Megakaryoblastic Transformation Research Articles

A Case Report, Suspected Megakaryoblastic Transformation In A Chronic Myeloid Leukemia Patient

Preliminary: Chronic myeloid leukaemia (CML) is a clonal hematopoiesis stem cell disorder, characterised by reciprocal translocation between chromosomes 9 and chromosomes 22, originally named the ‘Philadelphia chromosome’(Ph). The megakaryoblastic transformation of a CML is extremely rare, consisting <3% of transformed cases. Case description: A 68-year-old male presented with a CML history since 2000 and received Imatinib therapy. The patient currently showed anemia and splenomegaly. Laboratory results showed hemoglobin 8.1 g/dL, leukocyte count 31,740/?L, platelet count 7,000/?L, Immature Platelet Fraction (IPF) 29.2%, BCR-ABL gene fusion is positive. Bone marrow examination showed CML blastic crisis phase with 45% blasts which had megakaryoblast morphology so it was concluded as a CML that underwent a transformation into megakaryoblastic. The results of bone marrow aspirate using Sysmex-XN1000 showed a very high IPF value which indicated an increased megakaryopoietic proliferative activity. Immunophenotyping examination showed blast population with CD45 dim, low side scatter, with the expression of CD34+, CD33+, CD13+ corresponding to the megakaryoblast area. Examination of the CD41 and CD61 specific megakaryoblast markers was not performed due to reagent limitations. Discussion: Clinical features, morphology, immunophenotyping and molecular findings help the identification of CML with suspected megakaryoblastic transformation. Conclusion: A CML patient has been reported with suspected megakaryoblastic transformation based on the bone marrow morphology, immunophenotyping, molecular and elevated IPF examination.

Acute megakaryoblastic transformation from essential thrombocythemia

Essential thrombocythemia (ET) is a Philadelphia chromosome-negative myeloproliferative neoplasm characterized by sustained thrombocytosis. Its transformation into acute leukemia is a rare event (5% at 20years). Transformation can be spontaneous or related to therapy. Acute leukemias most often associated with transformation from ET are myeloblastic or myelomonoblastic leukemias. There are very few case reports of ET transforming into acute megakaryoblastic leukemia. Here we report a case of transformation to acute megakaryoblastic leukemia in an elderly female patient who was treated with hydroxyurea for ten years. After 10-years with stable disease she presented and rapidly deteriorated with acute megakaryoblastic leukemia with high JAK2V617F mutant allele burden and high p53 expression. This case provides another example of the poor outcome of acute megakaryoblastic transformation of essential thrombocythemia.

Biclonal (CD34+ CD42b+) Myeloblastic and Megakaryoblastic Transformation of Chronic Myeloproliferative/Myelodysplastic Disorders

Despite the widespread use of molecular and genetic assays (i.e. JAK2V617F, FLT-3, bcr-abl, PML-RARalpha) for diagnoses of myeloid neoplasms, some disease entities remain difficult to define. For instance, distinguishing between blastic phase of bcr-abl negative chronic myeloproliferative disease, unclassifiable (CMPD-U), transformed myelodysplastic/myeloproliferative disease-unclassifiable (MDS/MPD-U), acute megakaryocytic leukemia (AML FAB-M7), and idiopathic myelofibrosis (IMF) per the 2001 WHO classification system remains challenging. Common to all of these diagnoses are marrow dysplasia, presence of immature myelocytic and megakaryocytic cells, and reticulin myelofibrosis. Here we describe our institute experience with 11 patients (pts) who presented between 2004–2008 with acute myeloid neoplasms characterized by prominent myeloblastic and megakaryoblastic cell populations with myelofibrosis. Morphological diagnoses were: MDS-refractory anemia with excess blasts (n=1), blastic phase of MPD/MDS with myelofibrosis (n=5), atypical or mixed acute myelocytic and megakaryoblastic leukemia (n=4), and acute megakaryoblastic leukemia (n=1). Median age at diagnosis was 69 years (range 20–89). Six pts were male (55%) and five female. The majority presented with pancytopenia with a median white blood cell count of 2.55 × 109/l (range<0.01–237.5), median hemoglobin of 9.6gm/dl (range 5.6–10.6), and median platelet count of 57 × 109/l (range 14–296). The median percentage of peripheral blood blasts was 7% (range 0–52%) with a median of 28.5% (range 18.5–73%) blasts in the bone marrow. Organomegaly was present in 4/11 pts (1 hepatomegaly, 3 splenomegaly) at diagnosis. Only two pts reported a known antecedent MDS diagnosis (7 and 9 months prior to AML). One pt had relapsed disease with a prior diagnosis of AML FAB M1. Bcr-abl was negative in all cases; FLT-3 TKD/ITD was negative in all 9/9 cases tested (2 not available). 10/11 marrows underwent correlative cytogenetic tests showing normal karyotype in 2 pts and complex in 4 pts. Four pts had chromosome 7 aberrations (−7/del (7), t(7;17), der (7). One AML had inv(3)(q21q26). Dual immunohistochemical staining for CD34 and CD42b expression confirmed the presence of separate abnormal myeloblastic (CD34+) and megakaryoblastic cells (CD42b+) in all samples with a minority of cells expressing both antigens. All patients underwent therapy for AML/MDS: 8 received cytarabine/anthracyclines/etoposide (ADE) or Hidac-based induction regimens, 1 received subcutaneous cytarabine, 1 received Zarnestra therapy, and 1 Vidaza only. 7/11 pts were refractory to or died during chemotherapy. Three patients achieved complete remission, and two underwent allogeneic stem cell transplantation with overall survival (OS) of 18 and 8.5 months. One relapsed prior to autologous transplant. Median OS for 10 pts was 6.2months (range 0.5–18.5 months) with one pt lost to follow up.Conclusions: Acute bcr-abl negative myeloid disorders displaying biclonal CD34+ myeloblastic and CD42b+ megakaryoblastic cell populations with myelofibrosis most likely represent leukemic evolution from prior chronic (undiagnosed) MPD or MDS/MPD. Dual immunohistochemical staining for CD34/CD42b is invaluable in distinguishing between the two immature blastic populations with coexpression of both markers on some cells suggestive of a common leukemia stem cell origin. Clinical outcomes of these patients are poor, and allogeneic stem cell transplantation remains the best long-term treatment option if remission can be achieved.

