Prognostic impact of diffuse large B-cell lymphoma with extra copies of MYC, BCL2 and/or BCL6: comparison with double/triple hit lymphoma and double expressor lymphoma

Abstract

Background The poor outcome of high-grade B-cell lymphoma, with rearrangements of MYC, BCL2 and/or BCL6, also known as double-hit lymphoma or triple-hit lymphoma (DHL or THL), has been well documented, while the clinical significance of extra copies of MYC, BCL2 or BCL6 are still less well known. Methods In total, 130 cases of diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS) were included in our study. Fluorescence in situ hybridization and immunohistochemistry were performed in all cases to evaluate the genetic status and protein expression levels of MYC, BCL2 and BCL6. Results Among the 130 cases of DLBCL, the prevalence rates of extra copies of MYC, BCL2 and BCL6 were 10.8, 20.0 and 14.6%, respectively, and the corresponding rates of gene rearrangement were 10.0, 14.6 and 16.9%, respectively. In total, 7.7% (10/130) of patients were DHL/THL; 9.2% (12/130) of patients were DLBCL with MYC and BCL2 and/or BCL6 gene abnormalities including rearrangements or extra copies, while excluded DHL/THL. The positive protein expression rates of MYC, BCL2 and BCL6 were 46.9% (61), 75.4% (98) and 70.0% (91), respectively. Among the 51 cases with MYC/BCL2 co-expression, 14 cases showed concurrence of MYC, BCL2 and/or BCL6 genetic abnormalities, and the remaining 37 cases were classified as double-expressor lymphoma (DEL). MYC and BCL2 rearrangement and BCL2 extra copies were all associated with upregulated protein expression. Cases with concurrence of MYC, BCL2 and/or BCL6 genetic abnormalities were both associated with MYC/BCL2 co-expression. Patients with concurrence of MYC, BCL2 and/or BCL6 genetic abnormalities excluded DHL/THL had shorter OS ( P < 0.001) than patients with DLBCL with no genetic change, and showed no statistical different with patients with DHL/THL ( P = 0.419). Extra copies of MYC was independent prognostic factors for DLBCL. Conclusions Patients with MYC and BCL2 and/or BCL6 gene extra copies might show a trend towards poor prognosis, and the detection of extra copies of MYC, BCL2 and BCL6 might deserve more attention. Electronic supplementary material The online version of this article (10.1186/s13000-019-0856-7) contains supplementary material, which is available to authorized users.

PiggyBac-Generated CAR19-T Cells Plus Lenalidomide Cause Durable Complete Remission of Triple-Hit Refractory/Relapsed DLBCL: A Case Report

“…The 2016 revised World Health Organization guidelines of lymphoid neoplasms classified large B-cell lymphoma with rearrangements of MYC and BCL2 or/and BCL6 in a distinct category to be designated high-grade B-cell lymphoma, also called double-hit lymphoma (DHL) or THL ( 4 ). DHL comprises approximately 2–10% of newly diagnosed DLBCL cases, and THL is a rare subset, accounting for almost 1% in DLBCL ( 5 , 6 ). The largest series of THL to data included 40 patients, suggesting that its clinicopathologic features were similar to DHL and TP53 mutation was an independent predictor of poor prognosis ( 7 ).…”

“…For those with relapsed/refractory (RR) DLBCL, the median overall survival (OS) was only 6.3 months with conventional therapy (3). Triplehit lymphoma (THL) that carries concurrent MYC, BCL2 and BCL6 rearrangements is a relatively rare subset, identified in approximately 1% of DLBCL patients (4)(5)(6). These rearrangements result in highly aggressive clinical behavior, resistance to standard chemotherapy and extremely poor outcomes (7).…”

High-Grade B-Cell Lymphoma (HGBL) with MYC and BCL2 and/or BCL6 Rearrangements Is Predominantly BCL6-Rearranged and BCL6-Expressing in Taiwan

“…All staining was performed using the Ventana benchmark ULTRA IHC staining module (Ventana, Tucson, AZ, USA). As previously described [ 19 ], for COO determination based on Hans’ algorithm, positivity cut-off for CD10, IRF4/MUM1, and BCL6 expression was ≥30% stained cells, while the expression positivity cut-off for BCL2 or MYC was ≥50% or ≥40% of stained cells, respectively.…”

An IPI based immune prognostic model for diffuse large B-cell lymphoma

“…With the development of high-throughput technologies, germinal center B-cell-like (GCB) and activated B-cell-like (ABC) DLBCL subtypes were identified by gene expression profiling (GEP) based on cell-of-origin (COO) classification 5-7 . More recently, several key cytogenetic alterations including mutations, somatic copy number alterations (SCNA) and structural variants (SV), have been shown to classify distinct genetic subtypes within the COO subgroups, providing insights into disease heterogenous pathogenesis and candidate treatment targets 1, 3, 7-9 . Several prognostic factors including COO and the International Prognostic Index (IPI) have already been identified in the rituximab era, which still need to be further investigated in the context of targeted therapies 7, 9-12 .…”

“…More recently, several key cytogenetic alterations including mutations, somatic copy number alterations (SCNA) and structural variants (SV), have been shown to classify distinct genetic subtypes within the COO subgroups, providing insights into disease heterogenous pathogenesis and candidate treatment targets 1, 3, 7-9 . Several prognostic factors including COO and the International Prognostic Index (IPI) have already been identified in the rituximab era, which still need to be further investigated in the context of targeted therapies 7, 9-12 . Therefore, there is an urgent need to explore potential molecular mechanism and identify more key biomarkers and therapeutic targets.…”