Immunophenotyping of diffuse large B-cell lymphoma (DLBCL) defines multiple sub-groups of germinal centre-like tumours displaying different survival characteristics

Abstract

Abstract. Diffuse large B-cell lymphoma (DLBCL) forms a heterogeneous collection of aggressive non-Hodgkin's Lymphoma in which three principle classes of neoplasia have been defined according to gene expression and immunophenotyping studies. The present investigation sought to examine the immunophenotype of proposed subgroups and relate these to patient survival. A series of 155 DLBCL treated uniformly with anthracycline therapy in clinical trials, were stratified upon the basis of common biomarker expression with combination immunophenotype being related to patient overall survival. Stratification of tumours with respect to combined expression profiles of the three biological markers (CD10, Bcl-6 and MUM-1) revealed six groups showing significant differences in survival (p=0.014). The greatest difference resided between distinct populations of germinal centre (GC) cell tumours; the first being CD10-, Bcl-6 + , MUM-1 -and the second CD10 + Bcl-6 + MUM-1 + (p=0.002). The former group displayed median survival time of 143 months, the latter only 11 months. A third population of GC tumours (CD10 + Bcl-6 + and MUM-1 -) also displayed a relative short median survival (32 months). Of the three groups presenting a non-GC or activated B cell (NGC/ ABC) phenotype, only one (CD10 -, Bcl-6 + and MUM-1 + ) presented short-term median survival (27 months) comparable with poor prognosis GC sub-populations. Within the remaining ABC tumour groups (CD10 -Bcl-6 -MUM-1 -and CD10 -Bcl-6 -MUM-1 + ) patients presented intermediate median survival times of 54 and 58 months, respectively. Thus, the GC phenotype did not act as a universal indicator of good clinical prognosis, but rather multiple groups of GC tumours were associated with distinct overall survival profiles. Ultimately, the data allowed definition of a predictive algorithm defining three groups predicting poor, intermediate and good clinical prognosis. The first of these comprised two patient subpopulations with GC-like tumours together with one subpopulation of NGC/ABC, the second two sub-populations of ABC-like tumours, and the final a single group of GC-like tumours associated with optimal long-term survival.

STAT3 Targets Suggest Mechanisms of Aggressive Tumorigenesis in Diffuse Large B-Cell Lymphoma

“…This analysis also successfully re-identified many genes that have previously been shown to be biomarkers for each DLBCL subtype (Rosenwald et al 2002; Tirado et al 2012), including BCL2 , IRF4 , MME ( CD10 ), and BCL6 (Table 2). Surprisingly, the established ABC subtype biomarker MUM1 (Hans et al 2004; Sweetenham 2005; Anderson et al 2009) showed no significant expression change (FDR = 0.92) but did have a STAT3 BR 344 bp upstream of its TSS with significantly more binding in GCB (fold change = 0.46, FDR = 4.89 × 10 −3 ).…”

Evaluation of Clinical and Biological Prognostic Factors in Relapsed or Refractory Diffuse Large B-Cell Lymphoma Patients After Previous Treatment With Rituximab and Chemotherapy: Results of the PRO-R-IPI Study

“…However, most of these methods are not routinely used because of the substantial cost, technical complexity, and the requirement for fresh or frozen tissue. [4][5][6][7][8] In the present study, we attempted to evaluate whether immunohistochemical parameters (p53, Bcl-2, Bcl-6, and MUM1) are useful for determining the prognosis of patients with DLBCL after second-line treatment. None of the immunohistochemical parameters evaluated achieved statistical significance in our study, probably because of the small number of patients in the analysis set.…”

“…4,5 Recent studies have also attempted to define these groups using immunohistochemistry markers, such as B-cell lymphoma 6 (Bcl-6) and CD10 for the germinal center, and multiple myeloma 1 (MUM1), interferon regulatory factor 4, and CD38 for the postgerminal center. [6][7][8] Despite the fact that many clinical factors and biomarkers have been evaluated to predict the prognosis of patients with DLBCL, the International Prognostic Index (IPI) remains the easiest to apply and the most recognized index. The IPI is based on the evaluation of 5 clinical factors: age > 60 years, Ann Arbor stage III or IV disease, > 1 extra nodal site, European Cooperative Oncology Group performance status (ECOG PS) !…”

A 9 series microRNA signature differentiates between germinal centre and activated B-cell-like diffuse large B-cell lymphoma cell lines

“…IHC was performed using the automated Ventana BenchMark ® immunostaining system. Full details of conditions were described previously (24). All DLBCL cell lines were segregated on the basis of their immunophenotype and classified as either GC-like or ABC-like, based on the algorithm proposed by Hans et al (8).…”