Abstract
Recent studies provide convincing evidence that a combined immunohistochemical or fluorescence in situ hybridization (FISH) score of MYC, BCL2, BCL6 proteins and MYC translocations predicted outcome in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, by far, all these researches are based on Western populations. Therefore, we investigate the prognostic relevance of MYC-, BCL2- and BCL6-rearrangements and protein expression by immunohistochemistry and FISH from 336 de novo DLBCL, NOS treated with CHOP or R-CHOP. Breaks in MYC and BCL6, and fusion in IGH/BCL2 were detected in 9.7%, 20.0%, and 11.1% of the cases, respectively, and were not significantly associated with clinical outcomes. Protein overexpression of MYC (≥40%), BCL2 (≥70%) and BCL6 (≥50%) was encountered in 51%, 51% and 36% of the tumors, respectively. On the basis of MYC, BCL2 and BCL6 expression, double-hit scores (DHSs) and triple-hit score (THS) were assigned to all patients with DLBCL. Patients with high MYC/BCL2 DHS, high MYC/BCL6 DHS and high THS had multiple adverse prognostic factors including high LDH level, poor performance status, advanced clinical stage, high International Prognostic Index (IPI) score, and non-germinal center B-cell. In univariate analysis, high MYC/BCL2 DHS, high MYC/BCL6 DHS and high THS were associated with inferior OS and PFS in both CHOP and R-CHOP cohorts (P<0.05). The highly significant correlations with OS and PFS were maintained in multivariate models that controlled for IPI (P<0.05). DLBCLs with high DHSs and high THS share the clinical features and poor prognosis of double-hit lymphoma (P>0.05). These data together suggest that the immunohistochemical DHSs and THS defined a large subset of DLBCLs with double-hit biology and was strongly associated with poor outcome in patients treated with R-CHOP or CHOP.
Highlights
Diffuse large B-cell lymphoma (DLBCL) exhibits various morphologies, immunophenotypes, genetic aberrations, and clinical courses
Clinical and Immunophenotypical Characteristics We studied the series of 336 DLBCL, not otherwise specified (NOS) tumor samples by IHC on the tissue microarrays (TMAs) using antibodies for MYC, BCL2, BCL6 and Ki67 (Figure 1)
Ten patient cases which could not be scored for technical reasons were studied on the corresponding whole tissue sections from the original formalin-fixed paraffin-embedded (FFPE) tumor blocks
Summary
Diffuse large B-cell lymphoma (DLBCL) exhibits various morphologies, immunophenotypes, genetic aberrations, and clinical courses. These features vary across geographic regions, suggesting geographic heterogeneity as a characteristic of this type of lymphoma. Gene expression profiling has stratified DLBCL into prognostically different molecular subtypes based on cell of origin, including germinal center B-cell (GCB)-like, activated B-cell-like subtypes, and unclassified DLBCL [5,6]. These subtypes do not reliably predict the prognosis of individual patients [7]. In some studies this immunophenotypic subdivision do not correlate with prognosis [9,10], and does not currently determine therapy [11]
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