Article

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 Pathology, University of Frankfurt, Germany.
American Journal of Surgical Pathology (Impact Factor: 4.59). 12/2003; 27(11):1483-8. DOI: 10.1097/00000478-200311000-00014
Source: PubMed

ABSTRACT 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.

0 Followers
 · 
60 Views
  • [Show abstract] [Hide abstract]
    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.
    Der Pathologe 07/2012; 33(4). DOI:10.1007/s00292-012-1580-1 · 0.64 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: About 15% of patients diagnosed with classical Hodgkin's lymphoma (cHL) are considered high risk with unfavorable prognosis. The biology of the disease bears a direct relationship to its clinical course. However, some aspects of the disease are still being debated. Related topics include origin of neoplastic cells as circulating precursor versus germinal center B cell, and disease metastasis via hematogenous routes and the effect of HL circulation on relapse potential and further spread of the disease. The terminally differentiated giant neoplastic Hodgkin Reed-Sternberg (HRS) cells (HRSC) have limited proliferation and lack mobility. Therefore, they are unable to penetrate epithelium. Thus, the clinical aggressiveness of HRSCs that disseminate via both lymphatic and hematogenous may be determined by their molecular composition. This review discusses in detail the historical perspectives on scientific and clinical evidences of precursors of circulating HL cells and the prognostic importance of these circulating cells for predicting outcome.
    Critical reviews in oncology/hematology 10/2013; 89(3). DOI:10.1016/j.critrevonc.2013.09.004 · 4.05 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Composite lymphomas (CL) represent the occurrence of two distinct lymphomas in the same patient. Often, CL share a common cellular origin, thus representing a unique model to investigate the multistep genetic path leading to lymphomagenesis in general and to the specific development of each distinct lymphoma component in particular. Here, we present the molecular analysis of a case consisting of an unusual Hodgkin lymphoma (HL) and a mantle cell lymphoma (MCL), intimately admixed within one another in lymph nodes and bone marrow yet phenotypically distinct, in a patient who first presented with splenic/leukemic MCL two years earlier. MCL and Hodgkin and Reed/Sternberg (HRS) cells harbored identical immunoglobulin (Ig) VH gene rearrangements with shared somatic mutations, proving their common clonal origin from a (post-)germinal center (GC) B cell. This also demonstrates the (post-)GC origin of MCL with mutated IgV genes. Both lymphomas carried the same CCND1/IGH translocation and, unexpectedly for HL, expressed cyclin D1 and OCT2. Thus, HRS cells are able to preserve IGH locus activity (otherwise usually silenced in HL) to promote expression of an oncogene translocated into this locus. Both lymphoma populations further showed an identical TP53 function-impairing mutation, and later acquired a TP53 heterozygous deletion independently from one another (convergent evolution). The surprisingly close genetic relationship of the lymphomas, together with their histological intermingling and the clinical history of the patient, suggests subclonal evolution of HL from MCL as a plausible pathway in alternative to that so far described in CL, i.e. separate development from a common precursor. © 2013 Wiley Periodicals, Inc.
    International Journal of Cancer 02/2014; 134(4). DOI:10.1002/ijc.28422 · 5.01 Impact Factor