EBV-negative Aggressive NK-cell Leukemia/Lymphoma

Abstract

Aggressive natural killer cell leukemia (ANKL) is a systemic NK-cell neoplasm, almost always associated with 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 seven EBV-negative ANKL. All patients were adults, with median age of 63 years (range 22–83) and a M:F ratio of 2.5:1. Five patients were White, one Black and one 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 4 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, Beta F1, TCRγ, LMP1 and EBER. PCR 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 BMT and is alive with no disease (follow-up 15 months). 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.

Aggressive NK-Cell Leukemia

“…In contrast, a certain proportion of ANKL patients (~10%) are negative for EBV. Initial reports have suggested a better prognosis of EBV-negative ANKL than EBV-positive ANKL ( 9 ), but findings are not consistent ( 6 , 18 ). No morphologic or immunophenotypic features reliably discriminate between EBV-positive and EBV-negative ANKL ( 9 , 18 ).…”

“…Genetic alterations of ANKL have been largely unclear, in contrast to the wealth of information available for ENKL, a closely related disease of ANKL. With target sequencing of a limited number of ANKL patients, including EBV-negative cases, mutations in STAT3 or STAT5B , molecules of the JAK/STAT signaling system, have been identified, but not in JAK3 , the molecule in which recurrent mutations were first identified in ENKL ( 18 , 21 , 22 ).…”

Clinical Features, Pathogenesis, and Treatment of Large Granular Lymphocyte Leukemias

“…In most patients, clonal EBV is found in tumor cells, and EBV is considered to be the etiological agent ( 89 , 104 , 105 ). Rare cases of EBV-negative ANKL have been described ( 106 ). It tends to occur in older patients and is clinically and pathologically indistinguishable from EBV-positive ANKL, with a similar fulminant clinical course.…”

EBV-Positive Lymphoproliferations of B- T- and NK-Cell Derivation in Non-Immunocompromised Hosts

“…The aetiology is unknown but the strong association with EBV suggests a pathogenetic role of the virus [ 201 ]. Nevertheless, in the last years, cases of EBV-negative ANKL have been reported [ 210 , 211 ]. EBV-negative ANKL seems to be indistinguishable clinically and pathologically from the EBV-positive cases.…”

“…EBV-negative ANKL seems to be indistinguishable clinically and pathologically from the EBV-positive cases. However, patients with EBV negative disease tend to be older at presentation (median age 63 years) [ 211 ]. Some of the EBV-negative cases have been reported to evolve from chronic lymphoproliferative disorder of NK cells [ 207 , 211 , 212 ].…”