Abstract

Since diffuse large B-cell lymphomas (DLBCL) are biologically and clinically heterogeneous, various attempts have been made to distinguish subtypes of DLBCL. Using gene expression profiling two main subtypes have previously been identified, i.e germinal center B-cell like (GCB) with a favorable prognosis and non-GCB-cell like DLBCL with an unfavorable outcome (

Alizadeh et al.
Nature
403
,
503
–511,
2000
). Applying immunohistochemical analysis, using antibodies directed against CD10, BCL-6 and MUM1, the same investigators were capable of identifying the same subclasses of favorable (GCB) and non-favorable (Non-GCB) DLBCL phenotypes (
Hans et al.
Blood
103
,
275
–282,
2004
). To investigate the applicability of these three markers in de novo DLBCL patients at an age of 65 years or older with advanced stage disease, a cohort of 138 cases was studied. All patients were included in a multicenter clinical trial setting and received uniform treatment. Using the markers CD10, BCL-6 and MUM1, we assigned 40 cases (29%) into the GCB (CD10+ and/or BCL6+, MUM1) and 98 cases (71%) into the non-GCB-like (CD10, BCL6+, Mum1+ or CD10, BCL6, MUM1+) DLBCL group. In contrast to previous reports, no clinical significance was observed between the two subtypes (overall survival (OS), event-free survival (EFS), progression-free survival (PFS) and disease-free survival (DFS) P-values >0.2), indicating that the prognostic significance of this classification was not evident in this cohort of elderly patients. We previously identified a novel combination of markers that could discriminate between GCB and non-GCB in normal lymphoid tissue, i.e. CB2 and the activation protein CD40. B-cells present in the germinal center (GC) of healthy individuals appeared highly positive for both CD40 and CB2, a previously identified proto-oncogene that encodes for the peripheral cannabinoid receptor. Non-GCB-lymphocytes were mainly CB2 and CD40 negative or weakly positive. We used these two markers for immunohistochemical analyses in the same cohort of novo DLBCL. Single expression of CB2 (PFS (P<0.04) and DFS (P=0.02)) and CD40 (P<0.04) was associated with a favorable clinical outcome. A combined immunophenotypic profile of N-CB2 and CD40 resulted in improved outcome prediction (PFS, P=0.02). Moreover, our data show that CB2 and CD40 are novel markers that recognize DLBCL with a particular GC-like phenotype and have impact on the clinical outcome in a cohort of elderly DLBCL patients. We suggest that CB2 and CD40 may serve as novel markers in DLBCL outcome prediction.

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