Paraplegia as the presenting manifestation of extramedullary megakaryoblastic transformation of previously undiagnosed chronic myelogenous leukemia

Extramedullary tumors, also known as granulocytic sarcomas (GS), occur most frequently in acute myelogenous leukemia (AML). They may signal the onset of the accelerated phase of chronic myelogenous leukemia (CML) or the blastic transformation of a myeloproliferative disorder. Occasionally, a GS may be the presenting sign of undiagnosed AML, and rarely the presenting sign of undiagnosed CML or aleukemic leukemia. Paraplegia due to a spinal cord GS is an extremely rare presentation of undiagnosed leukemia. This is the first case report of paraplegia as the presenting manifestation of extramedullary megakaryoblastic transformation of previously undiagnosed CML. A 53-year-old woman reported back pain for 6 days, rapidly progressing to paraplegia. Physical examination noted a large abdominal mass and flaccid paralysis in both lower extremities. Spinal MRI revealed a T4-T6 vertebral mass causing spinal stenosis and cord compression. Tumor debulking and laminectomy were performed emergently. The tumor consisted of noncohesive blast cells. The CBC revealed a leukocyte count of 238,300/microl and a differential consistent with CML. Reexamination of the patient found that the abdominal mass was a giant spleen. Further immunohistochemical studies of the tumor were consistent with extramedullary acute megakaryoblastic blast transformation of CML. Although extramedullary blast crises herald the accelerated phases in approximately 10% of CML cases, megakaryoblastic blast transformation of CML accounts for less than 3% of these cases. The combination of acute paraplegia and megakaryoblastic transformation in a previously undiagnosed patient with CML is extremely rare and may pose a diagnostic dilemma.

Megakaryoblastic transformation of chronic myelomonocytic leukemia presenting with severe bone pain

A 77‐year‐old woman, who had suffered from osteoporosis with compression fractures of vertebrae, was admitted to our hospital because of increasing bone pain. She had anemia and monocytosis, and was diagnosed as chronic myelomonocytic leukemia (CMML). Although chemotherapy was initiated, she died from pneumonia. Autopsy revealed multiple tumors composed of megakaryoblastic cells in her bone marrow and extramedullary organs and, therefore, the pathological diagnosis was made as megakaryoblastic transformation of CMML. Severe bone pain was considered to be a symptom of megakaryoblastic transformation of CMML.

