eMedicine Specialties > Pediatrics: General Medicine > Oncology

Myelodysplastic Syndrome: Differential Diagnoses & Workup

Author: Prasad Mathew, MB, BS, DCH, Director, Hemostasis and Hematology Program, Professor of Pediatrics, University of New Mexico
Coauthor(s): Franklin Smith, MD, Marjory J Johnson Endowed Chair, Professor of Pediatrics, Division of Hematology/Oncology, Professor of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center; Glenda H Grawe, MD, Assistant Professor, Baylor College of Medicine Department of Pediatrics, Section of Emergency Medicine; Attending Physician, Texas Children's Hospital
Contributor Information and Disclosures

Updated: May 22, 2008

Differential Diagnoses

Acute Lymphoblastic Leukemia
Histoplasmosis
Acute Myelocytic Leukemia
Kostmann Disease
Anemia, Acute
Myelodysplasia
Anemia, Chronic
Myelofibrosis
Blastomycosis
Parvovirus B19 Infection
Chromosomal Breakage Syndromes
Transient Erythroblastopenia of Childhood
Cytomegalovirus Infection
Herpesvirus 6 Infection

Other Problems to Be Considered

Also consider autoimmune cytopenias and Diamond-Blackfan anemia.

The 2 major diagnostic challenges are distinguishing myelodysplastic syndrome (MDS) with a low blast count from aplastic anemia and other nonclonal bone marrow disorders and differentiating MDS with excess blasts from acute myeloid leukemia (AML).

Refractory cytopenia may be difficult to diagnose because bone marrow cellularity is often reduced (as in aplastic anemia), impeding the identification of the often subtle dysplastic changes that may be present. In the absence of a cytogenetic marker, the clinical course must be carefully monitored with repeated bone marrow examinations and biopsies at least 2-3 weeks apart. 

Differentiating MDS with increased blast count from de novo AML remains challenging, and thresholds of blast counts (set at 20% or 30%) are arbitrary and may not reflect the biology of these transitional states. De novo AML is chemotherapy-sensitive and is characterized by balanced translocations, such as t(8;21), t(15;17), t(9;11). The usual genetic changes in MDS, typically markers of chemoresistance, are aneuploidy and aberrations in chromosome numbers (eg, monosomy 7). Thus, individuals with typical cytogenetic abnormalities should be treated as having de novo AML, regardless of the blast count. Note that most patients with MDS have a blast count of less than 20%, whereas the vast majority of children with de novo AML have frankly leukemic marrow. For patients with borderline blast counts, other clinical signs (eg, organomegaly, chloroma, spinal fluid blasts) suggest a diagnosis of de novo AML.

Workup

Laboratory Studies

  • CBC count with differential and smear
    • Patients often have anemia with high mean cellular volume and RBC distribution width.
    • Patients may be neutropenic and thrombocytopenic.
    • In juvenile myelomonocytic leukemia (JMML), marked monocytosis may be present. The monocyte count in peripheral blood may exceed 1 million cells. Other diagnostic criteria for JMML include myeloid precursors in blood smears, clonal abnormality, granulocyte-macrophage colony-stimulating factor (GM-CSF) hypersensitivity of myeloid progenitors, and hemoglobin F levels above the reference range for age.
  • Hemoglobin electrophoresis: Elevated levels of fetal hemoglobin are associated with a poor prognosis and with JMML. 
  • Chromosomal analysis
    • Look for constitutional abnormalities if the patient has symptoms of Down syndrome (trisomy 21). Trisomy 21 with mosaicism occurs in 2-3% of cases in which 2 populations of cell types are present: a normal cell line with 46 chromosomes and a second cell line with trisomy 21. These children may appear phenotypically normal.
    • Order chromosomal fragility studies, including diepoxybutane and mitomycin C tests for Fanconi anemia.
    • Children with complex chromosomal aberrations combined with a low platelet count and/or elevated hemoglobin F levels have a notably worsened outcome.
    • The presence of monosomy 7 should prompt an evaluation of family members.
  • Bone marrow studies: Morphologic myelodysplasia involves dysplasia in 2 different myeloid cell lines or dysplasia that exceeds 10% in one single cell line, with evidence of a clonal cytogenetic abnormality in hematopoietic cells.
  • Viral studies: Perform viral studies for cytomegalovirus (CMV) and Epstein-Barr virus (EBV) to exclude marrow suppression due to a viral etiology.
  • Folate and vitamin B-12 studies: Obtain folate and vitamin B-12 levels to evaluate for possible defects or deficiencies.

