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Chronic Myeloid Neoplasms

Myelodysplastic syndromes

Myelodysplastic syndrome (MDS) - general


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

Clinical features
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● Clonal disorders of multipotent bone marrow stem cells with cytopenia(s), dysplasia in one or more of the major myeloid cell lines, ineffective or disorderly hematopoiesis, and increased risk of development of AML
● Note: myelodysplasia also means abnormal development of spinal cord
● “Ineffective hematopoiesis” means cytopenia (anemia most common) despite a cellular/hypercellular marrow with normal or increased precursors for one or more cell lines; cytopenias may be due to aberrant expression of various cytokines and accelerated apoptosis
● 15K new cases in US each year (Cancer 2008;112:1089)
● 25-45% of patients develop acute myeloid leukemia (AML)
● Must rule out MDS in any adult with unexplained cytopenias or monocytosis
● Threshold for cytopenia(s): hemoglobin <10g/dL, absolute neutrophil count <1.8 x 10 9/L, platelets <100 x 10 9/L
● Dysplasia should be evident in >10% of cells in one or more myeloid cell lines
● Mean age 65 years; may affect any age, but less than 50 years is uncommon
● Symptoms are related to cytopenias or defective platelet aggregation (Acta Haematol 2007;118:117), but 50% are initially asymptomatic
Primary MDS: etiology unknown (age 50+ years)
Secondary / therapy related MDS (t-MDS): due to radiation or alkylating agents (2-8 years after exposure), see below
Laboratory: usually macrocytic anemia with increased red cell distribution width (RDW) and low / normal reticulocyte count; variable neutropenia or thrombocytopenia
Mean survival: refractory anemia - 10 years, refractory anemia with ringed sideroblasts - 7 years; RA with multilineage dysplasia - 3 years (Leuk Res 2006;30:971), refractory anemia with excess blasts or chronic myelomonocytic leukemia - 1 year, therapy related MDS - 5 months; death often due to AML or bleeding / infection

Prognostic factors
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Poor:
● Multiple clonal chromosomal abnormalities, severe cytopenias (< 0.5 neutrophils or < 50K platelets), high %blasts in marrow or any blasts in blood, lack of ringed sideroblasts, abnormal localization of immature granulocyte precursors in bone marrow biopsy
● Patients with Auer rods and < 5% blasts usually progress rapidly to AML or death (Am J Clin Pathol 2005;124:191)
● Patients with RA, RARS or RCMD with peripheral blasts (even < 1%) have similar prognosis as refractory anemia with excess blasts-type 1 (Leuk Res 2008;32:33)
● Complex (>3 abnormalities) or chromosome 7 anomalies

Good:
● Younger age, normal/moderate neutropenia and thrombocytopenia, low blast percentage in marrow with no blasts in blood, no Auer rods in blasts, ringed sideroblasts present, normal karyotype or -Y, 5q- or 20q- alone

Diagnosis
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● Cellular marrow but peripheral blood cytopenias with dysplastic changes in hematopoietic cells
● Bone marrow biopsy / aspirate is necessary to confirm diagnosis and obtain material for additional studies; must correlate findings with complete clinical information; by definition, myeloblasts are < 20% (if 20% or more, classify as AML)

Treatment
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● Bone marrow transplant (Hematology Am Soc Hematol Educ Program 2006;205), support (antibiotics, transfusions)

Micro description
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Peripheral blood smear (general MDS findings):
Erythroid: dimorphic population of oval macrocytes and hypochromic microcytic RBCs, basophilic stippling, erythrocyte vacuoles, nucleated red blood cells, Howell-Jolly bodies
Granulocytes: neutropenia with immature, hypogranular forms, pseudo-Pelger-Huet neutrophils (2 lobes), monocytosis, myeloblasts
Platelets: thrombocytopenia, giant platelets
● Note: In severely cytopenic patients, buffy coat smears of peripheral blood can be used to perform differential

