Divergent evolution of metachronous follicular lymphoma and extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue from a common precursor

Abstract

The translocation t(14;18)(q32:q21)/IGH::BCL2 occurs at the pre-B stage of B-cell development in the bone marrow and is insufficient for malignant transformation, although it leads to the formation of in situ follicular B-cell neoplasia (ISFN). Despite that, the translocation is the genetic hallmark of follicular lymphoma (FL), it occurs infrequently in metachronous/synchronous lymphomas, including extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (EMZL), mantle cell lymphoma, and Hodgkin's lymphoma. In each of these scenarios, the two lymphomas often appear to be clonally related by analyses of IGH::BCL2 and/or rearranged IG genes. However, it remains largely unknown whether one lymphoma originates from the other or they develop independently. We studied five cases of metachronous EMZL and FL. In four cases, the two lymphomas were clonally related, as shown by identical IGH::BCL2 and/or rearranged IG genes or shared mutations. There were common and unique mutations between the paired EMZL and FL, indicating that they developed independently from a common premalignant cell population, harbouring IGH::BCL2 in three cases. Furthermore, case 1 presented with three metachronous FLs, and all of them originated from a common precursor cell population via divergent evolution. Our findings highlight the multi-malignant potential of IGH::BCL2-positive B-cells. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Keywords: BCL2 translocation; EMZL; clonal evolution; follicular lymphoma; mutational profiling.

Figure 1

Histological and immunophenotypic features of EMZL and FL in case 1. (A) Parotid biopsies and cervical lymph node (LN) show typical features of EMZL. (B) Intraparotid LN shows strong BCL2 expression in GC B‐cells, loss of zonal polarity, and attenuated mantle zone, while mesenteric LN and spleen display classic features of FL. FC: follicle centre.

Figure 2

Divergent evolution of metachronous EMZL and FL. All somatic genetic changes, including variants in 5’‐untranslated region (UTR), are included in the phylogenetic illustration. Synonymous changes are shown in blue text, subclonal changes in brown. LN: lymph node; ISFN: in situ follicular B‐cell neoplasia.

Figure 3

Multi‐malignant potential of IGH:BCL2‐positive cells. IGH::BCL2‐positive B‐cells, like reactive B‐cells, can readily undergo the GC reaction and transit from one B‐cell follicle to another, and thus are at a high risk of acquiring genetic changes, conferring multi‐malignant potential. CLL/SLL: chronic lymphocytic leukaemia/small lymphocytic lymphoma; MCL: mantle cell lymphoma; HL: Hodgkin's lymphoma.