Immunohistochemical Expression Patterns of Germinal Center and Activation B-cell Markers Correlate With Prognosis in Diffuse Large B-cell Lymphoma

Abstract

Recent studies with cDNA microarrays showed that diffuse large B-cell lymphoma (DLBCL) cases with gene expression profiles similar to germinal center (GC) B cells had much better prognosis than DLBCL cases with gene expression profiles resembling activated B cells. The goal of the current study is to evaluate if using a panel of GC B-cell (CD10 and Bcl-6) and activation (MUM1/IRF4 and CD138) markers by immunohistochemistry defines prognosis in patients with de novo DLBCL. Immunohistochemical stains for the above markers were performed on paraffin-embedded tissues from 42 de novo DLBCL patients. Median follow-up in all patients was 41 months (range, 1-103 months) and in surviving patients was 65 months (range, 14-103 months). These cases could be classified into three expression patterns: GC B-cell pattern (pattern A) expressing CD10 and/or Bcl-6 but not activation markers; activated GC B-cell pattern (pattern B) expressing at least one of GC B-cell markers and one of activation markers; and activated non-GC B-cell pattern (pattern C) expressing MUM1/IRF4 and/or CD138 but not GC B-cell markers. Patients with pattern A had much better overall survival than those with the other two patterns (Kaplan-Meier survival analysis, P < 0.008, log rank test). Using multivariate Cox proportional hazards regression analysis, the international prognostic index scores and the expression pattern of these markers were independent prognostic indicators. Our results suggest that expression patterns of this panel of GC B-cell and activation markers by immunohistochemistry correlate with the prognosis of patients with DLBCL. Immunohistochemical analysis on paraffin-embedded tissues is more readily available than gene expression profiling by cDNA microarray and may provide similar prognostic information.

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

“…Using two-dimensional contour plots, the non-AIDS diffuse large B-cell lymphomas clustered into distinct germinal center and activated B-cell types similar to reports by others. 1, 3,4 We found significant correlation between the germinal center and nongerminal center groups (defined using the three immunostain method described by Hans et al 3 ) and the germinal center and activated B-cell clusters using two-dimensional contour plots, which further validates this new method. We report the new observation that the AIDS-related diffuse large B-cell lymphomas formed a single cluster with an intermediate germinal center activated B-cell phenotype, suggesting a unique pathophysiology.…”

“…18 Later, it was shown that only three (CD10, BCL6, MUM1) or four (CD10, BCL6, CD138, MUM1) protein markers could accurately predict overall survival. 3,4 Additionally, the expression of the winged helix transcription factor Forkhead box-P1 has been shown to identify a subgroup of patients with especially poor prognosis among the non-germinal center type diffuse large B-cell lymphomas. 19 Prior to the introduction of highly active antiretroviral therapy, the incidence of AIDS-related non-Hodgkin's lymphomas was 60-200 times more frequent in AIDS patients compared to immunocompetent individuals.…”

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

“…In the multivariate survival analysis, older age, the presence of B-symptoms, abnormal serum LDH, more advanced clinical stage (III/IV), and TIMP-1 expression were related to poorer overall survival in the patients with diffuse large B-cell lymphoma. This result is in agreement with those of previous studies of diffuse large B-cell lymphoma using tissue microarray, [59][60][61][62] reflecting the reliability and robustness of our data. Therefore, TIMP-1 expression is an independent factor, and represents a marker for poor prognosis with potential therapeutic implications.…”

Expression of PKC-beta or cyclin D2 predicts for inferior survival in diffuse large B-cell lymphoma

“…Within the nongerminal center B-cell-like subgroup of DLBCL, bcl-2 expression is associated with a significantly worse overall survival and event-free survival, whereas bcl-2 expression is not predictive of survival within the germinal center B-cell-like subgroup. 23,43,44 Similarly, MUM1 has been reported to be associated with worse overall survival by some investigators, 23,43,44 but was not found to be predictive by others. 42 Uniform high expression of FoxP1 has been associated with a poor outcome.…”