Aggressive natural killer (NK) cell leukemia (ANKL) is a prototype of an Epstein-Barr virus (EBV)-associated lymphoid malignancy, which is characterized by a fulminant clinical course and a median survival interval <2 months. EBV negativity in ANKL is uncommon, and the characteristics of EBV-negative ANKL are not well defined. We compared the clinicopathological characteristics of EBV-negative ANKL patients (group 1, n = 2) with those of EBV-positive ANKL patients (group 2, n = 14) and reviewed the literature for reports on EBV-negative ANKL cases. EBV-negative and EBV-positive ANKL patients had similar clinical and pathological characteristics, but EBV-negative patients had a longer survival than EBV-positive patients (11.5 vs. 1.5 months, respectively). EBV-negative patients achieved complete remission, but tumors often relapsed after a short interval. In conclusion, EBV-negative ANKL is an uncommon malignancy that pursues a less aggressive clinical course than EBV-positive ANKL.

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