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Chronic Myeloid Neoplasms

MDS/MPN

Chronic myelomonocytic leukemia (CMML)


Reviewer: Nikhil Sangle, M.D. (see Reviewers page)
Revised: 10 August 2011, last major update August 2011
Copyright: (c) 2001-2011, PathologyOutlines.com, Inc.

Definition
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● Mean age 70 years, 70% male (Leuk Res 2008;32:587)

Variable clinical and hematologic presentations:
(1) Myelodysplastic features of blood cytopenias, ineffective hematopoiesis, dysplastic changes and increased blasts resembling refractory anemia, refractory cytopenia with multilineage dysplasia or refractory anemia with excess blasts; plus monocytosis (monocytes may have dysplastic features)
(2) Marked leukocytosis with monocytosis, organomegaly, normal hematopoiesis, normal red blood cell and platelet counts, no/minimal dysplastic changes or excess blasts; previously called Philadelphia chromosome negative CML

● 80% of cases arise de novo; 20% arise from prior myelodysplasia, occasionally with monocytosis (Am J Clin Pathol 2006;126:789)
● Splenomegaly in 30-50% with rare rupture (Am J Hematol 2007;82:405, Am J Surg Pathol 1983;7:197), hepatomegaly in 20%
● May have tumor forming accumulations of CD123+ plasmacytoid monocytes in lymph nodes, bone marrow or skin (Am J Surg Pathol 2004;28:585)
● More closely related to myelodysplasia than myeloproliferative neoplasms using loss of heterozygosity evaluation (Mod Pathol 2007;20:1166)
● Type 1: <5% blasts in blood or <10% blasts in bone marrow
● Type 2: 5-19% blasts in blood, 10-19% blasts in bone marrow or Auer rods present; also <20% blasts in blood or marrow; poorer prognosis
● If blasts + promonocytes are 20% of more of bone marrow differential count, classify as AML

Diagnosis
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● Persistent peripheral blood monocytosis of more than 109/L, with monocytes >10% of WBCs
● No BCR/ABL1 gene fusion
● No rearragement of PDGFRA or PDGFRB
● <20% blasts (includes myeloblasts, monoblasts and promonocytes)
● Peripheral blood may have dysplastic changes typical of myelodysplasia in one or more myeloid lineages, or dysplasia may be limited to monocytes
● Usually no marrow monocytosis (Mod Pathol 2006;19:1536)
● In absence of myelodysplasi, diagnosis can be established if the process is clonal, if monocytosis is > 3 months and other causes for monocytosis are excluded

Case reports
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● Colonic involvement (Nat Clin Pract Gastroenterol Hepatol 2007;4:229)
● Kidney involvement (Arch Pathol Lab Med 2001;125:657)
● Extramedullary tumors (Arch Pathol Lab Med 1996;120:62)

Treatment
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● Decitabine
● Median survival 19 months (Cancer 2007;109:713)
● Predictors of course of disesase include percentage of peripheral / marrow blasts, degree of leukocytosis, extent of anemia and splenomegaly / organomegaly

Micro description
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Peripheral blood: cytopenia(s), monocytes may be normal appearing or have dysplastic features of increased basophilic cytoplasm, abnormal granulation, hyperlobulated nuclei; other lineage cells may have dysplastic changes the most common being granulocytes
Bone marrow: hypercellular marrow with mildly increased monocytes (but not diagnostic by itself) and increased granulocytes; may have increased reticulin fibers; variable dysplastic changes in erythroid cells and megakaryocytes; cases with eosinophilia need screening for PDGFRA, PDGFRB and FGFR1 gene abnormalities in addition to looking for causes of eosinophilia

Micro images
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Peripheral blood:

Three mature monocytes


Blast with Auer rod


Increase in mature monocytes and neutrophils

Bone marrow biopsy:

Markedly hypercellular marrow


Plasmacytoid monocyte nodules: H&E and CD123


Comparison with CML and atypical CML

Bone marrow smear:

Increased monocytes and monocyte precursors


Increase in monocyte precursors and erythroid cytoplasmic vacuoles


Promonocytes and monocytes, neutrophils and erythroid precursors

Other sites:

Colonic infiltration


Kidney-suburothelial tissue-various images

Stains:

Alpha naphthyl acetate and methyl green stains (non specific esterase)


H&E and alpha naphthyl butyrate esterase


Plasmacytoid monocyte nodules: H&E and CD123

Positive stains
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● Myelomonocytic markers such as CD13, CD14, CD68, CD64 and CD33, CD123 (plasmacytoid monocytes), CD42b (abnormal megakaryocytes, Am J Clin Pathol 2000;113:814)
● Nonspecific esterase, alpha naphtyl butyrate esterase or alpha naphtyl acetate esterase - stain monocytes and promonocytes
● CD34 stains blasts, useful for subtyping or differentiating from AML
● Monocytic cells are chloracetate esterase (CAE) negative and lysozyme positive (compare to granulocytic cells which stain positive for both)

Flow cytometry
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● Monocytosis with two or more aberrant phenotypes such as decreased CD14, CD13, HLA-DR, CD64 or CD36, overexpression of CD56
● Or abnormal antigen expression of 2+ antigens plus 20% of marrow monocytes showing CD14+ expression, which is specific for CMML versus reactive monocytosis (Am J Clin Pathol 2005;124:799)

EM images
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Monocytes are atypical with large granules

Cytogenetics description
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● Abnormalities in 20-40%, including trisomy 8, monosomy 7, 7q-, abnormalities of 12p
● Occasionally t(5;12)(q33;p13)

Molecular description
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● RAS mutations in 1/3, JAK2 V617F mutations in 13% (Blood 2005;106:3370)

Differential diagnosis
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● CML (BCR/ABL1 gene fusion) and atypical CML (few monocytes identified by nonspecific esterase, no peripheral monocytosis, no CD123+ plasmacytoid monocytic nodules)

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


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