title: EBV-negative Aggressive NK-cell Leukemia/Lymphoma: Clinical, Pathologic, and Genetic Features.
abstract: Aggressive natural killer cell leukemia (ANKL) is a systemic NK-cell neoplasm, almost always associated with Epstein-Barr virus (EBV). Rare cases of EBV-negative ANKL have been described, and some reports suggested more indolent behavior. We report the clinicopathologic, immunophenotypic, and molecular characteristics of 7 EBV-negative ANKL. All patients were adults, with a median age of 63 years (range 22 to 83 y) and an M:F ratio of 2.5:1. Five patients were White, 1 Black, and 1 Asian. All patients presented acutely, with fever (6/7), cytopenias (6/7), and splenomegaly (4/7). Four patients had lymphadenopathy, 4 had extranodal disease. Bone marrow involvement was present in 5, with hemophagocytosis in 3. Peripheral blood was involved in 5 with the neoplastic cells containing prominent azurophilic granules. By immunohistochemistry and/or flow cytometry, the tumor cells lacked surface CD3 and were positive for CD56 (7/7), CD2 (5/5), CD8 (3/7), CD30 (4/5), and granzyme-B (6/6). They were negative for CD4, CD5, βF1, TCRγ, LMP1, and EBV-encoded RNA. Polymerase chain reaction for TCRG clonality was polyclonal. Mutational analysis revealed missense mutations in the STAT3 gene in both cases studied. Median survival was 8 weeks from the onset of disease. One patient received allogeneic bone marrow transplant and is alive with no disease (follow-up 15 mo). EBV-negative ANKL exists but is rare. It tends to occur in older patients and is indistinguishable clinically and pathologically from EBV-positive ANKL, with a similar fulminant clinical course. The high prevalence of Asian patients seen with EBV-positive disease seems less evident with EBV-negative cases.
authors.affiliation: *Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda ‡Department of Veteran Affairs, Maryland Healthcare System, Baltimore ∥Department of Pathology, Univerity of Maryland, St Joseph Medical Center, Towson, MD †Departments of Pathology and Dermatology, UT-MD Anderson Cancer Center, Houston, TX §Kaiser Permanente, Los Angeles, CA ¶Wayne Memorial Hospital, The Commonwealth Medical College, Scranton, PA.
authors.forename: Alina
authors.initials: A
authors.lastname: Nicolae
authors.forename: Karthik A
authors.initials: KA
authors.lastname: Ganapathi
authors.forename: Trinh Hoc-Tran
authors.initials: TH
authors.lastname: Pham
authors.forename: Liqiang
authors.initials: L
authors.lastname: Xi
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Torres-Cabala
authors.forename: Nahid M
authors.initials: NM
authors.lastname: Nanaji
authors.forename: Hongbin D
authors.initials: HD
authors.lastname: Zha
authors.forename: Zhen
authors.initials: Z
authors.lastname: Fan
authors.forename: Sybil
authors.initials: S
authors.lastname: Irwin
authors.forename: Stefania
authors.initials: S
authors.lastname: Pittaluga
authors.forename: Mark
authors.initials: M
authors.lastname: Raffeld
authors.forename: Elaine S
authors.initials: ES
authors.lastname: Jaffe
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D004252:DNA Mutational Analysis; D020031:Epstein-Barr Virus Infections; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007150:Immunohistochemistry; D016130:Immunophenotyping; D017403:In Situ Hybridization; D054066:Leukemia, Large Granular Lymphocytic / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D055815:Young Adult