype of the neoplastic cells between PMBL and cHL, there is a growing list of common characteristic hallmarks like mediastinal (thymic) origin, loss of MHC class I presentation, lack of immunoglobulin expression despite successfully rearranged IgH genes, lack and/or functional Oct2 deficiency, and frequent gains of 2p13-p16 and 9p24 involving REL and JAK2, respectively (Joos et al, 1996Barth et al, 2003;Savage et al, 2003;Ritz et al, 2005). Furthermore, two extensive studies on gene expression profiling revealed substantial similarities between PMBL and cHL cell lines in terms of commonly up-or downregulated genes (Rosenwald et al, 2003;Savage et al, 2003).…”

Clinicopathologic implications of tissue inhibitor of metalloproteinase-1-positive diffuse large B-cell lymphoma

“…24 Although four subtypes of diffuse large B-cell lymphoma were classified by cDNA microarray, the unclassified group was found to be heterogeneous and behaved in a manner similar to the activated B-cell group and the primary mediastinal group was found to characteristically develop from the mediastinum and was associated with a favorable prognosis. 13,14 Therefore, we classified diffuse large B-cell lymphoma cases into two groups: germinal center B-cell or nongerminal center B-cell group. The tissue microarray classification predicts survival similar to the cDNA microarray analysis.…”

“…11 Recent cDNA microarray studies have shown that diffuse large B-cell lymphoma can be divided into four distinct subgroups including: germinal center B-cell-like, activated B-cell-like, primary mediastinal, and unclassified gene expression profiles. [12][13][14][15] The activated B-cell and unclassified groups have a significantly inferior clinical outcome compared to the germinal center B-cell and primary mediastinal groups. The unclassified group is heterogeneous and not well defined, but has a poor outcome similar to that of the activated B-cell group.…”

“…The unclassified group is heterogeneous and not well defined, but has a poor outcome similar to that of the activated B-cell group. [12][13][14][15] In addition, although the clinical significance of EBV infection in diffuse large B-cell lymphoma is controversial, about 10% of diffuse large B-cell lymphoma is known to be associated with EBV. 16,17 However, TIMP-1 expression in diffuse large B-cell lymphoma has not been investigated using a large scale of clinical samples or at the protein level.…”