Autoimmune Lymphoproliferative Syndrome and Epstein-Barr Virus-Associated Lymphoma: An Adjunctive Diagnostic Role for Monitoring EBV Viremia?

Background. Autoimmune lymphoproliferative syndrome (ALPS) is a genetic disorder of lymphocyte homeostasis due to defects in FAS-mediated apoptosis. ALPS is characterized by childhood onset of chronic lymphadenopathy and splenomegaly, autoimmunity, an expanded population of double-negative T cells (DNTCs), and an increased risk of lymphoma. This propensity for lymphoma in ALPS is not well understood. It is possible that lymphomagenesis in some of these patients may result from Epstein-Barr virus (EBV) infection exploiting the defective T-cell surveillance resulting from impaired FAS-mediated apoptosis. Case Presentation. We report the first case, to our knowledge, of lymphoma in a patient with ALPS that was clinically heralded by progressively increasing EBV viremia. We discuss its practical implications and the possible immune pathways involved in the increased risk for EBV-associated lymphoproliferative disorders in ALPS patients. Conclusion. In patients with ALPS, distinguishing chronic lymphadenopathy from emerging lymphoma is difficult, with few practical recommendations available. This case illustrates that, at least for some patients, monitoring for progressively increasing EBV viremia may be useful. 1. Background Autoimmune lymphoproliferative syndrome (ALPS) is a Mendelian disorder of lymphocyte homeostasis caused by defects in FAS-mediated apoptosis [1]. The majority of cases to date are due to heterozygous germline mutations in the APT1 (TNFRSF6) gene, which encodes the cell surface-expressed transmembrane receptor, FAS (CD95) [2]. Ligation of FAS by its cognate ligand (FAS ligand; FAS-L) triggers B- and T-lymphocyte apoptosis. Mutations in FAS, FAS-L, or in the downstream molecules that constitute the apoptosis-inducing complex (i.e., Caspase-10) impair programmed cell death of lymphocytes. Consequently, ALPS is characterized by childhood onset of chronic (>6 months) noninfectious, nonmalignant lymphadenopathy and splenomegaly, associated with an increased circulating number of a unique T-cell population that is CD3+ and expresses the receptor but is CD4？ and CD8？, the so-called double-negative T cells (DNTCs). DNTCs are considered elevated when they are >1.5% of total lymphocytes or >2.5% of CD3+ lymphocytes in the setting of normal or elevated lymphocyte counts [2]. Additional diagnostic criteria for ALPS include polyclonal hypergammaglobulinemia, elevated vitamin B12 levels, and elevated immune biomarkers in plasma (e.g.,？soluble FAS-L, IL 10, and IL-18) [2]. The clinical course of ALPS is marked by increased rates of autoimmunity and of