Philadelphia Chromosome–Positive Thrombocythemia and Megakaryoblast Leukemia

Abstract

A case of well-documented and -illustrated megakaryoblastic transformation is described in a patient with thrombocythemia passing through a stage of myelofibrosis without features of chronic granulocytic leukemia. Immunocytologic studies with the use of conventional and monoclonal antibodies against platelet membrane glycoproteins and electron microscopic investigations, demonstrating bull's-eye granules and platelet peroxidase positivity, proved the megakaryocytic differentiation of the blast cells. From the onset of the disease as well as during the megakaryoblastic transformation, the Philadelphia (Ph1) karyotype, 46XX t(9:22) (q34:q11), was found in peripheral blood and bone marrow cells as the only clonal abnormality. Southern blot analysis of DNA extracted from the blast cells revealed a rearrangement within the bcr on chromosome 22 similar to findings in chronic granulocytic leukemia. The presentation with excessive small and abnormal megakaryocytes in the initial and subsequent bone marrow and the rapid progressive myelofibrosis and splenomegaly differentiate the Ph1 chromosome-positive thrombocythemia from the chronic myeloproliferation of thrombocythemia in its primary form or associated with polycythemia vera.

Bone Marrow Features and Natural History of BCR/ABL-Positive Thrombocythemia and Chronic Myeloid Leukemia Compared to BCR/ABLNegative Thrombocythemia in Essential Thrombocythemia and Polycythemia Vera

“…BCR/ABL+ET is a third variant with no features of CML in peripheral blood, with predominant hypertrophy of small megakaryocytes , and with no, minor or overt granulocytic hypertrophy consistent with CML. BCR/ABL positive ET usually progress to CML, and shows a high tendency to myelofibrosis and blastic transformation [13,14].…”

“…BCR/ABL positive CML is a malignant disease with an obligate transition into acute leukemia, whereas the BRC/ABL negative chronic myeloproliferative disorder (MPD) are featured by a benign neoproliferation of one, two or the three hematopoietic cell lines with a normal or near normal survival in the initial 10 to 15 years of followup [13]. Michiels et al and the German pathologists Georgii and Thiele recognized that small mono-or bi-nucleated megakaryocytes are diagnostic for the Ph-positive diseases ET and CML.…”

“…Michiels et al and the German pathologists Georgii and Thiele recognized that small mono-or bi-nucleated megakaryocytes are diagnostic for the Ph-positive diseases ET and CML. In contrast, large megakaryocytes with hyper-lobulated nuclei are pathognomonic for Ph-negative essential thrombocythemia (Figures 1 and 2) [13][14][15][16][17][18][19][20][21][22][23][24]. The Hannover Bone Marrow Classification of CML and MPD regarded myelofibrosis (MF) as a reactive secondary feature of myeloproliferative disease.…”

“…Thrombotic or hemorrhagic events are rare in cases of pronounced thrombocytosis associated with Ph-positive CML during follow-up [28,29]. The prognosis of BCR/ABL-positive ET is rather poor prognosis with the development of CML features, and a high risk of progression to myelofibrosis and blast crisis after a few to several years [13,14]. The bone marrow features of the presented case of Ph-positive ET showed that the megakaryocytes in BCR/ABL-positive thrombocythemia are indeed smaller than normal with hypolobulated round nuclei caused by BCR/ABL gene and protein induced maturation defect of the hematopoietic stem cells (Figure 1).…”

“…The bone marrow features of the presented case of Ph-positive ET showed that the megakaryocytes in BCR/ABL-positive thrombocythemia are indeed smaller than normal with hypolobulated round nuclei caused by BCR/ABL gene and protein induced maturation defect of the hematopoietic stem cells (Figure 1). This contrasts with clustered enlarged megakaryocytes in BCR/ABL-negative thrombocythemia in various MPDs (Figure 2) [13,14] due to growth advantage and benign proliferation of constitutively activated JAK2 or MPL somatic mutated megakaryocytes [30][31][32][33][34][35][36][37][38][39][40].…”