At a Glance

Myelodysplastic syndrome (MDS) is a group of diseases that are due to ineffective hematopoiesis. The primary clinical findings in these patients are related to the sequelae of cytopenias (i.e., fatigue/dyspnea, bruising/bleeding, and infections). The primary morphologic finding is that of dysplasia in a cytopenic patient and, typically, a hypercellular bone marrow. Because there are many causes of both dysplasia and cytopenias and because there are no single diagnostic tests for MDS, the diagnosis of MDS relies on the appropriate constellation of findings in a clinically suspicious patient with no other apparent cause for the symptoms.

There are multiple subtypes of myelodysplasia that can generally be classified into two grades. The low-grade myelodysplasias include refractory cytopenia with unilineage dysplasia (RCUD), refractory anemia with ringed sideroblasts (RARS), and myelodysplastic syndrome with isolated deletion of 5q (5q- MDS). There are four high-grade myelodysplastic subtypes: refractory anemia with excess blasts (RAEB)1, refractory anemia with excess blasts 2, therapy-related myelodysplastic syndrome and refractory cytopenias with multilineage dysplasia (RCMD).

The high-grade MDS subtypes have a propensity to develop increased blasts and may eventually transform into acute myeloid leukemia. Importantly, MDS-associated Acute Myeloid Leukemia (AML) is a separate World Health Organization (WHO) category clinically notable for its low response rate to standard anti-proliferative chemotherapy and poor prognosis. Even in those high-grade MDS patients who do not transform to AML, severe cytopenias can significantly shorten lifespan. High-grade MDS patients have a mean overall survival, ranging from 9 months to 3 years. Conversely, low-grade MDS may respond well to supportive therapy, hypomethylating agents, or immunomodulating agents, giving these patients mean overall survivals of 6-12 years.

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Because therapies vary depending on MDS subtype, a careful examination of all the laboratory data by a qualified pathologist is mandatory.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

A complete blood count (CBC) to identify the cytopenias is the first step in diagnosing Myelodysplasia. In particular, anemic MDS patients often present with a low reticulocyte count and a low immature platelet fraction reflecting their ineffective hematopoiesis. Moreover, the anemia in MDS is typically macrocytic. A morphologic review of the peripheral blood smear often reveals dysplasia in the neutrophils, including hypogranularity or atypically large granules in the cytoplasm (pseudoChediak-Higashi). Neutrophil nuclei can show hypolobation (pseudo-Pelger-Huet anomaly) or hyperlobation. Platelets may be large or agranular. Red cell morphology in the peripheral blood may be normal or macrocytic with anisopoikilocytosis.

Because MDS is a clinicopathologic diagnosis without pathognomonic findings, it is crucial that other causes of cytopenias and dysplasia be excluded. Once these other causes have been ruled out, a bone marrow biopsy and aspirate with karyotype is recommended for patients for whom no other cause of cytopenias can be identified. If the aspirate contains increased blasts, flow cytometry may be useful in characterizing the blasts. In some flow cytometry laboratories, evaluation of myeloid or erythroid maturation patterns can support the diagnosis of MDS in the appropriate context.

Blasts must comprise less than 20% of total cells on morphologic review of blood and bone marrow aspirate. If 20% or more blasts are seen in either blood or bone marrow, the best diagnosis is acute leukemia. There are two subcategories of MDS associated with increased blasts less than 20%. In RAEB2, blasts comprise 5-19% of total cells in blood or 10-19% in marrow. In RAEB1, blasts and promonocytes comprise less than 5% of cells in the blood and 5-9% in bone marrow.

Abnormal cytogenetics are detected in approximately 40% of MDS patients at presentation. There is no single pathognomonic cytogenetic finding in MDS. Karyotype has recently been shown in several studies to be as sensitive as fluorescent in situ hybridization (FISH) for the diagnosis of MDS. The karyotypic changes most often seen are deletion of 5q, monosomy 7, trisomy 8, deletion 20q, loss of Y. However, there are many more karyotypic changes also consistent with MDS but are of low frequency.

Of note, the findings in flow cytometry, karyotype, and histomorphology are all nonspecific and must be considered together in the appropriate clinical context before a diagnosis of MDS can be made.