Other Tests

  • Perform tissue typing of the patient and the family in anticipation of hematopoietic stem cell rescue.
  • Test for hypersensitivity to GM-CSF.

Procedures

  • Performing a bone marrow aspiration and biopsy is essential in establishing diagnosis and classification.
  • Bone marrow findings reveal evidence of morphologic myelodysplasia in at least 2 cell lines.
  • Biopsy may reveal dysplastic cells of various stages of differentiation with hypercellular findings.

Histologic Findings

On peripheral smears, dysplastic shapes and cells with odd-appearing nuclear and cytoplasmic ratios (eg, anisocytosis, macrocytosis, microcytosis, poikilocytosis) are apparent. Although macrocytosis can indicate megaloblastic anemia (vitamin B-12 or folate deficiency), it is often observed in most bone marrow failure syndromes, including MDS. RBCs are often dimorphic (both hypochromic and normochromic). The number of reticulocytes is reduced in relation to the degree of anemia.

Depending on the class, variable granulocytic abnormalities are present. Pseudo–Pelger-Huët anomalies (eg, hyposegmented mature neutrophils, hypogranulation of cytoplasm) are characteristic of dysgranulopoiesis observed with MDS. As additional immature elements are observed in periphery, these elements often appear bizarre with abnormal nucleus-to-cytoplasm ratios and are often oddly shaped. In addition, the number of eosinophils and basophils may increase in patients with adult-type MDS. On smears, platelets markedly vary in size. 

Myelodysplasia most commonly presents with a hypercellular marrow. In refractory anemia (RA), the ratio of erythroid to myeloid cells is abnormal, and the marrow appears similar to that of patients with megaloblastic anemia due to folate or vitamin B-12 deficiency. Erythroblasts are often large, with clumped chromatin and a large nucleolus. In refractory anemia with excess blasts (RAEB), the myeloid component of marrow increases. Small myeloblasts and promyelocytes predominate in the marrow. These cells are often dysmorphic with abnormal nucleus-to-cytoplasm ratios. 

Abnormal megakaryocytes may appear small (micromegakaryocytes) or large. They may have a variable number of nuclei in the same marrow sample.

The minimal diagnostic criteria for MDS includes at least 2 of the following:
  • Sustained, unexplained cytopenia (neutropenia, thrombocytopenia, or anemia)
  • At least bilineage morphologic dysplasia
  • Acquired clonal cytogenetic abnormality in hematopoietic cells 

In the prospective study of the European Working Group on MDS in Childhood, more than half of the patients with refractory cytopenia had a normal karyotype, followed in frequency by monosomy 7, trisomy 8, and other abnormalities.17 Loss of the long arm of chromosome 5 (5q-), the most frequent chromosomal aberration in adults with RA, is rare in childhood.

