Submitting Author: Evans, Harold Lance, MD
Institution: University of Maryland Medical Center
Additional authors:Zeba Singh MD, Qing Chen MD/PhD, Daniel Fix MD
Session: B Lymphoblastic Leukemia/Lymphoma

A 24 year old female with a history of asthma presented at a community hospital with flu like symptoms and a sore throat. She was initially given amoxycillin. She did not improve and developed substernal chest pain and dyspnea, as well as blurry vision. She returned to a community hospital two days later and was found to have a white count of 158K/uL, with 78% eosinophils. In addition, elevated troponin (3.49 ng/uL) and inferolateral ST depressions on EKG were noted. At this time she was transferred to University of Maryland Medical Center. At admission she had a WBC count of 188K/uL, 88% eosinophils, HGB 12.9 g/dL, platelets 54K/uL. Blood cultures were negative. She received imatinib and steroids, and underwent leukapheresis. Cardiac MRI was showed endomyocardial fibrosis and extensive mural thrombus. Four days after admission she became agitated and then unresponsive. She also became increasingly hypotensive, despite IVF resucitation and extensive pressor support, and died. The most likely etiology of shock was felt to be cardiogenic secondary to eosinophilic cardiomyopathy. Autopsy was declined.

A bone marrow biopsy (left posterior iliac crest), aspirate, and clot section were performed.

Concurrent CBC (post-leukopheresis - WBC 66.1k/uL, HgB 13.8g/dL, Hct 40.7%, MCV 87.9 fL, Plt 38k/uL (WBC differential neutrophils 32%, lymphocytes 1%, monocytes 1%, eosinophils 64%, basophils 2%.)

Gross pathology: White tand brown bone core measuring 1.5 cm x 0.2cm and a dark red blood clot measuring 1.5 x 1.1 x 0.2 cm, received in 10% neutral buffered formalin

Microscopic pathology:

Peripheral blood smear: Marked leukocytosis with marked mature eosinophilia and moderate neutrophilia. Some eosinophils showed three or four lobes. Blasts not identified in peripheral blood. Left-shited granulocytes were not noted. Erythrocytes mainly unremarkable. Platelets decreased in number and mainly normal in morphology.

Bone marrow aspirate: Spicules were present. The M:E ratio was greater than 10:1. The neutrophil lineage showed full maturation without left shift or dyspoiesis. There was a marked increase in eosinophils with a full spectrum of maturation. Erythroid maturation was complete without overt dysplasia. Megakaryocytes were present, with normal morphology. Blasts represented 4% of marrow cellularity by 200 cell aspirate count. No auer rods were identified. The blasts present were small to medium sized with dispersed chromatin and scant cytoplasm, occasional irregular nuclear contours, and rare cytoplasmic vacuoles. (A bone marrow aspirate differential count showed: blasts 4%, neutrophils and precursors 22%, eosinophils and precursors 58%, basophils 1%, monocytes <1%, lymphocytes 7%, plasma cells 1%, nucleated erythroid cells 7%.)

Bone marrow biopsy: The marrow was hypercellular for age (95%), with marked granulocytic hyperplasia and sheets of eosinophils. Full granulocytic maturation was present. There were foci with increased blast concentration, mainly paratrabecular. There was a mainly paratrabecular increase in small to medium sized blasts with dispersed chomatin, scant cytoplasm, and mainly irregular nuclear contours. Megakaryocytes were present in decreased proportion and showed mainly normal morphology. There was a relative erythroid hypoplasia. There was a moderate increase in reticulin fibrosis (2-3+ on a scale of 0 to 4).

Clot section: The clot section showed similar features to those seen in the aspirate and core biopsy.

Flow cytometry was performed on a whole bone marrow specimen. Within the dim CD45/variable side scatter gate, an abnormal population of B-lymphoblasts (up to 5% of events), which expressed CD10 (very bright), CD19, CD34, CD38, cytoplasmic CD79a, and HLA-DR, with aberrant expression of CD13 and CD33 (dim). CD20 was weakly expressed by a subset of blasts (10-15%). The blasts were negative for MPO, CD3 (surface and cytoplasmic), TdT, and all T-cell and myeloid markers tested. No atypical T-cell population was identified.

Immunohistochemistry performed on the formalin fixed, paraffin embedded core biopsy section showed that the core biopsy contained a population of CD34+,

Pax-5+, CD79a+ lymphoid blasts, estimated at approximately 10% of overall cellularity, but in some foci accounting for >30% of cellularity. The blasts showed subset expression of CD20. Blasts were clustered primarily in paratrabecular zones. CD117 demonstrated a few scattered mast cells. CD3 showed a few scattered T-cells.

Metaphase cytogenetics revealed a 46, XX karyotype.

Interphase FISH was negative for abnormalities involving PDGFRA, PDGFRB, FGFR1, and MLL genes, and was negative for t(9;22)/BCR-ABL translocation.

Clonality assessment by PCR showed clonal rearrangement of the TCR gamma chain gene; IgH gene rearrangement was negative

In this case, massive hypereosionophilia presented concurrently with incipient B acute lymphoblastic leukemia.

Other, more characteristic causes of massive hypereosinophilia were excluded. In particular, interphase FISH was negative for abnormalities involving PDGFRA, PDGFRB, FGFR1, and MLL genes, and was negative for t(9;22)/BCR-ABL translocation. There was no evidence of mast cell proliferation. No abnormal T-cell populations were noted by flow cytometry.

This is an extremely rare association. Less than 1% of cases of B-ALL are associated with hypereosinophilia. The vast majority of cases of massive hypereosinophilia for which a clonal proliferation can be documented do not show any element of B-ALL. In addition, in rare reported cases of concurrent B-ALL and hypereosinophilia, there has often been an underlying FGFR1 abnormality, which was not detected here, nor was the t(5;14) translocation involving IgH and IL-3 genes detected by metaphase cytogenetics.

1) Wilson, F and Tefferi, A. Acute lymphocytic leukemia with eosinophilila: Two case reports and a literature review. Leukemia and Lymphoma, 46(7):1045-1050, 2005

2) Roufosse, F., Garaud S., de Leval L. Lymphoproliferative disorders with associated hypereosinophilia. Seminars in Hematology, 49(2):138-48, 2012

B-lymphoblastic leukemia with hypereosinophilia

B-acute lymphoblastic leukemia with hypereosinophilia

Case 387