Bone marrow: (general MDS findings):
● Usually hypercellular or normocellular, 10% are hypocellular; iron stores often increased
● Disordered (dysplastic) differentiation affecting all 3 lineages
● Myelofibrosis in therapy related MDS
Erythroid: erythroid hyperplasia, ringed sideroblasts (iron-laden mitochondria visible as perinuclear granules with Prussian iron stain), megaloblastoid nuclear maturation, nuclear budding abnormalities (polypoid outlines, internuclear bridging, nuclear fragments, multinuclearity, nuclear hyperlobation), cytoplasmic vacuolization, PAS positive erythroblasts
Leukocytes: myeloblasts may be increased but < 20% of nonerythroid cells (or is defined as AML); abnormally localized immature precursors (ALIP), neutrophils with decreased secondary granules or 2 lobes (pseudo Pelger-Huet cells), toxic granulations, Dohle bodies, Auer rods, irregular nuclear segmentation, increased basophils or monocytes; rarely monocytic nodules (Am J Clin Pathol 2003;120:874); myeloid cells are myeloperoxidase negative; note that in ALIP, aggregates (3-5) or clusters (6+) of immature precursors are remote from trabeculae (normal maturing granulocytes extend from trabeculae or blood vessels towards central areas)
Megakaryocytes: megakaryocytes occur in clusters; single nuclear lobe, hypolobulation or multiple separate nuclei; micro-megakaryocytes present
Spleen: splenomegaly uncommon; erythrophagocytosis, red pulp plasmacytosis, extramedullary hematopoiesis or marked red pulp expansion due to monocytic proliferation; splenomegaly usually due to dyspoiesis, not proliferation (Am J Surg Pathol 1998;22:1255)

Micro images
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Erythroid: dysplastic changes


Erythroid: ringed sideroblasts

           
Dysplastic granulocytes

   
Megakaryocyte changes

Flow cytometry
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● Can predict morphologic erythroid dysplasia by the pattern of expression of CD105, CD71, H-ferritin in glycophorin-A positive cells (Leukemia 2006;20:549)
● Aberrant maturation patterns in granulopoeisis can predict morphologic dysplasia in granulocytic lineage (Am J Clin Path 2003;120:854)

EM description
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● Same findings as AML
● Erythroid cells show unusual shapes, redundant cell membranes, large vacuoles, duplication of nuclear membrane and nuclear blebs
● Maturing neutrophils show decreased primary and secondary granules of abnormal size and shape
● Monocytes show increased cytoplasmic microfilaments and abnormal granules
● Megakaryocytes and micromegakaryocytes show decreased granules and demarcation membranes, platelets are hypogranular or have large granules

Cytogenetics / molecular
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● Recommended to use karyotyping or FISH in all suspected patients
● MDS has no specific cytogenetic abnormalities, but abnormalities are present in 30% of de novo MDS and 80% of therapy related MDS
● Usually chromosomal losses not gains
● Common findings are complete or partial loss of #5 or #7, +8, 20q- or complex chromosomal abnormalities
● t(3;5) cases are due to NPM-MLF1 fusion, usually young males with good prognosis (Hum Pathol 2003;34:809)
● Cytogenetic abnormalities such as deletions of 7q, 5q, 13q, 11q, 12p, 9q and balanced translocations such as t(11;16), t(3;21), t(1;3) are considered presumptive evidence of MDS, in the setting of persistent cytopenias of undetermined origin

Differential diagnosis
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● Copper deficiency (Am J Hematol 2007;82:625), arsenic toxicity
● AML: 20% or more blasts, t(8;21), inv(16) or t(15;17) with any percentage of blasts
● Parvovirus B19 infection, storage of bone marrow aspirates in EDTA at room temperature (Am J Clin Pathol 2002;117:57), aplastic anemia (lower PCNA and CD34 expression, Am J Clin Pathol 1997; 107:268)
● Behçet's disease (J Clin Immunol 2007;27:145), vitamin B12 and folate deficiency, chemotherapeutic agents, granulocyte colony-stimulating factor, paroxysmal nocturnal hemoglobinuria
● Therefore need appropriate clinical history to correlate with morphologic and cytogenetic findings

Additional references
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Arch Pathol Lab Med 2005;129:1299, eMedicine #1, #2, Wikipedia

End of Chronic Myeloid Neoplasms > Myelodysplastic syndromes > Myelodysplastic syndrome (MDS) - general


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