More on Myelodysplastic Syndrome

Overview: Myelodysplastic Syndrome
Differential Diagnoses & Workup: Myelodysplastic Syndrome
Treatment & Medication: Myelodysplastic Syndrome
Follow-up: Myelodysplastic Syndrome
References
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Further Reading

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Keywords

myelodysplastic syndrome, MDS, MDS, chronic myelomonocytic leukemia, CMML, clonal hemopathy, juvenile chronic myeloid leukemia, JCML, juvenile myelomonocytic leukemia, JMML, monosomy 7, oligoblastic leukemia, preleukemia, refractory anemia, RA, smoldering acute leukemia, acute myelogenous leukemia, acute myeloid leukemia, AML, adult-type MDS, a-MDS, refractory anemia with ringed sideroblasts, RARS, refractory anemia with excess blasts, RAEB, refractory anemia with excess blasts in transition to AML, RAEBT

cytopenia, preleukemia, hematopoietic stem cell transplantation, HSCT, 5q- syndrome, 5q deletion syndrome, infantile monosomy 7, myeloproliferative disorders, bone marrow dysfunction, neurofibromatosis type 1, NF1, cytopenia, short stature, obesity, gonadal failure, hypothyroidism, cataracts, bone marrow failure, lymphadenopathy, therapy-related MDS, Down syndrome, myeloid leukemia of Down syndrome, ML-DS, pancreatic insufficiency, Fanconi anemia, Kostmann syndrome, Diamond-Blackfan anemia, dyskeratosis congenita

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Contributor Information and Disclosures

Author

Prasad Mathew, MB, BS, DCH, Director, Hemostasis and Hematology Program, Professor of Pediatrics, University of New Mexico
Prasad Mathew, MB, BS, DCH is a member of the following medical societies: American Society of Hematology
Disclosure: Nothing to disclose.

Coauthor(s)

Franklin Smith, MD, Marjory J Johnson Endowed Chair, Professor of Pediatrics, Division of Hematology/Oncology, Professor of Pediatrics, University of Cincinnati College of Medicine, Cincinnati Children's Hospital Medical Center
Disclosure: Nothing to disclose.

Glenda H Grawe, MD, Assistant Professor, Baylor College of Medicine Department of Pediatrics, Section of Emergency Medicine; Attending Physician, Texas Children's Hospital
Glenda H Grawe, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Emergency Physicians, Harris County Medical Society, Minnesota Medical Association, National Association of EMS Physicians, and Texas Pediatric Society
Disclosure: Draeger Honoraria Review panel membership

Medical Editor

Kathleen Sakamoto, MD, Professor, Department of Pediatrics, Division of Hematology-Oncology and Pathology and Laboratory Medicine, Mattel Children's Hospital, David Geffen School of Medicine, University of California at Los Angeles
Kathleen Sakamoto, MD is a member of the following medical societies: American Society of Hematology, American Society of Pediatric Hematology/Oncology, New York Academy of Sciences, Society for Pediatric Research, and Western Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc
Disclosure: Pfizer Inc Stock Investment from broker recommendation; Avanir Pharma Stock Investment from broker recommendation

Managing Editor

Timothy P Cripe, MD, PhD, Associate Professor of Pediatric Hematology/Oncology, University of Cincinnati; Director, Translational Research Trials Office, Department of Pediatrics, Cincinnati Children's Hospital Medical Center
Timothy P Cripe, MD, PhD is a member of the following medical societies: American Association for the Advancement of Science, American Society of Hematology, and American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.

CME Editor

Samuel Gross, MD, Professor Emeritus, Department of Pediatrics, University of Florida, Clinical Professor, Department of Pediatrics, UNC, Adjunct Professor, Department of Pediatrics, Duke University
Samuel Gross, MD is a member of the following medical societies: American Association for Cancer Research, American Society for Blood and Marrow Transplantation, American Society of Clinical Oncology, American Society of Hematology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Chief Editor

Robert J Arceci, MD, PhD, King Fahd Professor of Pediatric Oncology, Department of Oncology, Division of Pediatric Oncology, Johns Hopkins University School of Medicine
Robert J Arceci, MD, PhD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Pediatric Society, American Society of Clinical Oncology, American Society of Hematology, and American Society of Pediatric Hematology/Oncology
Disclosure: Nothing to disclose.

 
 
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