A 27-year-old woman was incidentally noted to have leukocytosis and macrocytic anemia during her pregnancy. She later presented for sustained leukocytosis, monocytosis for about one year, macrocytic anemia, and hepatosplenomegaly. There was no family history of cancer or personal evidence of a syndrome. PB, bone marrow (BM) aspirate, and core biopsy were submitted for morphology, flow cytometric immunophenotyping, cytogenetics, and molecular studies.
The PB smear (Fig. 1A) demonstrated granulocytic leukocytosis (WBC 35 x 109/L) with left-shifted neutrophils, including myelocytes and metamyelocytes [5%, green arrow; mature neutrophils (segmented/banded) 62%] and occasional dysplastic neutrophils, markedly relative and absolute monocytosis (29%, 7 x 109/L, blue arrow), severe anemia (hemoglobin 4.3 g/dL) with occasional coarse basophilic stippling (orange arrow), and mild thrombocytopenia (platelets 146 x 109/L). BM aspirate smear demonstrated left-shifted granulopoiesis with 3% myeloblasts (Fig. 1B, red arrow), scattered atypical/dysplastic neutrophils, increased monocytic cells (10%, blue arrow), dysplastic erythroids with ring sideroblasts (10% of erythroids, Fig. 1C, orange arrow) and nuclear irregularity (Fig. 1D, orange arrow), increased myeloid: erythroid ratio (7.9:1), and dysplastic hypolobated and small megakaryocytes (Fig. 1E, violet arrow). Core biopsy and clot sections (Fig. 1F) showed a hypercellular BM (cellularity ~100%) with increased left-shifted granulocytic and monocytic cells and occasional hypolobated megakaryocytes.
Flow cytometric analysis on the BM aspirate (Fig. 2) was performed on 10-color BD FACSCanto flow cytometer (Becton Dickinson, San Jose, CA) and analyzed using cluster analysis with Cytopaint Classic Software (Leukobyte, CA). Analysis revealed a 0.88% population of CD34(+)/CD117(+) myeloblasts (in red) with immunophenotypic aberration [CD56(+), CD5(dim+), CD33(dim+), CD11b (few +)], abnormal maturation pattern in neutrophils (in green) on the CD11b/CD13 plot, and increased immunophenotypically aberrant monocytes (in blue, 11% with a nearly uniform expression of CD56) and a high fraction of CD14(+)/CD16(-) classical monocytes (estimated at 96% of total monocytes).
The cytogenetic study revealed a normal female karyotype. Next Generation Sequencing (NGS) by Foundation Heme panel revealed mutations in CSF3R T618I [VAF (variant allele frequency) 11.2%)], KRAS G12D (5.8%), ASXL1 S1014fs*10 (48.2%), BCORL1 R1149W (51.5%), PTPN11 E76Q (2.0%), SETBP1 D868N (3.8%), and SETBP1 G870S (5.1%); there was no evidence of mutations in JAK2, MPL, CARL, TET2, or SRSF2, or fusion of BCR-ABL1. PTPN11 E76Q has been reported in hematologic malignancies and is likely a somatic mutation given its low VAF (2.0%). Overall, there are no-known risk factors for inherited predisposition syndromes.
The constellation of morphologic and immunophenotypic findings in conjunction with molecular abnormalities led to a diagnosis of CMML-1 with an unusual CSF3R T618I mutation. The follow-up clinical information regarding treatment and prognosis is not available.