Myelodysplastic Syndrome Workup

The workup in patients with possible myelodysplastic syndrome (MDS) includes a complete blood count with differential, peripheral blood smear, and bone marrow 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.

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 oval-shaped RBCs (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.

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 MPDs. 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.)

Dysplastic changes in WBC lineage (dysmyelopoiesis) show 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.

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 without (RCMD-) or with multi-lineage dysplasia (RCMD+) and 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. Identification of the syndrome or presence of this particular cytogenetic abnormality is useful because the majority of these patients will respond to the new drug lenalidomide (Revlimid).

Unclassified by the WHO are the group of patients with MDS whose conditions overlap with severe aplastic anemia and paroxysmal nocturnal hemoglobinuria. A group of MDS patients with the FAB-RA subtype who may have a hypoplastic marrow, usually human leukocyte antigen (HLA)-DR15 phenotype, are young (< 60 y) and may have negative cells to CD55 and CD59 respond to immunosuppression with anti-thymocyte globulin (ATG) or cyclosporin.^[11]

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.)

An international group of experts, the MDS Risk Analysis Workshop, developed the International Prognostic Scoring System (IPSS) for staging MDS.^[12] (See Table 2, below.)

Table 2. IPSS Score for Staging MDS^[12] (Open Table in a new window)

The first prognostic factor is the amount or percentage of myeloblasts identified in the patient's bone marrow study. Each increase of 10% over the reference range is equivalent to a half point.

The number of cytopenias is scored by the presence of 2-3 (anemia plus thrombocytopenia or neutropenia or pancytopenia), which is worth a half point. The presence of no cytopenias or a single one indicates a good prognosis.

The total score is added, and the patient is staged according to the following:

• Low: 0
• Intermediate 1: 0.5-1
• Intermediate 2: 1.5-2
• High: ≥ 2.5

Classification of the subtypes or categories of MDS has changed from the FAB classification to the WHO classification. (See Table 3, below.)

Table 3. Categories of FAB Classification Versus WHO Classification for Myelodysplastic Syndrome (MDS) (Open Table in a new window)

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.