Progression of follicular lymphoma and related entities: Report from the 2021 SH/EAHP Workshop

Abstract

Objectives The 2021 Society for Hematopathology and European Association for Haematopathology Workshop addressed the molecular and cytogenetic underpinnings of transformation and transdifferentiation in lymphoid neoplasms. Methods Session 4, “Transformations of Follicular Lymphoma,” and session 5, “Transformations of Other B-Cell Lymphomas,” included 45 cases. Gene alteration analysis and expression profiling were performed on cases with submitted formalin-fixed, paraffin embedded tissue. Results The findings from session 4 suggest that “diffuse large B-cell lymphoma/high-grade B-cell lymphoma with rearrangements of MYC and BCL2” is a distinct category arising from the constraints of a preexisting BCL2 translocation. TdT expression in aggressive B-cell lymphomas is associated with MYC rearrangements, immunophenotypic immaturity, and a dismal prognosis but must be differentiated from lymphoblastic ­lymphoma. Cases in session 5 illustrated unusual morphologic and immunophenotypic patterns of transformation. Additionally, the findings support the role of cytogenetic abnormalities—specifically, MYC and NOTCH1 rearrangements—as well as single gene alterations, including TP53, in transformation. Conclusions Together, these unique cases and their accompanying molecular and cytogenetic data suggest potential mechanisms for and unusual patterns of transformation in B-cell lymphomas and indicate numerous opportunities for further study.

The fifth edition of the WHO classification of mature B‐cell neoplasms: open questions for research

“…WHO-HAEM5 excludes cases with concomitant MYC and BCL6 rearrangements (without BCL2-R) from this entity, as these MYC-R and BCL6-R DH cases are genetically heterogeneous and as a group are essentially different from those with MYC-R and BCL2-R. Consequently, WHO-HAEM5 renames the entity diffuse large B-cell lymphoma/high-grade B-cell lymphoma with MYC and BCL2 rearrangements (DLBCL/ HGBL-MYC/BCL2) with the morphological connotation to recognise their variable morphology (Figure 3). The definition of this entity is therefore based on the [69]. These cases bear a mature B-cell phenotype (CD34 negative) and show a breakpoint distribution pattern and mutation profile like those of transformed FL [54,70].…”

“…Irrespective of morphological and immunophenotypic variations, most if not all DLBCL/HGBL-MYC/ BCL2 biologically result from high grade transformation of BCL2-translocation positive clones, which may present as a FL or occult in situ follicular B-cell neoplasms [69]. Despite being a seemingly homogeneous entity, there is mounting evidence pointing to variable clinical outcomes and disparate clinical and biological impacts inferred by MYC translocations with different partners.…”

Diverse and reprogrammable mechanisms of malignant cell transformation in lymphocytes: pathogenetic insights and translational implications

“…Although rare, the development of DLBCL with phenotypic and genomic evidence of immaturity following the mature B-cell neoplasms: FL and DLBCL, has been now firmly recognized ( 22 – 25 ). These DLBCL/lymphoblastic B-cell lymphoma/leukemia (LBLL) “chimeras” typically are TdT+, CD10+, CD45 low , and cell-surface Ig-negative, attesting to their at least partially immature phenotype.…”

“…Translocations of BCL-2 and/or BCL-6 in both pre-and post-dedifferentiation stages are another common feature, which raises the possibility that defects in double-stranded DNA break repair contribute to the emergence of DLCBCL/LBLL. Accordingly, three cases of TdT+ DLBCL/LBLL demonstrated expression of RAG1 ( 25 ), the gene encoding for an enzyme inducing DNA breaks to initiate immunoglobulin gene V(D)J recombination in immature B cells.…”

“…An in-depth molecular analysis of TdT+ DLBCL/LBLL cases has established a clonal relationship with preceding them FL and DBCL, by both shared rearrangement of immunoglobulin heavy chain ( IgH) gene and identical mutations of other genes, with additional mutations seen at the DLBCL/LBLL stage ( 22 – 25 ). Of note, all TdT+ DLBCL/LBLL cases tested so far ( 22 , 23 ) have displayed somatic hypermutations of the IgH gene, indicating that these lymphomas have indeed dedifferentiated from mature lymphoma cells, rather than have originated from a common, immature malignant progenitor B cell.…”