title: Fulminant EBV(+) T-cell lymphoproliferative disorder following acute/chronic EBV infection: a distinct clinicopathologic syndrome.
abstract: This study describes the clinicopathologic features of 5 patients who developed a fulminant Epstein-Barr virus (EBV)-positive clonal T-cell lymphoproliferative disorder (LPD) after acute EBV infection. One additional patient developed a similar disorder in the setting of long-standing chronic active EBV infection. Detailed immunophenotyping, in situ hybridization for EBV early RNA-1 (EBER1) and polymerase chain reaction (PCR) analyses for immunoglobulin (Ig) heavy chain and T-cell receptor (TCR)-gamma gene rearrangements were performed on paraffin-embedded tissue from all patients. In addition, EBV strain typing and detection of the characteristic 30-bp deletion of the latent membrane protein-1 (LMP-1) gene were performed by PCR. Controls included 8 cases of uncomplicated infectious mononucleosis (IM). Patients included 4 males and 2 females with a median age of 18 years (2-37 years). Three patients were Mexican, 2 were white, and 1 was of Asian descent. All presented with fever, hepatosplenomegaly, and pancytopenia; 5 were previously healthy, but had a clinical history of a recent viral-like upper respiratory illness (1 week to 2 months), and 1 patient had documented chronic active EBV infection for 7 years. Serologic data for EBV were incomplete but titers were either negative or only modestly elevated in 3 cases. In 1 case serology was consistent with severe chronic active EBV infection. In the remaining 2 cases serologic studies were not performed. All patients died within 7 days to 8 months of presentation with T-cell LPD. On histologic examination, the liver and spleen showed prominent sinusoidal and portal lymphoid infiltrates of CD3(+), beta F1(+), EBER1(+) T cells lacking significant cytologic atypia. Two cases were CD4(+), 2 cases were CD8(+), and 2 cases had admixed CD4(+) and CD8(+) cells without clear subset predominance. All were TIA-1(+), CD56(-). Only rare B cells were noted. Marked erythrophagocytosis was present. Molecular analysis revealed identical T-cell clones in 2 or more sites (liver, spleen, lymph node) in 5 cases. All patients carried type A EBV; 4 cases had wild-type EBV-LMP, and 2 showed the 30-bp deletion. This fulminant T-cell LPD after acute/chronic EBV infection is characterized by hepatosplenomegaly, often without significant lymphadenopathy, fever, liver failure, pancytopenia, and erythrophagocytosis indicative of a hemophagocytic syndrome. EBV serology may be misleading, with lack of elevated titers. The presence of an EBER1(+) T-cell infiltrate with scant B cells should alert one to this diagnosis. Although cytologic atypia is minimal, studies for T-cell clonality confirm the diagnosis. (Blood. 2000;96:443-451)
authors.affiliation: Hematopathology Section, Laboratory of Pathology, National Cancer Institute, and Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
authors.forename: L
authors.initials: L
authors.lastname: Quintanilla-Martinez
authors.forename: S
authors.initials: S
authors.lastname: Kumar
authors.forename: F
authors.initials: F
authors.lastname: Fend
authors.forename: E
authors.initials: E
authors.lastname: Reyes
authors.forename: J
authors.initials: J
authors.lastname: Teruya-Feldstein
authors.forename: D W
authors.initials: DW
authors.lastname: Kingma
authors.forename: L
authors.initials: L
authors.lastname: Sorbara
authors.forename: M
authors.initials: M
authors.lastname: Raffeld
authors.forename: S E
authors.initials: SE
authors.lastname: Straus
authors.forename: E S
authors.initials: ES
authors.lastname: Jaffe
mesh_terms: D000293:Adolescent; D000328:Adult; D002675:Child, Preschool; D020031:Epstein-Barr Virus Infections; D017809:Fatal Outcome; D005260:Female; D015326:Gene Rearrangement, B-Lymphocyte, Heavy Chain; D015334:Gene Rearrangement, gamma-Chain T-Cell Antigen Receptor; D004854:Herpesvirus 4, Human / Q000145:classification / Q000235:genetics; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D016130:Immunophenotyping; D017403:In Situ Hybridization; D008099:Liver / Q000473:pathology; D008232:Lymphoproliferative Disorders / Q000276:immunology / Q000473:pathology / Q000821:virology*; D008297:Male; D012367:RNA, Viral / Q000032:analysis / Q000235:genetics; D013154:Spleen / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
chemical_list: C099537:Epstein-Barr virus encoded RNA 1; D007143:Immunoglobulin Heavy Chains; D012367:RNA, Viral