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2013 SH/EAHP Workshop Case 185

2013 SH/EAHP Workshop Case 185. Julia Geyer and Attilio Orazi. Clinical information. 72 year old man diagnosed with essential thrombocythemia (ET) in 2001 (slides not available for review)

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2013 SH/EAHP Workshop Case 185

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  1. 2013 SH/EAHP WorkshopCase 185 Julia Geyer and Attilio Orazi

  2. Clinical information • 72 year old man diagnosed with essential thrombocythemia (ET) in 2001 (slides not available for review) • At the time of diagnosis the platelet count was 1.2 x 106/L and the clinical picture was complicated by a transient ischemic attack • Treated with Anagrelide and Hydroxyurea until October 2009 when he developed anemia and became transfusion-dependent

  3. Clinical information • A bone marrow biopsy (BM) performed in 12/2009 showed evidence of a chronic myeloproliferative neoplasm (MPN) with 1 to 2+ reticulin fibrosis and no increase in blasts • BM performed in 02/2010 showed increased fibrosis and 10% blasts by flow cytometry (unclear if peripheral blood contamination) • The patient was treated with 4 cycles of decitabine • BM in 05/2010 reported a markedly hypocellular bone marrow with 1+ fibrosis and without increased blasts

  4. Clinical information • The patient did well for 6 months until he again became transfusion-dependent in 11/2010 • BM showed accelerated phase MPN with 16% blasts and 3+ reticulin fibrosis • Treated with an investigational drug TG02 (oral multi-kinase inhibitor), however he remained transfusion-dependent and had detectable circulating blasts in peripheral blood (1-9% of all cells) • BM in 07/2011 showed 15% blasts, 3+ fibrosis and a new cytogenetic abnormality

  5. Clinical information • In September 2011, the patient was admitted due to acute renal insufficiency and altered mental status • BM showed 24% blasts • Treated with 7+3 induction regimen, complicated by tumor lysis syndrome, worsening renal failure, respiratory failure and sepsis • The patient passed away in 11/2011 • 10 years after initial diagnosis of ET, 21 months after diagnosis of accelerated phase MPN and 2 months after diagnosis of blast phase MPN

  6. CD42b

  7. CD61

  8. CD117

  9. Immunohistochemistry • An increased number of CD34(-), CD117(+) myeloid blasts • MPO highlighted rare left-shifted myeloid cells • Glycophorin C was positive in rare scattered erythroid cells • CD42b and CD61 highlighted a marked increase in the number of megakaryocytes, micromegakaryocytes and megakaryoblasts • These cells focally form large aggregates • TdT, CD56 and CD99 were negative

  10. Flow cytometry • Increased number of blasts that expressed CD34 (dim), CD117, CD13, CD33, HLA-DR, CD36, CD56 and CD41

  11. Molecular and cytogenetic analysis • Negative for JAK2, FLT3, NPM1 and CEBPA mutations • Normal male karyotype 46,XY • July 2011, new translocation: 46,XY,der(6)t(1;6)(q21;p21) • 8 months following diagnosis of accelerated phase and 2 months prior to diagnosis of blast phase MPN

  12. Proposed diagnosis • Myelofibrotic myeloproliferative neoplasm, megakaryoblastic blast phase Consensus diagnosis • Myeloproliferative neoplasm with myelofibrosis [post ET vs. PMF], accelerated phase progressing to megakaryoblastic blast phase

  13. Interesting features of the case • Disease progression is uncommon in patients with essential thrombocythemia • Since we did not have the opportunity to review the patient’s diagnostic BM, there is a possibility that based on the WHO criteria the correct initial diagnosis was that of early primary myelofibrosis with thrombocytosis

  14. Interesting features of the case: unique cytogenetic abnormality • Unlike CML, other MPNs have no specific cytogenetic abnormalities • Recurrent abnormalities are seen in ~30% of PMF patients and 5-10% of ET patients at diagnosis; this proportion increases with time after diagnosis (up to 40% of post-ET MF patients) • The type of cytogenetic abnormalities seen in PMF, PV, post-PV MF and post-ET MF is similar • The most frequent abnormalities are del(20q), del(13q), +8, +9, and abnormalities of chromosomes 1 and 7 Hussein K, et al. Eur J Haematol 2009 Tefferi A, et al. Br J Haematol 2001

  15. Initially identified in 3/81 patients with PMF • Subsequent cytogenetic database search identified additional 14/25791 patients • All patients had features typical of myelofibrosis • 10/14 patients had PMF • 3/14 patients had post-PV MF • 1/14 patient had post-ET MF • Median survival was 7.8 years • Only 1 patient progressed to AML

  16. Interesting features of the case: unique cytogenetic abnormality • Translocation t(1;6)(q21;p21) appears to be highly specific to patients with myelofibrosis • Likely a naturally occurring genetic signature of the disease and not a consequence of exposure to cytotoxic therapy or marker of disease transformation • In this particular case, it was acquired in the course of disease progression from accelerated phase to the blast phase Dingli D et al, Br J Haematol 2005 Zamecnikova A. Atlas Genet Cytogenet Oncol Haematol 2011

  17. Interesting features of the case: megakaryoblastic transformation • While de novo acute megakaryoblastic leukemia is very rare, megakaryoblastic transformation of myeloproliferative neoplasms likely occurs more frequently • Hernandez and colleagues reported 3/9 cases of blast phase MPN had megakaryoblastic proliferation • Megakaryoblasts are medium-sized to large cells with dense chromatin and scant to moderately abundant cytoplasm, often with irregular borders and projections (blebbing) • Some cases have lymphoblast-like appearance • Identified by their flow cytometric characteristics and/or by their immunohistochemical reactivity with CD41, CD42b, CD61, CD31 and vWF • Micromegakaryocytes (cell diameter <15 mm) are small nonlobulated megakaryocytes with a lower nuclear:cytoplasmic ratio and more abundant cytoplasm than megakaryoblasts Hernandez JM et al, J Clin Pathol 1992 Georgii A et al, Leuk Lymphoma 1996 Vianelli N et al, Haematologica 1996 Orazi A et al, Mod Pathol 2005

  18. Acute megakaryoblastic leukemia • Associated with Down syndrome • >50% of AML in these patients is megakaryoblastic • Majority of cases occur in children <5 years • Erythropoiesis and granulopoiesis are frequently dysplastic and fibrosis is common • Somatic mutation of GATA1 is pathognomonic • Associated with t(1;22)(p13;q13); RBM15-MKL1 • Young children, typically without Down syndrome • Marked organomegaly • Fibrosis, but no evidence of erythroid or myeloid dysplasia • Associated with AML, NOS • Both adults and children • Erythropoiesis and granulopoiesis are frequently dysplastic and fibrosis is common • No unique chromosomal or genetic abnormalities

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