Abstract
Follicular lymphoma (FL) is characterized genetically by a significant intraclonal diversity of rearranged immunoglobulin heavy chain (IGH) genes and a substantial cell migration activity (follicular trafficking). Recently, in situ follicular neoplasia (ISFN), characterized by accumulations of immunohistochemically strongly BCL2-positive, t(14;18)+ clonal B cells confined to germinal centers in reactive lymph nodes, has been identified as a precursor lesion of FL with low risk of progression to manifest FL. The extent of ongoing somatic hypermutation of rearranged IGH genes and interfollicular trafficking in ISFN is not known. In this study we performed an in depth analysis of clonal evolution and cell migration patterns in a case of pure ISFN involving multiple lymph nodes. Using laser microdissection and next generation sequencing (NGS) we documented significant intraclonal diversity of the rearranged IGH gene and extensive interfollicular migration between germinal centers of the same lymph node as well as between different lymph nodes. Furthermore, we identified N-glycosylation motifs characteristic for FL in the CDR3 region.
Highlights
Follicular lymphoma (FL) is genetically characterized by the recurrent chromosomal translocation t(14;18)(q32;q21), present in the majority of cases [1]
The goal of our study was to use a generation sequencing (NGS) approach to analyse the extent of somatic hypermutation (SHM) and migration patterns in a case of in situ follicular neoplasia (ISFN) manifested in multiple germinal centers of several lymph nodes in an individual without history or presence of a manifest FL
Immunostaining for BCL2 protein performed on all the nodes showed extensive ISFN lesions with typical intense positive staining of germinal centers of normal size with intact mantle zones in 16 of the 27 excised staging lymph nodes, without evidence for progression to manifest FL in any of the nodes
Summary
Follicular lymphoma (FL) is genetically characterized by the recurrent chromosomal translocation t(14;18)(q32;q21), present in the majority of cases [1]. The germinal center (GC) B-cell of origin of FL is subjected to ongoing somatic hypermutation (SHM) which results in an intraclonal sequence heterogeneity of neoplastic clones [2]. FL develops in the lymph node and infiltrates the bone marrow at an early time point of disease. Further migration of neoplastic cells between lymph nodes and bone marrow arises in both directions [3]. Due to the continuous exposure to the GC microenvironment and constitutive induced cytidine deaminase (AID) activity, a proportion of FL show increasing intraclonal diversity of rearranged.
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