Final Diagnosis -- Acute Megakaryoblastic Leukemia



Acute megakaryoblastic leukemia, by the World Health Organization (WHO) definition, is an acute myeloid leukemia in which at least 50% of blasts are of megakaryocytic lineage. This disease occurs in adults and children, comprising 3-5% of acute myeloid leukemias overall, and may occur de novo or following therapy for another malignancy.

In the pediatric population, acute megakaryoblastic leukemia (AMKL) accounts for approximately 10% of AMLs and is more frequent in children under the age of 3 years. There is a well-established association between AMKL and Down's syndrome as well as with mediastinal germ-cell tumors. The characteristics of AMKL in Down syndrome (AMKL-DS) are different from those in non-Down syndrome patients (AMKL-NDS). In AMKL-DS, the patients tend to be older at presentation, median age 24 months, with a low white blood cell count and a history of transient myeloproliferative disorder at birth and/or episodes of thrombocytopenia with spontaneous recovery; these patients tend to respond better to therapy. In non-Down syndrome patients, the mean age at presentation in 6 months, with a high white blood cell count and massive hepatosplenomegaly associated with the cytogenetic abnormality t(1;22) and no previous hematologic history; these patients tend to have poor response to therapy, the prognosis is particularly poor in infants with t(1;22).

The megakaryoblasts in the peripheral blood and bone marrow aspirate are usually of medium to large size with a round slightly irregular or indented nucleus with fine reticular chromatin and one to three nucleoli, although the nucleoli may also be inconspicuous or absent. The cytoplasm is basophilic on Wright-Giemsa stain, often granular and may show distinct blebs or pseudopods. In some cases, the blasts may be small with a high nuclear to cytoplasmic ratio and scant dark blue cytoplasm, resembling lymphoblasts and leading to misclassification as "atypical lymphocytes". The large and small blasts may be present in the same patient. Micromegakaryocytes, on the other hand, are small cells, with mature cytoplasm and one or two round nuclei with condensed chromatin, which are occasionally seen in the peripheral blood and should not be counted as blasts. Circulating hypogranular neutrophils may also be present. Platelet counts are usually low, but can be normal or high. Megakaryocytic fragments and dysplastic large gray-blue platelets, sometimes with azurophilic granules, are usually seen in the peripheral blood.

The blasts in AMKL may form small clusters in the marrow aspirate smears and biopsy, occasionally resembling metastatic solid tumor particularly neuroblastoma and rhabdomyosarcomas; cytoplasmic platelet shedding may be a useful clue to the diagnosis in these cases. The leukemic cell clustering may also lead to underestimation of the size of the leukemic population by flow cytometry, as the clustered cells tend to be removed during sample preparation. The bone marrow biopsy may demonstrate a uniform population of poorly differentiated blasts or a mixture of poorly differentiated blasts and maturing dysplastic megakaryocytes. Varying degrees of reticulin fibrosis may be present, usually in association with malignant cell clusters.

Cytochemical and immunostains for myeloperoxidase (MPO), Sudan Black and a-naphthyl butyrate esterase are negative in the megakaryoblasts, which are, however, Periodic Acid Schiff (PAS) positive and express one or more of the platelet glycoproteins: CD41 and/or CD61. Cytoplasmic expression of the latter markers is more specific and sensitive than surface staining, particularly by flow cytometry, due to the possible confounding effect of platelet adhesion to blasts and other cells. The more mature platelet marker CD42 is less frequently present. Positive cytoplasmic immunohistochemical staining for von Willebrand factor (Factor VIII) in the blasts on the bone marrow biopsy can be a reliable diagnostic marker, however, it is expressed later in megakaryocytic maturation and may be absent in most pediatric AMKL cases. The myeloid markers CD13 and CD33 may be positive. CD34, the pan-leukocyte marker CD45 and class II HLA-DR are frequently negative. CD7 may be aberrantly expressed, but other lymphoid markers and TdT are not expressed.

Electron microscopy may be helpful in making the diagnosis of AMKL by identifying platelet peroxidase (PPO), which requires an additional special processing technique for this evaluation. The peroxidase activity is confined to the nuclear membrane and rough endoplasmic reticulum, but is not specific to megakaryocytes and can be seen in erythroblasts and mast cells.

Acute megakaryoblastic leukemias have been associated with some cytogenetic findings, but there is no unique chromosomal abnormality associated with AMKL in adults. In children, there may be some association with t(1;22); these cases have distinct clinical features, including hepatosplenomegaly, and histologic features of a stromal pattern of marrow infiltration mimicking a metastatic tumor. Hyperdiploidy due to additional copies of chromosome 21, among others, and acquired abnormalities of this chromosome are frequent in patients with or without Down syndrome.

As mentioned above, the prognosis of acute megakaryoblastic leukemia is poor, particularly in non-Down Syndrome patients.


  1. WHO Classification of Tumours: Pathology and Genetics of Tumours of Haematopoietic and Lymphoid Tissues; Edited by E.S. Jaffe, N.L. Harris, H. Stein and J.W. Vardiman; Published by Intl. Agency for Research on Cancer IARC press 2001, pages 99 - 102.
  2. Pediatric Bone Marrow by Lila Penchansky; Publisher: Springer - Verlag 2004, pages 133-146.

Contributed by Suzanne Bakdash, MD, MPH and Sandra S. Kaplan, MD

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