Mutational Landscape of TdT+ Large B-cell Lymphomas Supports Their Distinction From B-lymphoblastic Neoplasms A Multiparameter Study of a Rare and Aggressive Entity

In the current World Health Organization classification, terminal deoxynucleotidyl transferase (TdT) expression in a high grade/large cell B-cell lymphoma (LBCL) indicates a B-lymphoblastic lymphoma/leukemia (B-LBL), although TdT expression in what appear to be mature LBCL or following mature B-cell neoplasms is reported. The frequency of TdT(+) LBCL, how to best categorize these cases, and their clinicopathologic features, molecular landscape, and relationship to classic B-LBL remain to be better defined. TdT expression was therefore assessed in 258 LBCL and the results correlated with the cytologic, phenotypic, and cytogenetic findings. Targeted mutational analysis, review of prior biopsies, and assessment of clinical associations was performed in the 6 cases with >10% TdT(+) cells. All 6 TdT(+) LBCL were blastoid-appearing, CD34(-), MYC+, BCL2(+), and had MYC rearrangements (R) (5/6 with BCL2 and/or BCL6-R). 5/6 had a prior TdT(-) LBCL and/or follicular lymphoma and all had an aggressive course. Fifteen nonsynonymous variants in 11 genes were seen in the 4/5 tested cases with mutations. TdT(+) and TdT(-) areas in 1 case showed identical mutations. The mutational profiles were more like those reported in germinal center B-cell type-diffuse LBCL rather than B-LBL. Evolution from preceding TdT(-) lymphomas was nondivergent in 1/3 tested cases and partially divergent in 2. The clinicopathologic and cytogenetic features of these 6 cases were similar to those found in a meta-analysis that included additional cases of TdT(+) LBCL or B-LBL following follicular lymphoma. Thus, TdT(+), CD34(-) large B-cell neoplasms with MYC rearrangements and often a double hit are rare, frequently a transformational event and aggressive but are distinct from classic B-LBL.

Automated summary

In the current classification of the World Health Organization, TdT expression in high grade/large cell B-cell lymphoma indicates B-lymphoblastic lymphoma/leukemia. However, there are reports of TdT expression in mature LBCL or following mature B-cell neoplasms. The frequency, categorization, clinicopathologic features, molecular landscape, and relationship to classic B-LBL of TdT(+) LBCL remain to be better defined. In this study, TdT expression was assessed in 258 LBCL and correlated with cytologic, phenotypic, and cytogenetic findings. Mutational analysis, review of prior biopsies, and assessment of clinical associations were performed in 6 cases with >10% TdT(+) cells. The 6 TdT(+) LBCL cases were blastoid-appearing, CD34(-), MYC+, BCL2(+), and had MYC rearrangements (R) (5/6 with BCL2 and/or BCL6-R). They had a prior TdT(-) LBCL and/or follicular lymphoma and all had an aggressive course. The mutational profiles were more like those reported in germinal center B-cell type-diffuse LBCL rather than B-LBL. The clinicopathologic and cytogenetic features of these 6 cases were similar to those found in a meta-analysis that included additional cases of TdT(+) LBCL or B-LBL following follicular lymphoma. Thus, TdT(+), CD34(-) large B-cell neoplasms with MYC rearrangements and often a double hit are rare, frequently a transformational event and aggressive but are distinct from classic B-LBL.