Marked eosinophilia masking B lymphoblastic leukemia
Authors: Hui Yu, Gerald Wertheim, Sadhna Shankar, Michele Paessler, Richard Aplenc, Vinodh Pillai
Journal: American Journal of Hematology (2015)

A 13-year-old male presented with progressive shortness of breath and cough. A CBC showed leukocytosis (WBC 133850/μl, hemoglobin 7.8 g/dl, hematocrit 25.8%, platelet 532000/μl) with marked eosinophilia (eosinophils 71%, segmented neutrophils 15%, bands 4%, basophils 4%, monocytes 1%, lymphocytes 3% with absolute eosinophil count of 95170/μl). Radiological studies showed cardiomegaly and bilateral pleural effusions consistent with restrictive cardiomyopathy. A workup for infectious and autoimmune causes of eosinophilia were negative. Bone marrow aspirate was spicular and hypercellular with atypical hyperlobated eosinophils. Bone marrow biopsy showed that the majority of the cellularity was composed of atypical eosinophils (upper panel, middle). Flow cytometric studies were negative for an abnormal blast population. Conventional cytogenetics revealed a normal karyotype, FISH studies were negative for PDGFRA, PDGFRB, FGFR1, BCR-ABL1 or CBFB-MYH11 translocations, and comparative genomic hybridization studies were unremarkable. Molecular studies for PDGFRA, MPL W515, MPL S505, JAK2 V617F, JAK2 Exon 12, and JAK2 Exon 13 mutations were negative. With a presumptive diagnosis of hypereosinophilic syndrome, he was treated with prednisone, hydroxyurea and imatinib for 2 months. There was a decrease in WBC but not resolution of his eosinophilia or his cardiac symptoms. On review of bone marrow biopsies at our institution, dense paratrabecular aggregates composed of small lymphoid cells (upper panel, middle, and right) were noted that were positive for CD19, CD34, and TdT (lower panel, left, and middle) consistent with lymphoblasts. Though the overall blast count was less than 25%, focally, the blast count was very high, consistent with a diagnosis of B-lymphoblastic leukemia (B-LL). A repeat bone marrow biopsy performed to confirm the diagnosis revealed small lymphoid blasts that constituted 11% of the cellularity in the aspirate (lower panel, right) and approximately 50% in the biopsy (not shown). Flow cytometric studies showed an abnormal blast population that was CD45(dim), CD10(bright), CD19, CD34, CD38(dim), and TdT. Routine karyotype, FISH, and genome wide single nucleotide polymorphism studies did not reveal any abnormalities. Next generation sequencing (FoundationOne™ Heme panel) revealed an IL3-IgH rearrangement and PIK3CA mutation. The presence of an IL3-IgH rearrangement is diagnostic of B-LL regardless of blast count confirming the initial diagnosis. The patient subsequently received standard therapy for acute lymphoblastic leukemia. He achieved a morphological remission with positive minimal residual disease (MRD) at the end of induction but was in a MRD negative remission at the end of consolidation. Additionally, his eosinophilia and secondary cardiomyopathy resolved. Eosinophilia is associated with a number of reactive and malignant conditions that should be ruled out after comprehensive testing and careful analysis of the bone marrow. Eosinophils can mask an underlying or co-existing leukemia. They can be either part of the neoplastic clone, as in acute myeloid leukemia with inv(16), or can be reactive to the leukemic clone as in B-ALL with IL3-IgH translocation. The detection of lymphoblasts in this patient was complicated by the small size of blasts in the peripheral blood and aspirate. The presence of large clusters lymphoid-appearing cells, packed against the trabeculae by the eosinophilic infiltrate, was the first clue that this represented leukemia, and led to the confirmatory immunohistochemical studies. The negative cytogenetic and FISH results are likely due to the low levels of blasts in the aspirates. The IL3-IgH translocation was demonstrated by sensitive next-generation sequencing. The results emphasize the need for an extensive pathologic workup for unexplained hypereosinophilia with particular attention to careful morphologic, immunophenotypic and molecular studies.