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Leukemia - Acute

AML not otherwise categorized

Acute megakaryoblastic leukemia (AMKL, M7)

Reviewer: Daniela Mihova, M.D. (see Reviewers page)
Revised: 2 February 2013, last major update September 2012
Copyright: (c) 2001-2013, PathologyOutlines.com, Inc.

General
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● Up to 10% of AML in children, 5% or less of adult AML (Orphanet (May 2004))
● See also Myeloid leukemia associated with Down syndrome
● Associated with marrow fibrosis due to megakaryoblast secretion of fibrogenic cytokines, which makes marrow aspiration difficult
● In adults, median age 57 years, 59% have prior hematologic disorder or myelodysplastic syndrome (Blood 2006;107:880)
● 19% had prior chemotherapy, classify now as AML-MRC (myelodysplasia related changes) or t-AML
● Survival: poor, median overall survival is 6 months
● Peripheral blood: often contains micromegakaryocytes and atypical platelets
● Down Syndrome (DS): 150x increased risk of AML compared to non-Down children age 0-4 years; 70% are AML M7 compared to 3-6% in non-Down children
● DS children ages 0-3 years: ALL vs AML risk is 1:1.2 compared to 4:1 for non-DS children

Clinical features
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● Thrombocytopenia, may have thrombocytosis, dysplastic features in neutrophils, erythroids, megakaryocytes and platelets
● Infrequent hepatosplenomegaly
● Associated with germ cell tumors in young boys

Diagnosis
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● WHO 2008: 20%+ blasts
● 50%+ blasts of megakaryocytic lineage are present in bone marrow
● Must exclude AML-MRC (myelodysplasia related changes), AML with t(1;22)(p13;q13); inv(3)(q21;q26.2); t(3;3)(q21;q26.2) and Down syndrome-related
● Megakaryocytic lineage is based on CD41+, CD61+ or positive platelet peroxidase reaction on EM

Case reports
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● 1 year old child with anemia and thrombocytopenia (Univ of Pittsburgh Case #439)
● Child with bi-allelic deletions within 13q14 and transient trisomy 21 with absence of GATA1 (Pediatr Blood Cancer 2011;57:516)
● Young boy with coexisting mediastinal germ cell tumor (Clin Transl Oncol 2007;9:329)
● 25 year old man with findings on FNA and CSF (Cytojournal 2011;8:17)
● 25 year old man with i(12p) related disease after primary mediastinal germ cell tumor (J Korean Med Sci 2011;26:1099)
● 58 year old woman with coexisting myeloid sarcoma of femur (Srp Arh Celok Lek 2011;139:805)
● Diagnosis 15 years after kidney transplantation (Ann Hematol 2011;90:843)
● "Cannibalistic" phagocytosis in acute megakaryoblastic leukemia (AML M7) with t(10;17)(p15;q22) (Leuk Lymphoma 2010;51:1944)
● Coexistence of meningeal infiltration and multiple lymphadenopathy as the initial presentation of de novo adult acute megakaryoblastic leukemia (Leuk Res 2011;35:e50)

Micro description
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● Megakaryoblasts (often better morphology on biopsy than smear) are medium / large cells with blue vacuolated, agranular, eosinophilic cytoplasm containing fine granules, cytoplasmic projections (blebs and pseudopods) resembling platelets, irregular cytoplasmic borders and cytoplasmic zoning; may occur in clusters
● Nuclei are round or slightly indented with finely reticular, dense chromatin and 1-3 nucleoli
● Myelofibrosis or increased marrow reticulin is common; may also have small lymphoid-like blasts

Micro images
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Bone marrow smears (Wright-Giemsa):

Blasts have abundant cytoplasm


Promegakaryocytes (larger than blasts, cytoplasmic budding, irregular nuclei, coarse chromatin) and large blasts


Touch prep shows 3 blasts with basophilic cytoplasm, coarse chromatin and distinct nucleoli

