Plasticity of Mature B Cells Between Follicular and Classic Hodgkin Lymphomas

Abstract

Follicular lymphoma and classic Hodgkin lymphoma can be associated in composite and/or sequential lymphomas. Common IGH and BCL2 rearrangements have already been identified between both contingents of these entities, but mutation profiles have not yet been investigated. The main objective of this study was to analyze the transdifferentiation process that may occur between Hodgkin and follicular contingents in sequential and composite lymphomas to better characterize these entities. From 2004 to 2020, a retrospective multicentric study was performed, including 9 composite and 13 sequential lymphomas. Clinical data were retrospectively collected. Fluorescent in situ hybridization of BCL2 and BCL6 rearrangements, polymerase chain reaction of IGH and IGK rearrangements, next-generation sequencing of IGK rearrangement, and targeted next-generation sequencing (TNGS) on a panel of genes frequently mutated in lymphomas were performed on each contingent of composite and sequential lymphomas. For TNGS, each contingent was isolated by laser capture microdissection. Clinical presentation and evolution were more aggressive in sequential than composite lymphomas. By fluorescent in situ hybridization, common rearrangements of BCL6 and BCL2 were identified between both contingents. Similarly, a common clonal relationship was established by evaluating IGH and IGK rearrangement by polymerase chain reaction or next-generation sequencing. By TNGS, the same pathogenic variants were identified in both contingents in the following genes: CREBBP, KMT2D, BCL2, EP300, SF3B1, SOCS1, ARID1A, and BCOR. Specific pathogenic variants for each contingent were also identified: XPO1 for Hodgkin lymphoma contingent and FOXO1, TNFRSF14 for follicular lymphoma contingent. This study reinforces the hypothesis of a transdifferentiation process between Hodgkin and follicular contingent of sequential/composite lymphomas.

Classical Hodgkin lymphoma following follicular lymphoma: a case report

“…It is generally accepted that FLs and HLs originate from transformed mutating and antigen-selected germinal center B-cells and preapoptotic germinal B-cells, respectively [ 19 ]. Some composite or sequential lymphomas exhibited shared genetic alterations, including translocation involving Bcl-2 or Bcl-6, or clonality of IgH or immunoglobulin kappa chain rearrangement These findings suggest neoplastic transdifferentiation occurring between the different components of the two lymphomas [ 20 ]. Trecourt et al [ 20 ] reported that mutations in BCL2 , CREBBP , KMT2D , EP300 , and ARID1A are frequently observed in both sequential and composite lymphomas of FL and HL.…”

“…Some composite or sequential lymphomas exhibited shared genetic alterations, including translocation involving Bcl-2 or Bcl-6, or clonality of IgH or immunoglobulin kappa chain rearrangement These findings suggest neoplastic transdifferentiation occurring between the different components of the two lymphomas [ 20 ]. Trecourt et al [ 20 ] reported that mutations in BCL2 , CREBBP , KMT2D , EP300 , and ARID1A are frequently observed in both sequential and composite lymphomas of FL and HL. These mutations, which are found usually in FLs but not in HLs, may serve as driver mutations in the development of these lymphomas.…”

“…These mutations, which are found usually in FLs but not in HLs, may serve as driver mutations in the development of these lymphomas. However, different mutations specific to each contingent may have been secondary or passenger mutations [ 20 ]. Thus, it is plausible that this particular case also exhibited genetic alterations shared between FLs and HLs, although these specific alterations were not assessed in this study.…”

“…Furthermore, an anaplastic large-cell lymphoma was excluded based on the PAX-5 expression. Given that the IgH rearrangement clonality and BCL2 gene translocation may sometimes be found in both HLs and FLs of consequent lymphoma [ 10 , 14 - 17 , 20 ], pathologists should not rely on them for molecular investigations. While HLs and FLs have been shown to have different peaks in IgH gene rearrangement PCR, they were observed to have IgH clonality [ 17 ].…”

Deciphering the spectrum of cutaneous lymphomas expressing TFH markers

“…TCR Clonality was assessed using the BIOMED-2 primer sets for TCR gamma (TCRG). TNGS have been performed as previously reported 11,23 . The applied panel of 47 genes is detailed in Suppl.…”