Analysis of a Clonally Related Mantle Cell and Hodgkin Lymphoma Indicates Epstein-Barr Virus Infection of a Hodgkin/Reed-Sternberg Cell Precursor in a Germinal Center
Department of Internal Medicine, University of Cologne, Köln, North Rhine-Westphalia, GermanyAmerican Journal of Surgical Pathology (Impact Factor: 5.15). 12/2003; 27(11):1483-8. DOI: 10.1097/00000478-200311000-00014
The simultaneous occurrence of a Hodgkin lymphoma (HL) and a non-Hodgkin lymphoma (NHL) is a rare event, and single cell analyses of such composite lymphomas revealed that NHL and Hodgkin/Reed-Sternberg (HRS) tumor cells are frequently descendants of the same tumor clone precursors. Here we present a composite lymphoma consisting of a mantle cell lymphoma (MCL) and an HL with EBV- and EBV+ HRS cells. Analysis of rearranged V genes of single cells revealed a clonal relationship between MCL and HL tumor cells. Although V gene rearrangements of the MCL were unmutated, mutations were observed in HRS cells. Besides mutations shared by all HRS cells, the EBV+ HRS cells carried identical additional mutations. These findings show that both lymphomas derive from a common precursor, most likely a pre germinal center (GC) B cell that already carried some transforming event(s). However, the presence of mutations in the V genes of the HRS cells further corroborates the importance of the GC reaction for the pathogenesis of HL. Importantly, the finding that only a subclone of the HRS clone, defined by a particular mutation pattern, was EBV infected represents a strong indication that EBV infection of the HRS cell precursor happened in the GC.
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ABSTRACT: Die Zytologie stellt ein wichtiges diagnostisches Instrument in der täglichen Praxis der Hämatopathologie dar. Durch den zytologisch erfolgten Nachweis nichthämatologischer Ursachen einer Knotenbildung (z. B. Speicheldrüsenneoplasien, Tuberkulose, Melanom- oder Karzinommetastasen) besteht seltener die Notwendigkeit einer chirurgischen Exzision. Die kombinierte Anwendung morphologischer, immunphänotypischer sowie molekularer Analysen und der fachliche Austausch machen diese Untersuchungstechnik sicher. Somit stellt die zytologische Untersuchung in verschiedensten Situationen eine Alternative zur Exzisionsbiopsie dar – auch bei primären hämatologischen Erkrankungen und insbesondere bei Rezidiven.
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ABSTRACT: Hodgkin lymphoma (HL) can rarely occur during the course of B-cell non-Hodgkin lymphoma (B-NHL), where both the HL and NHL tumours have been reported to be clonally related in most of the few combination lymphomas so far investigated. We here investigated a case that developed HL 15 yr after being diagnosed with an indolent B-cell lymphoma, classified as a splenic marginal zone lymphoma (SMZL). Analysis of rearranged immunoglobulin genes in the SMZL clone and in single Hodgkin Reed-Sternberg cells revealed presence of identical V gene rearrangements, thus demonstrating a clonal relationship. In contrast to previously described B-NHL/HL combinations, in this case both types of tumour cells carried unmutated V gene rearrangements. We conclude that the HL evolved from an unmutated tumour precursor, either the SMZL clone itself or a common earlier precursor.
Article: Pathogenesis of Hodgkin's lymphoma[Show abstract] [Hide abstract]
ABSTRACT: In Hodgkin's lymphoma (HL), the B cell origin of the tumour cells, the Hodgkin and Reed-Sternberg (HRS) cells, has been disclosed by molecular single cell analysis about 10 yr ago. This finding formed the basis for various studies aimed to better understand the pathogenesis of this peculiar malignancy and the pathophysiology of the HRS cells. Work of our groups in this regard was focussed recently on two main topics, namely the study of differential gene expression in HRS cells and the pathogenesis of composite lymphomas. Composite lymphomas are combinations of HL and B cell non-Hodgkin lymphomas, that turned out to be often clonally related. By molecular analysis of several composite lymphomas for potential transforming events, we identified examples of both shared as well as distinct transforming events. Comparing gene expression profiles of HL-derived cell lines with the corresponding profiles from other B cell lymphomas and normal B cell subsets revealed a global down-regulation of the B cell-specific gene expression signature in HRS cells. Moreover, we identifed aberrant expression and activity of multiple receptor tyrosine kinases in HRS cells of classical and to a lesser extend lymphocyte predominant HL, which appears to be a unique feature of HL, and may offer novel strategies for treatment.
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