Differential diagnosis of CNL. (A) Paraneoplastic neutrophilia associated with plasma cell myeloma. A 65-year-old man with recurrent plasma cell myeloma presented with marked leukocytosis (WBC, 55 × 109/L; 88% neutrophils). The peripheral blood smear shows normal neutrophil morphology, and NGS studies showed no pathogenic mutations. (B, C) Atypical chronic myeloid leukemia. A 74-year-old man presented with leukocytosis (WBC, 60 × 109/L; 73% neutrophils, 5% metamyelocytes, 5% metamyelocytes, 2% blasts). The peripheral smear shows striking dysgranulopoiesis, with nuclear hyposegmentation and nonlobation (B) or hypersegmentation (C), as well as hypogranulation of neutrophils. A circulating blast is present (lower center of image C). (D) MDS with mutated TP53/MDS with biallelic TP53 inactivation presenting with neutrophilia due to concurrent infection. A 70-year-old man presented with anemia (Hb, 8.5 g/dL) and leukocytosis (WBC, 25.4 × 109/L; 82% neutrophils). The peripheral smear shows markedly dysplastic neutrophils, with nuclear hyposegmentation and hypogranulation. The patient was found to have cellulitis; following treatment of the infection, the WBC normalized to 4.08 × 109/L. (E, F) Primary myelofibrosis (prefibrotic) with neutrophilia. A 49-year-old woman presented with leukocytosis (WBC, 39.6 × 109/L; 85% neutrophils) and thrombocytosis (platelet count, 1256 × 109/L). The peripheral blood smear (E) shows normally granulated neutrophils, without left shift, potentially simulating CNL. The bone marrow biopsy (F) is markedly hypercellular with a granulocytic predominance, also simulating CNL. However, the megakaryocytes are enlarged and hyperchromatic and exhibit prominent clustering, features that suggest a “classic” MPN rather than CNL. NGS showed a JAK2 V617F mutation and the absence of CSF3R mutation.