| Session: Chronic myelogenous leukemia |
| Case number: 186 |
Submitter(s): Karl S. Theil, Raymond R. Tubbs.
Clinical history
A 63 year old man with a 3 month history of chronic myelogenous leukemia (CML) in chronic phase (1% blasts) was treated with imatinib mesylate (Gleevec®) 400 mg/d and within 2 months had normalization of WBC and resolution of splenomegaly. Cytogenetic analysis showed a 45,X,-Y,t(9;22)(q34;q11.2)[20] karyotype, and interphase FISH using dual-color, dual-fusion probes for BCR-ABL1 was positive: nuc ish(ABL1 x 3),(BCR x 3),(ABL1 con BCR x 2). One month later he presented with progressive leukocytosis, thrombocytopenia, and splenomegaly. A CBC showed: WBC 47,500/uL; Hgb 11.0 g/dL; MCV 94.5 fL; and platelets 36,000/uL. There were 77% blasts, 10% neutrophils, 12% monocytes, and 1% eosinophils.
Details of gross/microscopic pathology:
Peripheral blood smear (figure 1) showed blasts with high nuclear:cytoplasmic ratios, agranular cytoplasm; nuclei with irregular nuclear outlines and variably prominent nucleoli; and no Auer rods. The marrow aspirate (figure 2) showed 95% blasts with identical morphology. A marrow biopsy (figure3) (figure 4) was 90% cellular; normal hematopoiesis was replaced by an infiltrate of blasts (figure 5).
Immunophenotype (flow cytometry/immunohistochemistry):
Flow cytometry of the marrow aspirate showed 87% blasts expressing a precursor B lymphoblast phenotype: CD45+, CD34+, CD19+, CD10+, CD20+, HLA-DR+, TdT+, cIgM-, and sIgM-, without aberrant myeloid (CD13, CD33, CD14, CD117, CD65), NK (CD56), or T lymphoid antigen (CD2, CD5, CD7) expression.
Cytogenetics:
Cytogenetic analysis of the marrow aspirate (figure 6) showed a 44,X,-Y,del(9)(p21),der(9)t(9;22)(q34;q11.2),-20,der(22)t(9;22)(q34;q11.2)hsr(22)(q11.2)add(9)(q34)[16]/45,idem,+21[4] karyotype.
Molecular analysis:
Interphase FISH using dual-color, dual-fusion probes for BCR (green) and ABL1 (orange) genes (Abbott Molecular, Inc., Des Plaines, IL) demonstrated an abnormal signal pattern, with 99% of nuclei showing BCR-ABL1 amplification (3-6 clustered BCR-ABL1 fusion signals per nucleus).(figure 7) Metaphase FISH (figure 8) (figure 9) demonstrated the expected ABL1 and BCR signals on chromosomes 9 and 22, respectively, and amplification of multiple tandem BCR-ABL1 fusion signals in the homogeously staining region of the abnormal Philadelphia chromosome: der(22)t(9;22) .ish t(9;22)(ABL1+,BCR+;BCR x 2~6,ABL1 x 2~6).
Interesting feature(s) of submitted case:
While the majority of patients with CML respond to treatment with imatinib mesylate, a subset develop disease relapse or progression during therapy. Molecular mechanisms of resistance include acquired mutations in the BCR-ABL1 protein or overexpression of the tyrosine kinase that may be related to genomic amplification of BCR-ABL1. Although infrequent, genomic amplification has been observed in both lymphoid and myeloid blast phases of CML. It is important to recognize aberrant FISH signal patterns that correlate with gene amplification (double minutes, homogenously staining regions, or extra copies of the Philadelphia chromosome).
Proposed diagnosis:
Chronic myelogenous leukemia, blast phase (precursor B lymphoblastic leukemia) with genomic amplification of BCR-ABL1.
Panel diagnosis:
agree with proposed diagnosis
Comments:
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