Megakaryoblastic Transformation Associated with Disseminated Intravascular Coagulation in the Course of Polycythemia Vera: A Case Report

Megakaryoblastic Transformation Associated with Disseminated Intravascular Coagulation in the Course of Polycythemia Vera: A Case Report

Absence of the Human Retinoblastoma Gene Product in the Megakaryoblastic Crisis of Chronic Myelogenous Leukemia

The human retinoblastoma gene (RB) product, which is involved in the control of cell cycle and tumor suppression, is constitutively expressed as a nuclear phosphoprotein in normal human cells. We examined leukemic cells from 22 patients with blast crisis of chronic myelogenous leukemia (CML) for alterations of the RB expression. Western blotting and flow cytometry with anti-RB-protein antibodies showed that all of five cases with megakaryoblastic crisis lacked the expression of the RB-encoded protein, whereas none of 17 cases with the other phenotypes such as myeloblastic or lymphoblastic crisis showed any abnormality. These findings suggest that megakaryoblastic transformation of CML might be lineage-specifically associated with loss of the RB protein.

Absence of the human retinoblastoma gene product in the megakaryoblastic crisis of chronic myelogenous leukemia

The human retinoblastoma gene (RB) product, which is involved in the control of cell cycle and tumor suppression, is constitutively expressed as a nuclear phosphoprotein in normal human cells. We examined leukemic cells from 22 patients with blast crisis of chronic myelogenous leukemia (CML) for alterations of the RB expression. Western blotting and flow cytometry with anti-RB-protein antibodies showed that all of five cases with megakaryoblastic crisis lacked the expression of the RB-encoded protein, whereas none of 17 cases with the other phenotypes such as myeloblastic or lymphoblastic crisis showed any abnormality. These findings suggest that megakaryoblastic transformation of CML might be lineage-specifically associated with loss of the RB protein.

Cytogenetic findings in adult acute leukemia and myeloproliferative disorders with an involvement of megakaryocyte lineage

Cytogenetic analyses were performed on 12 adult patients with abnormal megakaryoblastic proliferation which was detected by ultrastructural cytochemical study (platelet peroxidase) and platelet-megakaryocytes-specific monoclonal antibodies (TP-80, Plt1, AN51, and KOR-77). The patients consisted of two patients with myelodysplastic syndromes (MDS), three with acute megakaryoblastic leukemia (AMKL), six with megakaryoblastic transformation in Philadelphia-positive chronic myelogenous leukemia (CML-meg-BC), and one case of chronic myeloproliferative disorder (CMPD). Among them, an inversion of the long arm of chromosome 3 [inv(3)(q21q26)] was found in one AMKL patient with a normal platelet count. Chromosome change at band 3q26 was also found in one MDS patient without thrombocythemia. Furthermore, the long arm of chromosome 13, where rearrangements in myelofibrosis are clustered (13q12----q22) was seen in one MDS patient. Trisomoy of chromosome 19 was found in one AMKL patient and three CML-meg-BC patients. These findings indicate that cytogenetic abnormalities involving 3q26, 13q, and trisomy 19 are associated with hematologic neoplasia with megakaryocytic lineage in adult patients, although these abnormalities were not related to the survival of the patients. During the period of this study, two acute myelogenous leukemia patients (AML-M2 and AML-M5b) with chromosome rearrangements at band 3q21 and thrombocythemia were found, indicating that chromosome abnormality at band 3q21 is related to quantitative platelet dysfunction, whereas that at 3q26 is related to hematologic malignancies with a proliferation of megakaryocytic lineage.

An immunomorphometric study on megakaryocyte precursor cells in bone marrow tissue from patients with chronic myeloid leukemia (CML)

An immunomorphometric study was performed on trephine biopsies of the bone marrow in 41 patients with chronic myeloid leukemia (CML) to determine number and size of megakaryocytic precursor cells (pro- and megakaryoblasts). For specific staining, a monoclonal antibody against platelet glycoprotein IIIa (Y2/51) was employed which is applicable on routinely fixed and paraffin embedded tissue. In comparison with control specimens from 15 patients, in CML morphometric analysis revealed an increase in the total amount of megakaryocytes per square and cubic millimeter marrow tissue, but particularly in patients with thrombocythemia. Moreover, a non-disorderly expansion of the megakaryocyte precursor pool was recognizable by showing a relative frequency of pro- and megakaryoblasts in congruence with the normal value. In this context a significant correlation between the counts for Y2/51-positive megakaryocytic elements and promegakaryoblasts with the corresponding platelet values was encountered. The more mature stages of megakaryopoiesis (pro- end megakaryocytes) disclosed a relevant shift to smaller cell forms with rounded cell perimeters and a more compact aspect of their nuclei. Additionally, in 6 patients with CML, evolution into a subacute and manifest (micro)-megakaryoblastic transformation accompanied by myelofibrosis could be demonstrated by a retrospective review of file material.

