Co-Expression of MYC and BCL2 Protein in R-CHOP Treated De Novo Diffuse Large B-Cell Lymphoma Predicts Poor Outcome
Graham W Slack, King L Tan, David W Scott, Susana Ben-Neriah, Nathalie A Johnson, Laurie H Sehn, Joseph M Connors, Randy D Gascoyne. BC Cancer Agency, Vancouver, BC, Canada; McGill University, Montréal, QC, Canada
Background: De novo diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with a variable response to R-CHOP combination therapy. Dual rearrangement of MYC and BCL2 in DLBCL (“double-hit” lymphoma) is an established predictor of aggressive behavior and poor response to therapy. The significance of dual MYC and BCL2 protein expression in R-CHOP treated de novo DLBCL is not established.
Design: 178 cases of formalin-fixed paraffin-embedded R-CHOP treated de novo DLBCL in a tissue microarray were independently evaluated by two pathologists for expression of MYC, BCL2 (Dako 124 and Epitomics E17), CD10, BCL6, MUM1, GCET1, FOXP1 and LMO2 by immunohistochemistry. MYC-positivity was defined as ≥40% cells with nuclear staining. BCL2-positivity was defined as ≥30% cells with cytoplasmic staining using either 124 or E17 antibody. MYC and BCL2 expression were correlated with overall (OS) and progression free survival (PFS), the International Prognostic Index (IPI) score, cell of origin (COO) immunophenotype, and MYC and BCL2 gene rearrangement. Clinical data were available for all patients. The COO immunophenotype was determined using Hans, Choi, and Tally algorithms. MYC and BCL2 status was successfully determined by FISH analysis in 155 cases.
Results: The patient population consisted of 112 males and 66 females ranging from 16-90 years in age (median 65 years). 62 cases were MYC+, 129 cases were BCL2+, and 50 cases were MYC+/BCL2+ (28%). Kaplan-Meier univariate analysis showed MYC+/BCL2+ DLBCL, compared with MYC+/BCL2- and MYC- DLBCL, was associated with inferior 5-year OS (40% vs. 74% vs. 84%, p=0.001) and PFS (32% vs. 64% vs. 85%, p=0.002). MYC+/BCL2+ DLBCL was significantly associated with a non-GCB COO immunophenotype by Choi (p=0.004), Hans (p=0.020), and Tally (p=0.002) criteria. MYC was rearranged in 20 (13%) total cases and 13 (24%) MYC+ cases (p=<0.001). 10 cases were dual MYC /BCL2 rearranged, 6 of which were MYC+/BCL2+ (p=0.019). Cox regression multivariate analysis showed MYC+/BCL2+ expression maintained prognostic significance in OS (p=0.008) and PFS (p=0.035), independent of IPI, COO immunophenotype, and dual MYC/BCL2 rearrangement.
Conclusions: In R-CHOP treated de novo DLBCL co-expression of MYC and BCL2 occurs in 28% of cases. MYC expression occurs in a sizable proportion of patients independent of MYC translocation and importantly, co-expression of MYC and BCL2 independently predicts inferior OS and PFS.
Monday, March 19, 2012 8:15 AM
Platform Session: Section C, Monday Morning