Immunohistochemical and molecular characteristics with prognostic significance in diffuse large B-cell lymphoma.

Linah Kilany,Mariano Provencio,Syed A Aziz,Carmen Bellas,Diego García,Belen Navarro,Paloma Martín,Victor Abraira,Yolanda Vicente

doi:10.1371/journal.pone.0098169

Linah Kilany, Mariano Provencio + Show 7 more

Open Access

https://doi.org/10.1371/journal.pone.0098169

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Journal: PloS one	Publication Date: Jun 2, 2014
Citations: 72	License type: CC BY 4.0

Affiliation: Hospital Universitario Puerta de Hierro Majadahonda

Abstract

Diffuse large B-cell lymphoma (DLBCL) is an aggressive non-Hodgkin lymphoma with marked biologic heterogeneity. We analyzed 100 cases of DLBCL to evaluate the prognostic value of immunohistochemical markers derived from the gene expression profiling-defined cell origin signature, including MYC, BCL2, BCL6, and FOXP1 protein expression. We also investigated genetic alterations in BCL2, BCL6, MYC and FOXP1 using fluorescence in situ hybridization and assessed their prognostic significance. BCL6 rearrangements were detected in 29% of cases, and BCL6 gene alteration (rearrangement and/or amplification) was associated with the non-germinal center B subtype (non-GCB). BCL2 translocation was associated with the GCB phenotype, and BCL2 protein expression was associated with the translocation and/or amplification of 18q21. MYC rearrangements were detected in 15% of cases, and MYC protein expression was observed in 29% of cases. FOXP1 expression, mainly of the non-GCB subtype, was demonstrated in 37% of cases. Co-expression of the MYC and BCL2 proteins, with non-GCB subtype predominance, was observed in 21% of cases. We detected an association between high FOXP1 expression and a high proliferation rate as well as a significant positive correlation between MYC overexpression and FOXP1 overexpression. MYC, BCL2 and FOXP1 expression were significant predictors of overall survival. The co-expression of MYC and BCL2 confers a poorer clinical outcome than MYC or BCL2 expression alone, whereas cases negative for both markers had the best outcomes. Our study confirms that DLBCL, characterized by the co-expression of MYC and BCL2 proteins, has a poor prognosis and establishes a significant positive correlation with MYC and FOXP1 over-expression in this entity.

Highlights

Diffuse large B-cell lymphoma (DLBCL) is the most common Bcell lymphoma and is curable in more than 60% of patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone [1]
Cell-of-origin classification based on gene expression profiling (GEP), has demonstrated that a germinal center (GC) profile predicts better survival than an activated B-cell-like (ABC) profile among DLBCL patients treated using chemotherapy with or without rituximab [3,4,5,6]
The GC/non-GC phenotype made according to Hans’ algorithm had no prognostic impact, which is consistent with the majority of studies of R-CHOP patients [15,40,41]

Summary

Introduction

Diffuse large B-cell lymphoma (DLBCL) is the most common Bcell lymphoma and is curable in more than 60% of patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (a treatment known as R-CHOP) [1]. DLBCL is an aggressive non-Hodgkin lymphoma with marked biologic heterogeneity. This heterogeneity has been recognized in clinical presentation and morphology as well as in molecular and cytogenetic features. Cell-of-origin classification based on gene expression profiling (GEP), has demonstrated that a germinal center (GC) profile predicts better survival than an activated B-cell-like (ABC) profile among DLBCL patients treated using chemotherapy with or without rituximab [3,4,5,6]. The correlation between the gene expression profiling subgroups of DLBCL and those defined as GC and ABC using immunohistochemistry is highly variable, and the prognostic value of these algorithms has not been validated [10,11,12]

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