Myelodysplastic Syndrome Workup

Updated: Sep 28, 2016
  • Author: Emmanuel C Besa, MD; Chief Editor: Koyamangalath Krishnan, MD, FRCP, FACP  more...
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Workup

Approach Considerations

The workup in patients with possible myelodysplastic syndrome (MDS) includes a complete blood count with differential, peripheral blood smear, and bone marrow studies with cytogenetic studies. Findings on these studies are used to stage the disease. Because MDS has heterogeneous clinical manifestations and varying clinical outcomes, staging is necessary to determine prognosis and guide the approach to therapy.

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Complete Blood Count and Peripheral Blood Smear

Significant changes are found in the blood counts and morphology of patients with MDS. The peripheral blood count may show a single cytopenia (anemia, thrombocytopenia, or neutropenia) in the early phase or bicytopenia (2 deficient cell lines) or pancytopenia (3 deficient cell lines) in later stages.

Anemia varies in degree from mild to severe. It is usually macrocytic (mean cell volume of >100 fL) with red blood cells (RBCs) that are oval-shaped (macro-ovalocytes). It is usually dimorphic (2 or more populations), with a normal or a hypochromic microcytic population (RARS) coexisting with the macrocytes. Punctate basophilia is observed in RBCs.

Neutropenia may vary from mild to severe. Morphologic abnormalities are often observed in the granulocytes. These can include bilobed or unsegmented nuclei (pseudo–Pelger-Huet abnormality) or hypersegmentation on the nuclei (6-7 lobes) similar to megaloblastic diseases.

Granulation abnormalities vary from an absence of granules to abnormal distribution inside the cytoplasm (Dohle bodies).

Platelet counts are decreased (rarely increased). Abnormalities such as giant hypogranular platelets and megakaryocyte fragments are present.

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Bone Marrow Studies

In most cases, bone marrow changes include hypercellularity with trilineage dysplastic changes. A small number of patients may have a hypocellular marrow. This often overlaps with aplastic anemia. Increased marrow fibrosis may be confused with other myeloproliferative disorders. Dysplastic changes in RBC lineage (dyserythropoiesis) are characteristic. In the absence of vitamin B-12 or folate deficiencies, the bone marrow usually exhibits asynchronous maturation of nuclei and cytoplasm similar to that described in megaloblastic anemias.

Other changes include binuclearity or multinuclearity in the erythroid cell precursor cells and the presence of ringed sideroblasts (iron accumulation in the mitochondria). Refractory anemia with ringed sideroblasts (RARS) is one of the MDS types in the French-American-British (FAB) Cooperative Group classification system. (See the image below.)

Bone marrow film (1000× magnification) demonstrati Bone marrow film (1000× magnification) demonstrating ring sideroblasts in Prussian blue staining in a refractory anemia with excess of blasts in transformation. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.

Dysplastic changes in white blood cell (WBC) lineage (dysmyelopoiesis) involve myeloid hyperplasia with an increased number of myeloblasts and an expanded myelocyte and metamyelocyte population (midstage bulge). This separates it from acute leukemia (leukemic hiatus or absence of mid stage). In the FAB classification, the percentage of myeloblasts separates RA (< 5%), RAEB (5-20%), RAEB in transformation (>20, < 30%), and acute myeloid leukemia (AML; >30%).

The 2008 update of the WHO classification considers single-lineage dysplasia as a valid criterion for diagnosis of MDS, and refractory cytopenia with unilineage dysplasia (RCUD) became an official entity in that classification. In 2004, WHO revised the percentage of blasts that defines AML from 30% to 20%; thus, the RAEB in transformation entity has become officially AML.

Morphologic abnormalities are evident in nuclear-cytoplasm dissociation in maturation and when the pseudo–Pelger forms are also present in bone marrow.

Dysthrombopoiesis in the platelet production cell lineage consists of micromegakaryocytes (dwarf forms) with poor nuclei lobulation and giant platelets budding off from their cytoplasm.

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Cytogenetic Studies

Cytogenetic techniques have evolved from individual chromosome identification by banding techniques to the new, more sensitive color-coded methods. Separating individual chromosomes is dependent on the ability to induce the cell into mitosis to identify abnormalities. The new technique uses fluorescent in situ hybridization (FISH) and color-coded chromosomes to enable observation of the intact cell without requiring mitosis.

Cytogenetic studies of the bone marrow cells indicate mutations into clonal cell lines, with abnormal chromosomes in 48-64% in different series. With higher-resolution techniques (eg, FISH), some practitioners claim a 79% rate of chromosomal abnormalities in patients with primary MDS.

Chromosomal abnormalities are clonal and include 5q-, monosomy 7 (-7) or 7q-, trisomy 8 (+8), and numerous other less frequent abnormalities. Multiple combinations may be present; this indicates a very poor prognosis. A single abnormality, except those involving chromosome 7, usually indicates good prognosis and survival.

The WHO classification is helpful in predicting subgroup differences in prognosis and response to treatment in patients with MDS. Refractory cytopenias are divided into those in which multi-lineage dysplasia is absent (RCMD-) or present (RCMD+) and those with ringed sideroblasts (RCMD+/+RS) or without ringed sideroblasts (RCMD/-RS).

A new subcategory includes patients with isolated deletion of chromosome 5q (5q-) and less than 5% blasts, called the 5q- syndrome. [17] Identification of the syndrome or presence of this particular cytogenetic abnormality is useful because the majority of these patients will respond to treatment with lenalidomide (Revlimid).

