The cytological features of NPM1‐mutated acute myeloid leukemia

A 69-year-old woman with a previous history of type 2 diabetes mellitus presented with a 2-week history of worsening abdominal pain, reduced oral intake, and lethargy. She was pyrexial (39°C) with a sinus tachycardia. Her full blood count showed: hemoglobin concentration 119 g/l, white cell count 151.5 × 109/l, and platelet count 33 × 109/l. The blood film showed many circulating blast cells. These were of medium size with a high nucleocytoplasmic ratio. Many of them had an indentation in the nucleus, producing a cup-like shape when viewed in profile; when viewed from above, the invagination sometimes simulated a giant nucleolus (images). Nuclear indentations were apparent also in smear cells. Cytoplasmic basophilia varied from moderate to strong. A minority of basophilic blast cells had cytoplasmic blebs. Some blast cells contained Auer rods, usually one but up to three per cell, these often being related to the nuclear indentation. The cytological features were considered strongly suggestive of acute myeloid leukemia (AML) with NPM1 mutation and further investigations were arranged. A bone marrow aspirate showed 89% blast cells with similar cytological features to those in the peripheral blood. Flow cytometry gated on the blast population showed expression of CD33, CD117 and CD123 with partial expression of HLA-DR and myeloperoxidase. CD34 was not expressed. Blast cells were also negative for CD13, CD11b, CD14, CD64, CD56, and CD7. Standard cytogenetic analysis yielded no metaphases but molecular analysis showed both a 4 bp insertion in NPM1 and a FLT3-internal tandem duplication (ITD) of 24 bp. The patient responded to broad-spectrum antibiotics without a focus of infection being identified, and entered complete remission following the initial course of cytarabine and daunorubicin. Cup-shaped blast cells are associated with NPM1 mutation, particularly when there is coexisting FLT3-ITD.1, 2 They can also occur with AML associated with FLT3-ITD without NPM1 mutation. The nuclear pockets are shown on ultrastructural examination to be occupied by a collection of mitochondria, lysosomes and endoplasmic reticulum.1, 2 The light microscopy features of NPM1-mutated AML are sufficiently distinctive to suggest this diagnosis. The CD34-negativity, often with HLA-DR also being negative, could lead to confusion with the variant form of acute promyelocytic leukemia but the nuclear shape differs.