title: The ambiguous boundary between EBV-related hemophagocytic lymphohistiocytosis and systemic EBV-driven T cell lymphoproliferative disorder.
abstract: Epstein Barr virus (EBV)-related hemophagocytic lymphohistiocytosis (EBV-HLH) is a form of acquired, infection-related HLH which typically represents a fulminant presentation of an acute EBV infection of CD8+ T cells with 30-50% mortality rate. Systemic EBV-positive lymphoproliferative disease of childhood (SE-LPD) is a rare T cell lymphoproliferative disorder predominantly arising in the setting of acute EBV infection, often presenting with HLH. Since both entities have been associated with clonal T cell populations, the discrimination between these diseases is often ambiguous. We report a unique case of a 21 years old female who presented with clinical and laboratory findings of florid HLH in the setting of markedly elevated EBV titers (>1 million) and an aberrant T cell population shown to be clonal by flow cytometry, karyotype, and molecular studies. This case raises the differential of EBV-HLH versus SE-LPD. Review of the literature identified 74 cases of reported EBV-HLH and 21 cases of SE-LPD with associated HLH in 25 studies. Of those cases with available outcome data, 62 of 92 cases (67%) were fatal. Of 60 cases in which molecular clonality was demonstrated, 37 (62%) were fatal, while all 14 cases (100%) demonstrating karyotypic abnormalities were fatal. Given the karyotypic findings in this sentinel case, a diagnosis of SE-LPD was rendered. The overlapping clinical and pathologic findings suggest that EBV-HLH and SE-LPD are a biologic continuum, rather than discrete entities. The most clinically useful marker of mortality was an abnormal karyotype rather than other standards of clonality assessment.
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center Nashville TN, USA.
authors.forename: Megan C
authors.initials: MC
authors.lastname: Smith
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center Nashville TN, USA.
authors.forename: Daniel N
authors.initials: DN
authors.lastname: Cohen
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center Nashville TN, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Greig
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center Nashville TN, USA.
authors.forename: Ashwini
authors.initials: A
authors.lastname: Yenamandra
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center Nashville TN, USA.
authors.forename: Cindy
authors.initials: C
authors.lastname: Vnencak-Jones
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center Nashville TN, USA.
authors.forename: Mary Ann
authors.initials: MA
authors.lastname: Thompson
authors.affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center Nashville TN, USA.
authors.forename: Annette S
authors.initials: AS
authors.lastname: Kim
mesh_terms: D001706:Biopsy; D003937:Diagnosis, Differential; D020031:Epstein-Barr Virus Infections / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000821:virology; D005260:Female; D005434:Flow Cytometry; D004854:Herpesvirus 4, Human / Q000302:isolation & purification; D006801:Humans; D007150:Immunohistochemistry; D007621:Karyotyping; D051359:Lymphohistiocytosis, Hemophagocytic / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000821:virology; D016399:Lymphoma, T-Cell / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000601:surgery / Q000821:virology; D036102:Peripheral Blood Stem Cell Transplantation; D011237:Predictive Value of Tests; D013601:T-Lymphocytes / Q000276:immunology* / Q000821:virology; D016896:Treatment Outcome; D055815:Young Adult
keywords: EBV-related HLH; EBV-related T cell lymphoma; Systemic EBV-positive lymphoproliferative disease of childhood; atypical T cell population; clonal EBV-related HLH