Unclassified by the WHO are the group of patients with MDS whose conditions overlap with severe aplastic anemia and paroxysmal nocturnal hemoglobinuria. This group includes MDS patients with the FAB-RA subtype who may have a hypoplastic marrow, usually have a human leukocyte antigen (HLA)-DR15 phenotype, are young (<60 years), may have cells deficient in CD55 and CD59, and respond to immunosuppressive treatment with anti-thymocyte globulin (ATG) or cyclosporin. [18]

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Histologic Findings

The presence of dysplastic changes in the peripheral blood smear and trilineage dysplasia and hypercellular marrow in the absence of vitamin deficiency is diagnostic of MDS. The presence of typical chromosomal abnormalities supports the diagnosis and contributes to determining the prognosis of MDS. (See the following images.)

Blood film (1000× magnification) demonstrating a v Blood film (1000× magnification) demonstrating a vacuolated blast in a refractory anemia with excess of blasts in transformation. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
This bone marrow film (400× magnification) demonst This bone marrow film (400× magnification) demonstrates an almost complete replacement of normal hematopoiesis by blasts in a refractory anemia with an excess of blasts in transformation. Note the signs of abnormal maturation such as vacuolation, double nucleus, and macrocytosis. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
Bone marrow film (1000× magnification) demonstrati Bone marrow film (1000× magnification) demonstrating ring sideroblasts in Prussian blue staining in a refractory anemia with excess of blasts in transformation. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
Bone marrow film (1000× magnification) demonstrati Bone marrow film (1000× magnification) demonstrating granular and clotlike positive reaction in periodic acid-Schiff staining in a refractory anemia with excess of blasts in transformation. Courtesy of U. Woermann, MD, Division of Instructional Media, Institute for Medical Education, University of Bern, Switzerland.
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Staging

In 1997, an international group of experts, the MDS Risk Analysis Workshop, developed the International Prognostic Scoring System (IPSS) for staging MDS. [15] The IPSS was revised in 2012 to accommodate advances in defining cytogenetic abnormalities. [16] The revised IPSS (IPSS-R) also includes a more detailed consideration of cytopenias. (See Tables 2-4, below.) An online calculator for determining an individual patient's R-IPSS score is available on the MDS Foundation Web site.

Table 2 Cytogenetic abnormalities assigned an IPSS-R value for scoring (Open Table in a new window)

Cytogenetic prognostic subgroups Cytogenetic abnormalities 
Very good -Y, del(11q)
Good Normal, del(5q), del(12p), del(20q), double



including del(5q)



Intermediate Del(7q), +8, +19, t(17q), any other single or



double independent clones



Poor -7, inv(3)/t(3q)/del(3q), double including



-7,/del(7q), complex: 3 abnormalities



Very poor Complex: >3 abnormalities

 

Table 3.Calculation of IPSS-R score (Open Table in a new window)

  Points Assigned
0 0.5 1 1.5 2 3 4
 



 



 



Variable



Cytogenetic subgroup Very Good   Good   Intermediate Poor Very Poor
Bone marrow blasts (%) ≤2   >2-



<5



  5-10 >10  
Hemoglobin (g/dL) ≥10   8-9.9 <8      
Platelet count (x 109/L) ≥100 50-99.9 <50        
Absolute neutrophil count (x 109/L) ≥0.8 <0.8          

Table 4. IPSS-R prognostic risk scores and categories (Open Table in a new window)

Risk Score Risk Category
≤1.5 Very Low
>1.5-3 Low
>3-4.5 Intermediate
>4.5-6  High
>6 Very High

 

Calculation of the IPSS-R score in 7012 patients with MDS resulted in the following risk categorizations [16] :

  • Very low: 19%
  • Low: 38%
  • Intermediate: 20%
  • High: 13%
  • Very high: 10%

Clinical outcome according to IPSS-R risk category in those patients is outlined in Table 5, below.

Table 5. Clinical outcome by IPSS-R risk category (Open Table in a new window)

  IPSS-R Risk Category
  Very Low Low Intermediate High Very High
Clinical Outcome Median survival (years) 8.8 5.3 3.0 1.6 0.8
Median time to 25% acute myelogenous leukemia evolution (years) NR 10.8 3.2 1.4 0.7

 

 

Classification of the subtypes or categories of MDS has changed from the FAB classification to the WHO classification. (See Table 6, below.)

Table 6. Categories of FAB classification versus WHO classification for myelodysplastic syndrome (MDS) (Open Table in a new window)

FAB



Classification



WHO–2004



Classification



WHO–2008



Classification



RA RA RCMD 5q- RCUD RCMD 5q-
RARS RARS RCMD-RS RARS RCMD-RS RARS-T
RAEB RAEB-1 RAEB-2 RAEB-1 RAEB-2
CMML CMML-1 CMML-2 CMML-1 CMML-2
RAEB-T AML AML

FAB – French-American-British Cooperative Group; WHO – World Health Organization; RA – Refractory anemia; RARS – RA with ringed sideroblasts; RAEB – RA with excess blasts; RAEB-T – RAEB in transition to AML; AML – Acute myelogenous leukemia; CMML – Chronic myelomonocytic leukemia; RCMD – Refractory cytopenia with multilineage dysplasia; RCUD – Refractory cytopenia with unilineage dysplasia

CMML in the FAB classification requires an actual monocyte count of more than 1000/μL with trilineage dysplasia.

WHO classifies CMML into the following:

  • Juvenile and proliferative CMML under MDS/myeloproliferative neoplasma (MPN have more than 13,000/μL monocytes plus splenomegaly.
  • CMML under MDS is limited to monocytosis of less than 13,000/μL with trilineage dysplasia.
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