Distinct clonotypic Epstein–Barr virus-induced fatal lymphoproliferative disorder in a patient with wiskott-aldrich syndrome

Abstract

Recently, reports of Epstein-Barr virus (EBV)-induced lymphoproliferative disorders (LPD) have increased in number among immunosuppressed recipients of organ transplants. The importance of analyzing both the immunoglobulin gene and EBV termini is advocated for the investigation of pathogenetic mechanisms for clonal proliferation in EBV-induced LPD; however, the oncogenic mechanisms of EBV-induced LPD remain unclear. Furthermore, there are very few clonotypic studies of EBV-induced LPD in patients with primary immunodeficiency diseases. The authors studied the clonality of an EBV-induced fatal LPD in a 20-year-old patient with Wiskott-Aldrich syndrome (WAS), an X-linked recessive primary immunodeficiency disease. An autopsy showed non-Hodgkin lymphoma of B-cell origin with diffuse large cells in both systemic lymph nodes and extranodal organs. Immunohistochemical and Southern blot analyses showed polyclonal rearrangement of immunoglobulin genes in most of the lesions except for the pulmonary hilar lymph node. Furthermore, the analysis of restriction fragment length polymorphism with several fragments from EBV genome indicated that EBV genomes in all lesions were identical; however, a single but different-sized EBV termini was detected in every EBV-positive lesion when probed with the EcoRI-Dhet spanning terminal repeat region of EBV. The EBV-induced fatal LPD in a patient with WAS showed the characteristic clonotype, polyclonal immunoglobulin gene rearrangement, and monoclonal EBV terminal configuration. Furthermore, EBV termini in each lesion varied in size. This particular clonotype implicates several unique pathogenetic mechanisms for clonal proliferation of EBV-induced LPD.