(Table 1)(Table 2)

Table 1
CBC Bone Marrow Morphology Cytogenetics
Unilineage or multilineage cytopenias Dysplasia of at least 10% of cells in at least one lineage -5q, -7, +8, +12, -20q, complex
Table 2
Grade Subtype Blood Findings Bone Marrow Findings
Very Low Isolated 5q- MDS Anemia Small, hypolobated megakaryocytes
Normal or increased Plts Isolated 5q- cytogenetics
No blasts <5% blasts
Low Refractory Cytopenias with Unilineage Dysplasia Uni- or bilineage cytopenias Unilineage dysplasia
Rare blasts (<1%) <5% blasts
Refractory Anemia with Ringed Sideroblasts Anemia Erythroid dysplasia with >15% ringed sideroblasts and <5% blasts
No blasts
High Refractory Cytopenias with Multilineage Dysplasia At least one lineage cytopenia At least 2 lineages with dysplasia
Rare blasts (<1%) <5% blasts
Refractory Anemia with Excess Blasts 1 Cytopenias Dysplasia
<5% blasts 5-9% blasts (no Auer rods)
Refractory Anemia with Excess Blasts 2 Cytopenias Dysplasia
5-19% blasts 10-19% blasts (no Auer rods)

What Lab Results Are Absolutely Confirmatory?

No lab test is absolutely confirmatory for MDS. Review of the patient’s history with a particular focus on other exposures associated with dysplasia and cytopenias in combination with morphology, karyotype, and occasionally flow cytometry can aid in the diagnosis of MDS. In some cases, cytopenic patients can be followed for months or years before a definitive diagnosis can be made.

What Other Diseases Should Be Considered and How Do I Distinguish Between Them?

There are numerous causes of dysplasia and cytopenias that must be ruled out before a diagnosis of MDS can be made. Secondary bone marrow disorders include nutritional deficiencies (i.e., vitamin B12, folate, copper), toxic exposures (i.e., benzene, zinc, heavy metals, ethanol), pharmaceutical side effect (i.e., recent chemotherapy, growth factor stimulation, some antimicrobials, immunosuppressive agents), viral infections (i.e., parvovirus B19, acute Ebstein-Barr virus (EBV) infection), and autoimmune/rheumatologic diseases (i.e., systemic lupus erythematosus, rheumatoid arthritis). These myelotoxic insults lead to secondary dysplasia and cytopenias. Many of these potential exposures can be ruled out with a careful patient history or widely available clinical chemistry tests (i.e., red cell folate, serum vitamin B12, copper and zinc levels, anti-nuclear antibodies (ANA), rheumatoid factor (RF) and parvovirus B19 or EBV titers if clinically suspicious for infection).

Primary bone marrow disorders associated with dysplasia and cytopenias include myelodysplastic/myeloproliferative neoplasia, including chronic myelomonocytic leukemia (CMML). CMML requires a sustained monocytosis greater than 1,000 per microliter. Myelodysplastic/ myeloproliferative neoplasia (MDS/MPN) also present with a cytosis of at least one lineage, rather than purely cytopenias. Finally, MDS/MPN often present with splenomegaly, which is very rare in pure MDS. Late stage myeloproliferative neoplasia can be associated with cytopenias and red cell and megakaryocytic dysplasia. The bone marrow biopsy typically shows diffuse, dense fibrosis and morphologically atypical megakaryocytes.

Of note, these patients should be distinguished with a careful history that shows a preceding leukocytosis or thrombocytosis. However, when patient history is scant or unreliable, late stage MPN can be very challenging to distinguish from MDS with fibrosis. Again, splenomegaly would be rare in MDS but more common in MPN.

What is the Prognosis?

Prognosis in MDS is dependent on the particular MDS subtype. Whereas RAEB2 patients have a median overall survival of 9 months, 5q- MDS patients have a median overall survival of nearly 12 years. The International Prognostic Scoring System for MDS is based on blast count, karyotype, and cytopenias. This system breaks MDS populations into good, intermediate-1, intermediate-2, and high risk patients with mean overall survivals of approximately 68 months, 42 months, 14 months, and 5 months, respectively.

The only curative therapy for MDS is allogeneic bone marrow transplantation, although newer pharmaceutical approaches with hypomethylating agents, histone deacetylation inhibitors, and immunomodulatory drugs are being pursued.