Clinical and Pathological Features that Predict High-Grade B-Cell Lymphomas (HGBCLs) with MYC and BCL2 or BCL6 Translocations (Double-Hit Lymphoma): A Systematic Review and Meta-Analysis

Background/Objectives: High-grade B-cell lymphomas (HGBCLs) with MYC and BCL2 or BCL6 translocations, colloquially referred to as double-hit lymphomas (and abbreviated here to DHL), are aggressive malignancies. Differentiating DHL from non-DHL HGBCLs is important, as DHL patients may benefit from more intensive treatment regimes. We aimed to identify predictive clinicopathological, morphological and immunophenotypic features that could guide selection of HGBCLs for fluorescence in-situ hybridization (FISH), which is expensive and less accessible in some centers. Methods: We conducted a PRISMA systematic review and meta-analysis on 29 studies identified from four databases (PubMed (MEDLINE), Ovid (Embase), Web of Science and Scopus). We calculated risk ratios (RRs) to compare features between DHL and non-DHL HGBCL, and between MYC/BCL2 and MYC/BCL6 DHL patients. Results: DHL patients were associated with higher Ann Arbor stage (RR 1.15, p = 0.028, I2 = 38.7%), International Prognostic Index (IPI) score (RR 1.27, p = 0.047, I2 = 37.9%), elevated lactate dehydrogenase (RR 1.26, p = 0.012, I2 = 34.0%) and germinal center B-cell-like (GCB) immunophenotype (RR 1.21, p = 0.043, I2 = 35.8%) compared to non-DHL HGBCL patients. c-Myc im-munopositivity, extranodal disease and bone marrow involvement were more likely in DHL, albeit not reaching statistical significance. Extranodal disease (p = 0.015, I2 = 0.0%), central nervous system involvement (p = 0.044, I2 = 0.0%) and non-GCB immunophe-notype (p = 0.016, I2 = 71.1%) were more likely in MYC/BCL6 compared to MYC/BCL2 DHL patients. BCL2 immunopositivity, CD10 immunopositivity and MUM1 im-munonegativity were more likely in MYC/BCL2 DHL although the differences were not statistically significant. Conclusions: Our results have associated DHL with features of aggressive disease and found GCB immunophenotype as a histopathological feature with statistically significant predictive value for MYC/BCL2 DHL. Heterogeneity within the non-DHL HGBCL group and variation in immunohistochemical cut-off values between studies limited identification of other predictive features. Larger, consistently designed, prospective cohort studies could provide further evidence for a screening strategy for DHL.