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.

Renal tubular atrophy predicts a poor prognosis in chronic renal failure, but the molecular mechanisms that regulate tubular atrophy are unknown. Because the Fas apoptosis pathway has been implicated in disease pathogenesis and Fas is expressed in kidney, we hypothesized that Fas-mediated renal tubule epithelial cell (RTC) apoptosis contributes to tubular atrophy in chronic renal failure. Immunohistochemical analyses of renal sections from two murine models of progressive renal disease revealed increases in RTC Fas expression and apoptosis compared with tissue sections from age-matched control kidneys. Increased RTC apoptosis was not accompanied by compensatory hyperplasia, suggesting that RTCs targeted for Fas-dependent apoptotic deletion contribute to tubular atrophy. These data are supported by in vitro studies that showed that interleukin-1alpha or tumor necrosis factor-alpha, cytokines that are secreted in chronic renal failure, stimulated increases in Fas expression in cultured RTCs. Both murine kidney cortex and RTCs in culture demonstrated constitutive expression of Fas ligand, a feature that is characteristically restricted to lymphocytes and immune-privileged tissues and previously unrecognized in RTCs. Functional studies revealed that interleukin-1alpha-stimulated RTC Fas expression was accompanied by increased apoptosis, which was inhibited by blocking anti-Fas ligand antibodies. The data suggest that up-regulated RTC Fas binds to Fas ligand on adjacent RTCs, which then leads to RTC death by fratricide. We propose this pathway as an initiating mechanism of tubular atrophy.

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In this study, we evaluated the prognostic significance of multiple myeloma-1/interferon regulatory factor-4 (MUM1/IRF4) expression in B-cell chronic lymphocytic leukemia (B-CLL). Our results demonstrated that the absence of MUM1/IRF4 expression showed the highest relative risk among the factors analyzed in determining the probability for death in patients with B-CLL using univariate and multivariate Cox regression analysis. Pa-

At high levels of expression, RTC Fas promotes apoptosis in a JNK-independent manner. At low basal expression, Fas induces JNK activation, but not apoptosis, consistent with novel roles for RTC Fas as a mediator of cell stress or chronic inflammation.

We performed a retrospective immunohistochemical study of the relationships between clinical manifestations and outcomes of diffuse large B-cell lymphoma (DLBCL) and expression of oncogenic proteins in 21 cases of DLBCL at various clinical stages. Cases of nodal origin expressed p53 more often and presented with high clinical stage more frequently than those of extranodal origin. Expression of c-Myc or p53, but not Bcl-6, Bcl-2, or Bcl-1, showed a statistically significant positive correlation with high clinical stage at presentation and with high or high-intermediate risk. Coexpression of c-Myc and p53 occurred in 7 of 12 patients with high clinical stage but was absent in patients with low clinical stage; coexpression was more frequent in patients with high or high-intermediate risk than in patients with low or low-intermediate risk. Four patients with this coexpression pattern demonstrated an unusually aggressive clinical course (median survival, 7 months). Coexpression of c-Myc and p53 seems to be a better indicator than the MIB1 proliferative index for identification of a cohort of aggressive disease in patients with DLBCL.

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