Definition
Malignant neoplasm exhibiting both myelodysplastic and myeloproliferative features and characterized by peripheral monocytosis
Diagnostic Criteria
Diagnosis requires ALL of the following five criteria
Persistent blood monocytosis , >1 x
103 /μL AND
Usually mature but may have abnormal granules or nuclei (abnormal monocytes)
Neutrophilia and/or eosinophilia (see below) may be present
No Philadelphia chromosome or BCR-ABL1 fusion ANDNo abnormalities of PDGFRA or PDGFRB or 11q23 (which suggest AML)
ANDBlasts plus promonocytes <20% in both bone marrow and peripheral blood
AND
Any one of the below features:
Dysplasia in one or more myeloid lineages (most common)Demonstration of an aquired clonal cytogenetic or molecular genetic abnormality in the marrow
At least 3 months duration of monocytosis, with other causes ruled out (see Differential Diagnosis)
Systemic mastocytosis may coexist with CMML
CMML should be divided into prognostic groups:
CMML-1
Blasts + promonocytes <5% in blood and <10% in marrow
CMML-2
Blasts + promonocytes 5-19% in blood and 10-19% in marrow OR
Auer rods present in blood or marrow
CMML with eosinophilia may be diagnosed if blood eosinophils >1.5 x 103 /μL
All other CMML criteria must be fulfilled, including lack of PDGFRA and PDGFRB abnormalities
May exhibit tissue damage from eosinophilia (see Clinical)
Bone marrow is usually hypercellular with dysplastic features
Occasional cases may be hypocellular
Nodules of plasmacytoid dendritic cells present in 20% of cases
Monomorphous cells with sharp borders and round nuclei
Inconspicuous nucleoli, fine chromatin
CD123 positive
Reticulin stain may show mild to moderate fibrosis
Spleen frequently shows red pulp involvement
Any of the following
may be found in extramedullary sites such as skin and lymph nodes
CMML
Plasmacytoid dendritic cell nodules
Blastic transformation
Dita Gratzinger MD PhD
Original posting: 11/6/11
General Criteria for Myelodysplasia
Myelodysplasia is defined by morphologic features of abnormal cellular maturation in at least one bone marrow lineage
Not all features are applicable to all disorders
Dyserythropoeisis
Peripheral blood erythrocyte abnormalities
Normocytic, normochromic anemia
Macrocytosis
Dimorphic red blood cells (RBC)
Mixture of normal RBC and hypochromic microcytic RBC
Basophilic stippling
Poikilocytosis
Varying shapes, frequently macro-ovalocytes
Bone marrow erythroid lineage abnormalties
Erythroid hyperplasia or hypoplasia
Megaloblastoid / megaloblastic changes
Dyssynchronous maturation of nucleus and cytoplasm of erythroid precursors
Nucleus lags behind cytoplasm
Ring sideroblasts
≥5 iron granules encircling ≥1/3 of the nucleus
Usually either many or none
Cytoplasmic vacuoles
Also seen in copper deficiency
Nuclear changes
Multinuclearity
Nuclear budding, hyperlobulation and satellite nuclei
Internuclear bridging
Dysgranulopoiesis
Peripheral blood and/or bone marrow findings (easier seen in peripheral blood)
Hypogranularity
Pale cytoplasm almost indistinguishable from background on slide
Nuclear hypolobation or irregular hypersegmentation (>5 lobes)
Pseudo Pelger-Huet anomaly
Two equal size nuclear lobes connected by a thin strand of chromatin
Infrequent findings
Abnormal cytoplasmic granules (pseudo Chediak-Higashi granules)
Giant grey to red granules
Dohle bodies
Small blue cytoplasmic inclusions
Often found at periphery of cell
Auer rods
Rod-like structures formed by fusion of primary granules
May be found in blasts or maturing granulocytes
Dysmegakaryopoiesis
Peripheral blood platelet abnormalities
Giant
Larger than a red blood cell
Bizarre
Irregular shapes and protrusions
Hypogranularity
Compare to normal platelets with purple granules
Bone marrow megakaryocyte abnormalities
Micromegakaryocytes
Smaller than a promyelocyte
Nuclear hypolobation
Prominent in 5q- syndrome
A single lobe is typically seen in a small megakaryocyte
Multinucleation
Distinct nuclei without a connecting strand of chromatin
Cytoplasmic hypogranularity
Supplemental Studies
Immunologic stains (flow and sections)
Leukemic cells
Positive: CD33, CD13, CD163
Variable: CD14, CD68, CD64
Occasional aberrant expression:
Decreased CD13, CD14, CD15, CD64, CD36, HLA-DR
Overexpression of CD2, CD56
Increased CD34 may indicate transformation to AML
CAUTION - monoblasts and promonocytes are often CD34 negative
Morphologic assessment is more important than simple CD34 count
Plasmacytoid dendritic cells
Positive: CD123, CD14, CD43, CD68, CD68R, CD45A, CD4, Granzyme B
Weak: CD33
Variable: CD56, CD2, CD5
Negative: TIA1, perforin
Nonspecific clonal cytogenetic abnormalities present in 20-40%
Following are not present, by definition
BCR-ABL1 (including p190 isoform), PDFGRA, PDFGRB
Nonspecific molecular abnormalities present in up to 70%, including
RAS (40%), TET2, CBL, JAK2, RUNX1
Differential Diagnosis
CML -CPCMML -1Myeloid Neoplasm with PDGFRB
Ph Chromosome and/or BCR-ABL1 Translocation
Almost 100%
Absent
Absent
WBC
Left shifted neutrophilia*
Monocytosis, may have left shifted neutrophilia
Variable, may have left shifted neutrophilia, monocytosis, eosinophilia
Blood eosinophils
Often increased
Not increased
Variable
B lood basophilsIncreased
Not increased
Variable
Blood monocytes
Variable,** <1x103 /μL
Always >1x103 /μL
often <1x103 /μL
Blood immature granulocytes
>20%
Usually <10%
often <10%
Blood blasts
Usually <2%
<5%
Variable
Granulocytic dysplasia
Absent
+/-
Variable
*rare p230 BCR-ABL1 isoform may show mature neutrophilia, **rare p190 BCR-ABL1 isoform associated with monocytosis
Non-neoplastic Monocytosis
Infectious
Inflammatory
Reaction to another maligancy, such as lymphoma
Clinical
Median age 65-75
Increased blasts (CMML-2) associated with increased risk of transformation to AML and poorer prognosis
High risk cytogenetics (chromosome 7 abnormalities and complex karyotypes) correlate with poor survival
"Myeloproliferative variant" (WBC > 13 x
103 /μL) has poorer survival than "myelodysplastic variant" (WBC < 13 x
103 /μL)
Not clear if this is independent of blast count and cytogenetic predictors
Understanding of prognostic significance of molecular alterations is rapidly evolving
RAS and RUNX1 mutations likely are poor prognosis factors
Classification / Lists
WHO 2008 Classification of Myeloid Neoplasms
Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPN)
Bibliography
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Vardiman JW eds. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, World Health Organization Classification of Tumours 2008
Orazi A, Germing U. (2008) The myelodysplastic/myeloproliferative neoplasms: myeloproliferative diseases with dysplastic features. Leukemia, 22, 1308–1319.
Bacher U, Haferlach T, Schnittger S, Kreipe H, Kröger N. Recent advances in diagnosis, molecular pathology and therapy of chronic myelomonocytic leukaemia. Br J Haematol. 2011 Mar 9. doi: 10.1111/j.1365-2141.2011.08631.x. [Epub ahead of print] PubMed PMID: 21401573.