Near-haploid cell line in megakaryoblastic transformation of Philadelphia-positive chronic myeloid leukemia

A case of near haploidy in a patient with an acute megakaryoblastic transformation of Philadelphia (Ph)-positive chronic myeloid leukemia (CML) was studied. Cytogenetic studies revealed persistence of a Ph-positive pseudodiploid cell line and the emergence of a Ph-positive near-haploid cell line, i.e., 46,XX,t(9;22)(q34;q11)/28,XX,t(9;22),+8,+14,+18,+29. The near-haploid cell line is a rare cytogenetic finding. The patient rapidly deteriorated and died.

Megakaryoblastic transformation of chronic granulocytic leukemia

Three cases of megakaryoblastic transformation of chronic granulocytic leukemia (CGL) are reported. In each case, the leukemic transformation had morphologic features suggesting megakaryocytic differentiation. This was confirmed by positive immunostaining with a monoclonal antibody (HP1-1D) specific for platelet and megakaryocyte glycoprotein IIb/IIIa antigen, which was expressed by the majority of the leukemic blasts in all three cases. Cases with evidence of multilineage differentiation of the leukemic transformation were excluded. A striking feature in two patients was the manifestation of lytic bone lesions and soft tissue masses at presentation. A biopsy of a lytic bone lesion and soft tissue mass in one patient revealed a megakaryoblastic leukemic infiltrate, which by immunocytochemical staining was positive for the megakaryocytic markers, glycoprotein IIb/IIIa antigen, and Factor VIII (von Willebrand factor) antigen. In contrast to granulocytic sarcomas, the megakaryoblastic sarcoma did not stain cytochemically for chloroacetate esterase. The mean survival after acute transformation was 5.3 months. The three cases of megakaryoblastic transformation represented a significant proportion of all CGL blastic transformation cases (ten cases) evaluated by bone marrow examination in our institution during a 13-month period. Megakaryoblastic transformation of CGL may occur more frequently than has been appreciated, and can present as lytic bone lesions or as soft tissue megakaryoblastic sarcomas.

Chronic myeloid leukemia: Manifesting as spontaneous splenic rupture and terminating in megakaryoblastic transformation

We report a case of chronic myeloid leukemia with spontaneous splenic rupture as the initial presenting feature; there was a successful surgical outcome, but this case terminated in megakaryoblastic transformation. Results are reported based on morphological, immunological, cytochemical, ultrastructural, immunocytochemical studies, and in vitro liquid culture studies. The megakaryocytic nature of the blast cells was identified through the demonstration of platelet peroxidase activity by ultrastructural cytochemistry and the presence of platelet and megakaryocyte-specific antigen using monoclonal antibody, as well as the anti-factor VIII antibody by immunocytochemical technique.

Proliferation in liquid culture of megakaryocytes from the blood of patients with primary myelofibrosis and other myeloproliferative disorders

Using a short term liquid system we have shown that blood from sonic patients with primary myelofibrosis (PMF) and chronic granulocytic leukaemia (CGL) in megakaryoblastic transformation (CGL-Mk) gives rise to large numbers of progenitor cells committed to the megakaryocyte (Mk) lineage. As assessed by indirect immunofluorescence the number of cells reacting with three antiplatelet monoclonal antibodies, C17, J15 and AN51, increases during the culture period. There is no equivalent increase in cultures from the blood of normal individuals or patients with essential thrombocythaemia (ET). Furthermore plasma-free supernatants from cultures of the cells from patients with PMF and CGL-Mk stimulate the rate of proliferation of fibroblasts from normal bone marrow. These data provide further evidence for the involvement of the Mk lineage in PMF and CGL and suggest that the excess fibrosis seen in these conditions may be caused by a factor emanating from Mks.

Surface Features of Leukaemic Megakaryocytic Precursors

Megakaryoblasts and maturing megakaryocytic precursor cells from 5 patients with megakaryoblastic leukaemia were studied by scanning electron microscopy (SEM). The diagnosis in all cases had been established by ultrastructural cytochemistry on the basis of a positive platelet peroxidase reaction with negative staining for myeloperoxidase. 1 case presented as acute myelofibrosis and 4 as acute megakaryoblastic transformation of chronic granulocytic leukaemia. Under the SEM, megakaryoblasts and maturing megakaryocytic precursors showed typical surface features including the presence of rounded and irregular blebs, broad folds and pseudopodia. The nature of these surface blebs is still unclear but they probably represent surface membrane alterations relating to imminent platelet shedding at least in the more mature precursors. These surface microprojections are distinctly different from those encountered on leukaemic lymphoblasts, myeloblasts and monoblasts. It is suggested that SEM may be used in conjunction with the PPO reaction as in aid in the diagnosis of megakaryocytic leukaemias.