Comparison of Myocyte Enhancer Factor 2B Versus Other Germinal Center-associated Antigens in the Differential Diagnosis of B-Cell Non-Hodgkin Lymphomas.

Myocyte enhancer binding factor 2B (MEF2B) is a transcriptional activator of the BCL6 proto-oncogene in normal germinal center (GC) B-cells. Limited data exists concerning its expression in B-cell lymphomas, and comparison with other GC-associated antigens is lacking. Its role in the differential diagnosis of B-cell lymphomas, particularly in the distinction of follicular lymphoma (FL) versus marginal zone lymphoma (MZL), remains to be determined. We evaluated MEF2B expression, in comparison with additional GC markers, LIM domain-only transcription factor 2 (LMO2), and human GC-associated lymphoma (HGAL), in a variety of B-cell lymphomas, with particular emphasis on their utility in differentiating FL from MZL. MEF2B was positive in all FL and Burkitt lymphomas, 8/9 mantle cell lymphomas, 2/24 splenic MZL, 1/10 chronic lymphocytic leukemia/small lymphocytic lymphomas, and 38/44 diffuse large B-cell lymphoma (DLBCL), but was negative in all extranodal MZL of mucosa-associated lymphoid tissue, nodal MZL, and B-lymphoblastic lymphomas. Focusing on low-grade FL versus MZL, MEF2B was 100% sensitive and 95% specific for FL, which was similar to BCL6, but superior to LMO2 (sensitivity 87%, specificity 86%) and HGAL (sensitivity 97%, specificity 86%). Importantly, MEF2B was positive in 4/4 FL with plasmacytoid differentiation, which were CD10, only weakly BCL6, and included 1 case that lacked both LMO2 and HGAL expression. MEF2B was positive in 22/25 (88%) GC-type DLBCL, but was also positive in 16/19 (61%) non-GC-type DLBCL. MEF2B shows superior sensitivity and specificity than LMO2 and HGAL in the differential diagnosis of FL versus MZL and is particularly useful in FL with plasmacytoid differentiation, which may have morphologic and immunophenotypic overlap with MZL. MEF2B, however, is not specific for GC-derived B-cell lymphomas as it is also apparently positive in most mantle cell lymphoma and many non-GC-type DLBCL.

Further Exploration of the Complexities of Large B-Cell Lymphomas With MYC Abnormalities and the Importance of a Blastoid Morphology.

The 2016 World Health Organization classification recognized "high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements" (double/triple-hit lymphoma [DTHL]) and "high-grade B-cell lymphoma, not otherwise specified," which includes non-DTHL with a "blastoid" or "intermediate" cytology. Although extensively studied, many questions remain, including which cases belong in these categories, which factors mitigate their adverse prognosis, and when to perform fluorescence in situ hybridization studies. Therefore, the clinicopathologic features of 187 large B-cell lymphomas with MYC, BCL2, and BCL6 fluorescence in situ hybridization were investigated. There were 47 DTHLs, 36 cases with MYC and BCL2 and/or BCL6 extra signals (ES) and/or rearrangements (ES group, excludes DTHLs), 9 with MYC rearrangements only (single-hit lymphoma), and 95 with no MYC abnormalities (NM). Patients with DTHLs, but not single-hit lymphomas, had a significantly worse prognosis compared with those with NM (P=0.0079). The ES group with at least 1 rearrangement had a worse prognosis compared with the NM/ES without rearrangement group (P<0.02). Blastoid, but not intermediate cases, were enriched in DTHLs (P<0.0001) and had a significantly worse prognosis even among DTHLs (P=0.0282). The prognosis of the diffuse large B-cell lymphoma and intermediate groups was similar. International Prognostic Index score was of prognostic importance for the entire group and for DTHLs (P=0.0074). About 93% of DTHLs were of GCB type but 24% had <40% MYC+ cells. Among the DTHLs, MYC+BCL2+ double expressor cases had a worse prognosis (P=0.0328). These results highlight the importance of morphologic, phenotypic, and clinical variations among the DTHLs and suggest that a diagnosis equivalent to DTHL should not be made based solely on ES for MYC and BCL2 and/or BCL6.