Bone marrow biopsy:
 
Extensive infiltration by blasts with sparse cytoplasm, frequent convoluted nuclei with fine chromatin and distinct nucleoli


Marked proliferation of megakaryocytes with variation in size and nuclear morphology

Stains:
               
CD61                                   (figures C, D)

          
Reticulin stain shows marked increase in reticulin fibers

          
CD34-red, podocalyxin-brown    CD42b (figure c)


PAS+ large megakaryocytes and micromegakaryocytes, also immature cells and erythrocyte precursors

Cytology images
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FNA and CSF

Positive stains
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● CD41 and CD61 (megakaryocyte specific), CD42b (Mod Pathol 2005;18:603), CD34, CD36, factor VIII and von Willebrand factor
● Variable CD13, CD33, CD71, alpha naphthyl acetate esterase, PAS and HLA-DR
● Rarely positive for alpha-1-antitrypsin, alpha-1-antichymotrypsin or lysozyme (Am J Surg Pathol 1987;11:883)

Negative stains
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● Myeloperoxidase, Sudan Black B, CD14, CD64 and glycophorin A

Electron microscopy description
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● Megakaryoblasts have demarcation membranes and “bulls-eye” alpha granules with peroxidase activity in nuclear envelope and endoplasmic reticulum, but not in granules and Golgi complex

Differential diagnosis
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● ALL
● AML-M0
● Blastic transformation of CML
● AML-M1
● AML-M5a
● Metastatic small blue cell tumors in children

Acute megakaryoblastic leukemia with t(1;22)(p13;q13); RBM15-MKL1

General
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● Uncommmon; <1% of AML; translocation appears to be specific to AMKL (Atlas of Genetics and Cytogenetics)
● WHO 2008: AML generally showing maturation in the megakaryocyte lineage, with indicated translocation, without Down syndrome
● Infants and young children (<3 years old), usually girls
● Most cases present within first month of life with marked hepatosplenomegaly (Blood 1991;78:748), prominent myelofibrosis, anemia, thrombocytopenia and moderately elevated WBC
● Tissue involvement resembles metastatic tumor
● Poor outcome (Leukemia 2000;14:216); but may respond well to intensive chemotherapy

Case reports
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● 1 month old infant with hepatic involvement and no initial marrow involvement (Pediatr Dev Pathol 2008;11:55)
● 9 month old girl with proliferation of erythroid and megakaryocytic lineages (Rinsho Ketsueki 1999;40:230)
● 59 year old man with RBM15-MKL1 (OTT-MAL) fusion transcript (Am J Hematol 2005;79:43)
● Hemophagocytosis by leukemic megakaryoblasts (J Pediatr Hematol Oncol 2012;34:576)

Micro description
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● Bone marrow is normocellular to hypercellular with prominent collagenous and reticulin fibrosis; blasts may be spindled and form intertwining bundles resembling metastatic disease (Am J Clin Pathol 1992;98:214)
● If <20% blasts on aspirate smear, check bone marrow for fibrosis which may mask blast count; if blasts are actually <20%, closely monitor for more definitive evidence of AML
● Small and large megakaryoblasts (medium to large with basophilic agranular cytoplasm, possibly with distinct blebs or pseudopods; round slightly irregular nuclei, fine reticular chromatin, one to three nucleoli), micromegakaryocytes, undifferentiated blasts, but no dyserythropoiesis and no dysgranulopoiesis

Micro images
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Various images

Positive stains
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● CD41+, CD61+ (cytoplasmic CD41 and CD61 more sensitive and specific), CD42+, CD36+; CD13 and CD33 may be positive

Negative stains
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● CD34, HLD-DR, CD45
● Cytochemistry: negative for Sudan Black and myeloperoxidase

End of Leukemia - Acute > AML not otherwise categorized > Acute megakaryoblastic leukemia (AMKL, M7)

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