Mutation profiling highlighted that terminal deoxynucleotidyl transferase-positive large B-cell lymphomas carry genetic signatures distinct from B-lymphoblastic leukemia/lymphoma, aiding more accurate differentiation between the two, according to a recent study.
Researchers examined 31 cases of terminal deoxynucleotidyl transferase (TdT)–positive B-cell neoplasms to clarify the differential diagnosis between TdT-positive large B-cell lymphoma (LBCL) and B-lymphoblastic leukemia/lymphoma (B-ALL/LBL). The study, published in The Journal of Pathology, included diffuse large or high-grade B-cell lymphomas (DLBCL/HGBCL) with MYC and BCL2 rearrangements, DLBCL not otherwise specified, HGBCL-not otherwise specified, B-ALL/LBL, and two unclassifiable cases. TdT expression varied among all groups and did not independently distinguish LBCL from B-ALL/LBL based on immunophenotype.
Mutation profiling by targeted next-generation sequencing of 187 genes showed that TdT-positive DLBCL/HGBCL with MYC and BCL2 rearrangements contained mutations typically seen in follicular lymphoma and its high-grade transformation, including BCL2, KMT2D, CREBBP, TP53, and CCND3. These cases also frequently had variants in genes affected by somatic hypermutation (SHM), consistent with a germinal center B-cell origin. In contrast, B-ALL/LBL cases lacked SHM-related mutations and displayed variants in TP53, KRAS, and PAX5, genes often involved in precursor B-cell neoplasms.
Mutation-load comparison demonstrated that TdT-positive LBCLs had a higher frequency of SHM target gene mutations than B-ALL/LBL. Analyses of clonal evolution in three cases showed that TdT-positive HGBCL could develop from IGH::BCL2-positive follicular lymphoma following acquisition of MYC translocation, indicating shared clonal ancestry. Despite overlapping immunophenotypic features such as CD20 loss and variable MUM1 expression, genetic analysis provided evidence for distinct cellular origins: germinal center-derived in TdT-positive LBCL and precursor B-cell in B-ALL/LBL.
The authors concluded that mutation profile analysis, including SHM target genes, could be highly valuable in the differential diagnosis of TdT-positive DLBCL/HGBCL and B-ALL/LBL.
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