| Session: Ph- chronic myeloproliferative disease |
| Case number: 094 |
Submitter(s): Gerald Wertheim, Robin Edwards, Adam Bagg.
Clinical history
A 39-year-old woman was diagnosed with essential thrombocythemia [ET] in April 1999 (WBC 11.0, Hgb 13.8, Plt 1974, t(9;22)-negative). The thrombocytosis was well controlled with hydroxyurea. Six years following diagnosis (2005), she developed t(9;22)-negative acute myeloblastic leukemia [AML #1], presumably evolved from the ET. Remission was achieved following AML induction/consolidation chemotherapy, with the hematologic picture returning to baseline ET. However, following the fourth round of consolidation therapy (2006), she relapsed with AML [AML #2], which was now t(9;22)-positive. Treatment with imatinib was initiated with poor response.
Details of gross/microscopic pathology:
H&E stained sections from a bone marrow biopsy (1999) revealed a hypercellular marrow with trilineage hematopoiesis with a marked expansion of abnormal, hyperlobated megakaryocytes arranged in loose clusters. Subsequent bone marrow studies in 2005 and 2006 showed an increased number of myeloblasts (>95% and 15%), indicative of florid acute transformation and early recurrence, respectively. Overt relapse manifested soon after the latter timepoint (2006) in the peripheral blood.[figure1][figure2][figure3]
Immunophenotype (flow cytometry/immunohistochemistry):
Flow cytometry of AML #1 from 2005 demonstrated that the blasts were predominantly CD13+, CD33+, CD34+, HLA-DR+, MPO (subset)+. Flow cytometry of bone marrow from AML #2 in 2006 showed that the blasts had a similar immunophenotype, albeit now with subset acquisition of CD10 and TdT (but no other lymphoid markers).
Cytogenetics:
Cytogenetics performed on the initial bone marrow demonstrated a normal 46, XX karyotype. Cytogenetics performed on the bone marrow of AML #1 (2005) showed 45,XX,-7,del(12)(p13). Studies on the AML#2 demonstrated 19 of 25 cells with 46,XX,-7, t(9;22)(q34;q11.2),+21. A BCR-ABL1 fusion gene was detected by FISH analysis in the latter specimen.[figure4]
Molecular analysis:
RT-PCR analysis of multiple peripheral blood samples obtained from AML #2 identified the presence of the e1a2 BCR-ABL1 fusion transcript. RT-PCR analysis of archived specimens from the intervening ET phase was negative for this fusion. PCR analysis of peripheral blood during both the ET and AML phases of the disease failed to identify a JAK2 (V617F) mutation.[figure5]
Interesting feature(s) of submitted case:
Blastic transformation of essential thrombocythemia to AML and, more interestingly, secondary acquisition of a Philadelphia chromosome/BCR-ABL1 fusion are both rare events. Indeed, the latter is generally believed to be an initiating event in neoplastic transformation. This case is, to our knowledge, the first description of a Philadelphia chromosome/BCR-ABL1 negative myeloproliferative disorder [ET] progressing to a Philadelphia chromosome/BCR-ABL1 positive AML.
Proposed diagnosis:
Essential thrombocythemia progressing to acute myeloblastic leukemia with acquisition of a Philadelphia chromosome/BCR-ABL1 fusion as a secondary event.
Panel diagnosis:
Specimen from 1999 shows features of CIMF/PMF
Comments:
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