| Session: Mast cell disease |
| Case number: 162 |
Submitter(s): Arshad N. Ahsanuddin, Christopher Corless, Karen P. Mann.
Clinical history
46 M with lightheadedness for 1 week.
Admission CBC:
WBC 92.6 10E+3 cells/ul
RBC 2.36 10E+6 cells/ul
Hgb 7.7 g/dl
Hct 22.0 %
MCV 93.4 fl
MCH 32.7 pg
MCHC 35.0 g/dl
RDW 18.8 %
PLT 57 10E+3/ul
MPV 8.3 fl
Admission Manual Differential:
Band 1%
Seg 9%
Lymph 3%
Mono 4%
Eos 0%
Baso 0%
Metamyelo 1%
Myelo 0%
Promyelo 0%
Blast 82%
Admission Meds: Geodon 20mg.
Details of gross/microscopic pathology:
Peripheral Smear: A marked increase in blasts is seen, with large oval and occasionally indented nuclei; prominent, multiple nucleoli; and moderately abundant cytoplasm (Figure 1). A subset of blasts contains Auer rods.
Bone Marrow Aspirate Smear: Blasts comprise 60% of the nucleated cells (Figure 2). Mast cells comprise 20% of nucleated cells.
Bone Marrow Core Biopsy (B5 fixation and acid decalcification): Cellularity is markedly increased to greater than 95%, with 60% blasts. Pale areas comprise 20%, composed of mononuclear cells with moderate amounts of pale cytoplasm, in a paratrabecular and perivascular pattern (Figure 3), which are positive with a CD117 stain, indicating mast cell aggregates (Figure 4).
Immunophenotype (flow cytometry/immunohistochemistry):
The pre-treatment bone marrow aspirate contains 51% myeloblasts with coexpression of CD13, partial CD15, partial CD19, CD34, CD38, partial CD56, CD117, HLA-DR, and low density CD45. A small population of mast cells is indicated by the arrow (Figure 5). The post-treatment bone marrow aspirate shows a marked decrease in blasts and a prominent mast cell population, indicated by the arrow (Figure 6).
Cytogenetics:
Cytogenetics: 46,XY,t(8;21)(q22;q22),del(9)(q22q34) in 20/20 metaphases (Figure 7). FISH for AML1/ETO was positive for AML1/ETO (Figure 8) in 64% of cells using a double fusion probe: nuc ish (ETOx3)(AML1x3)(ETO con AML1x2) [129/200].
Molecular analysis:
Molecular Analysis: Allele-specific PCR for the D816 codon of the KIT gene indicated a point mutation (Figure 9). Sequencing did not reveal this mutation, indicating that the mutant allele was less than 30% of DNA analyzed. Conventional PCR for exon 14 and 20 of the FLT3 gene followed by EcoRV restriction digestion revealed a point mutation at the D835 codon of the FLT3 gene (Figure 10).
Interesting feature(s) of submitted case:
The D816 mutation of KIT is associated with systemic mastocytosis with imatinib resistance, as well as an early molecular contributor to core binding factor leukemias such as t(8;21) and inv(16) AML. The D835 mutation of FLT, like the KIT D816 mutation, has been posited to be a type I mutation, giving cellular survival and proliferative advantages. These mutations require a cooperative, ""second hit"" type II mutation, such as the t(8;21) AML1-ETO fusion, to generate a differentiation blockade leading to a leukemic phenotype.
Proposed diagnosis:
Systemic Mastocytosis with Associated Acute Myeloid Leukemia with t(8:21)(q22;q22), (AML1/ETO).
Panel diagnosis:
SM-AHNMD/AML
Comments:
Studies performed by the panel: WT c-kit, CD25+, probably WT JAK-2
Images:
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