A 39-year-old man presented with fever, pancytopenia, hepatosplenomegaly, and hyperbilirubinemia, as well as elevated triglycerides, ferritin (>88 888 μg/L), and soluble interleukin-2 receptor (58 370 U/mL). The diagnostic criteria of hemophagocytic lymphohistiocytosis (HLH) were met. Bone marrow was empty, without hemophagocytosis. The patient received etoposide, dexamethasone, and rituximab because of a high Epstein Barr virus (EBV) load; IV immunoglobulin; and, later, cyclosporine and ruxolitinib. After 2 months without improvement, ultrasound showed new hypodense lesions in the spleen, confirmed by positron emission tomography/computed tomography with high standard uptake value (13.8). Ultrasound-controlled puncture and biopsy of the spleen was performed. Modified Wright staining (panel A; magnification ×60) of the spleen smear showed blasts with dispersed chromatin and a basophilic scanty cytoplasm. Flow cytometry revealed a CD2⁺/CD56⁺ natural killer (NK) cell population. Histology showed extensive infiltration with blasts of T/NK-cell phenotype with EBV association and expression of CD2, CD3, CD16, and CD56 (panel B; magnification ×40; anti-CD56 immunohistochemical stain [DAB; Dako EnVision]); EBV-encoded small RNA; and a high proliferation index of 90% (Ki-67). In correlation with the clinical presentation, aggressive NK-cell leukemia (ANKL) associated with HLH was diagnosed, for which prognosis is poor. The patient died despite therapy with cyclophosphamide, doxorubicin, vincristine, prednisolone, asparaginase, and cytarabine.

Particularly in patients with ANKL associated with HLH, the neoplastic cells may present as leukemic cells with basophilic cytoplasm.