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Chronic Myeloid Neoplasms

MDS/MPN

Juvenile myelomonocytic leukemia (JMML)


Reviewer: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 5 February 2012, last major update August 2011
Copyright: (c) 2001-2012, PathologyOutlines.com, Inc.

Definition
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● Formerly called juvenile chronic myelogenous leukemia
● Resembles CMML more than CML
● 70% are children less than 3 years old, range of 1 month to teenagers
● 10% associated with neurofibromatosis 1 and deletion of NF1 gene
● Due to stem cell defect causing deranged hematopoiesis
● Varied clinical presentation may include failure to thrive, malaise, fever, bleeding, pallor, lymphadenopathy and hepatosplenomegaly; less frequently skin, lung and GI involvement; rarely CNS involvement (J Pediatr Hematol Oncol 2007;29:770)
● Most patients die of disease, although it may wax and wane
● Diagnosis: absolute monocyte count > 1 x 109/L AND <20% blasts + promonocytes in marrow AND no Philadelphia chromosome AND no BCR-ABL AND at least two of the following: HbF increased for age, myeloid precursors in blood smear, WBC > 10 x 10 9/L, clonal abnormality or GM-CSF hypersensitivity of myeloid progenitors in vitro (Leukemia 2003;17:277, Table)
● Typically WBC is 20-30 x 109/L with granulocytes and monocytes, occasional dysplasia but not prominent

Case reports
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● Related to EBV infection (Leuk Res 2008;32:181)

Treatment
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● Bone marrow transplant (Blood 2005;105:410)
● Cord blood may provide graft versus leukemia effect (Pediatr Blood Cancer 2008;50:665)
● Rarely transforms to AML but fatal if untreated
● Bad prognosis if age > 2 years, high HbF and low platelet count (Blood 1997;89:3534)

Micro description
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Peripheral blood: leukocytosis with neutrophilia, monocytosis, nucleated red blood cells
Bone marrow: hypercellular with granulocytic hyperplasia, 5-30% monocytes, decreased megakaryocytes, blasts + promonocytes <20%, dysplasia not prominent, reticulin fibrosis rare
Phenotyping: no specific immunophenotypic abnormality

Positive stains
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● CD68 and lysozyme helpful to identify the monocytic component
● Cytochemical stains for NSE, alpha naphtyl acetate esterase / butyrase helpful to identify monocytic cells

Micro images
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Peripheral blood:

Increased leukocytes, primarily monocytes (3 at top) and neutrophils / myelocyte and monocyte are at lower left, also 2 late polychromatic normoblasts

Bone marrow biopsy:

Markedly cellular marrow with numerous myelocytes, also scattered erythroid precursors with clear cytoplasm and round dense nuclei, megakaryocytes are reduced

Bone marrow smear:

Numerous myelocytes and a few monocytes, only slightly increased blasts

4 year old child with isolated monosomy 7 of childhood, anemia, thrombocytopenia and leukocytosis:

Peripheral blood shows mature monocytes and neutrophils


Bone marrow biopsy is markedly hypercellular with immature neutrophils and monocytes, scattered erythroid precursors and reduced megakaryocytes


Bone marrow smear shows increased monocytes, promonocytes and large multinucleated polychromatic erythroid precursors

Stains:

Fetal hemoglobin of peripheral blood shows 50% of cells contain HbF (Kleihaur-Betke stain)

Cytogenetics description
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● Usually normal, occasionally monosomy 7
● NO Philadelphia chromosome or BCR-ABL

Molecular description
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● Somatic mutations in NRAS, KRAS, or PTPN11 occur in 60% of cases
● PTPN11 mutations also occur in Noonan syndrome (Blood 2005;106:2183), no FLT3 activation (Haematologica 2007;92:1557)

Differential diagnosis
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Wiskott-Aldrich syndrome: atopic dermatitis-like eczema, no intracellular WASP expression, WASP gene mutation (J Pediatr Hematol Oncol 2007;29:836)

Additional references
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US National Cancer Institute, Wikipedia

End of Chronic Myeloid Neoplasms > MDS/MPN > Juvenile myelomonocytic leukemia (JMML)


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