Malleable Immunoglobulin Genes and Hematopathology – The Good, the Bad, and the Ugly

Abstract

Immunoglobulin gene rearrangement analysis is one of the more commonly performed assays available on the hematopathology menu of clinical molecular pathology laboratories. The analysis of these rearrangements provides useful information on a number of different levels in the evaluation of lymphoproliferations. An appreciation of the various mechanisms involved in the numerous physiological pathways affecting the immunoglobulin genes , and hence antibody molecules, is central to an understanding of B-cell development vis-à-vis the generation of immunological diversity. Knowledge about the intricate complexities of these mechanisms is also germane to an evaluation of testing methodologies. With this information, it is easier to develop an understanding of how contemporary molecular testing of immunoglobulin gene rearrangements has evolved, from historically quite heterogeneous, fairly flawed, and rather ugly approaches to current more-standardized protocols. In addition, recognition of how such genetic changes with good intentions can turn bad has fostered increasing insights into the pathogenesis of B-cell lymphomas and leukemias. Despite the significant improvements in the design of immunoglobulin gene rearrangement assays, numerous pitfalls and caveats remain. Accordingly, it is crucial to consider such testing a tool , and although most useful , it is one of many tools that may be required to build cogent diagnoses. (J Mol Diagn

Molecular Analysis of Genetic Markers for Non‐Hodgkin Lymphomas

“…Morphologic, flow cytometric, and immunohistochemical evaluation remain the mainstay of diagnosis for suspected lymphomas. Antigen receptor gene rearrangements can provide supportive evidence to permit the diagnosis of neoplasia when the morphology is unusual or the tissue available for analysis is limited and/or lacks the usual architectural cues (Bagg, 2008). One of the most common indications for testing for ARGR is to establish whether a lymphoid proliferation is reactive or neoplastic, particularly in those cases in which the histology and immunophenotype are equivocal.…”

The Role of Molecular Pathology in the Diagnosis of Cutaneous Lymphomas

“…N represents nucleotides inserted and deleted by TdT. Adapted with permission from [4]. (b) TRG@ gene structure, VJ rearrangement, and PCR primer annealing sites.…”

B Cells Behaving Badly: A Better Basis to Behold Belligerence in B-Cell Lymphomas

“…All 3 of these translocations are a consequence of errors in the normally physiologic DNA breakage and rejoining that occurs in the IGH@ locus, either at the time of V(D)J recombination in the bone marrow and mediated by RAG1/RAG2 (recombinase-activating genes 1 and 2) in FL and MCL, or somatic hypermutation or class-switch recombination mediated by activation-induced cytosine deaminase in BL. 3 However, unlike several myeloid neoplasms (typified by acute myeloid leukemias with recurrent genetic abnormalities and chronic myelogenous leukemia) and some B-cell lymphoblastic leukemias, in which translocations define specific entities, none of these 3 translocations is definitional; that is, none is either completely diagnostically specific or sensitive for the lymphoma with which it is linked. Therefore, for each lymphoma type, there are variable proportions of well-recognized cases that lack these hallmark translocations and yet they display numerous other defining and characteristic histologic and immunophenotypic features, allowing for their specific diagnosis.…”