Myelodysplastic Syndromes

Myelodysplastic syndromes (MDSs) are heterogeneous clonal hematopoietic stem cell disorders, characterized by ineffective hematopoiesis, cytopenia(s) (anemia, neutropenia, and/or thrombocytopenia), and unilineage or multilineage dysplasia, with increased risk of acute myeloid leukemia (AML). Although MDSs and AML exhibit similar features, MDSs are defined by a lower percentage (<20%) of blasts in blood and bone marrow. MDSs may be asymptomatic. When symptomatic, the most common symptoms are pallor, weakness, and exertional dyspnea secondary to anemia; hepatomegaly or splenomegaly; and arthralgias. Mutations in hematopoietic stem cells in MDSs usually arise from unknown causes but may be associated with chemotherapy, radiation, or environmental toxins. Inherited genetic abnormalities or other hematologic conditions may be associated with MDSs, particularly in younger patients.   Cytogenetic and molecular studies play a key role in the evaluation of patients with MDSs; results are used to establish a diagnosis, stratify patients into prognostic groups, guide medical management, and monitor disease progression.

Quick Answers for Clinicians

Which conditions must be distinguished from myelodysplastic syndromes?

Myelodysplastic syndromes (MDSs) may present similarly to other conditions associated with cytopenias, dysplasia, or clonality. Dysplasia or cytopenia may be induced by nutritional deficiencies (eg, of vitamin B12, folate, or copper), toxins (eg, arsenic, lead, zinc, or alcohol), drugs (eg, chemotherapeutic agents), infections (eg, HIV), congenital disorders (eg, congenital dyserythropoietic anemia), paroxysmal nocturnal hemoglobinuria (PNH), and anemias (eg, sideroblastic anemia, aplastic anemia). These conditions can be distinguished from MDSs using a combination of morphologic findings, clinical presentation, detailed history, and laboratory testing (potentially including cytogenetics and molecular testing).

Clonal disorders that must be distinguished from MDSs include clonal hematopoiesis of indeterminate potential (CHIP) and acute myeloid leukemia (AML). CHIP will exhibit somatic mutations associated with hematologic malignancy but will not meet the diagnostic criteria for MDSs or other disorders. AML can be distinguished from MDSs by the percentage of blasts and/or the presence of cytogenetic and molecular features associated with AML. For more information, see the ARUP Consult Acute Myeloid Leukemia topic.

Finally, an MDS in the presence of prominent myeloproliferative features (eg, thrombocytosis, megakaryocytic proliferation, or leukocytosis) is more appropriately characterized as a myelodysplastic/myeloproliferative neoplasm (MDS/MPN).

What are the criteria for diagnosing myelodysplastic syndromes?

The National Comprehensive Cancer Network (NCCN) suggests that the minimal diagnostic criteria for a myelodysplastic syndrome (MDS) are at least one cytopenia that has been stable for at least 6 months (or for 2 months if a specific karyotype or bilineage dysplasia has been identified) and the exclusion of other disorders that may have caused dysplasia or cytopenia. 

What are the differences between pediatric and adult myelodysplastic syndromes, and how do they affect testing?

Most myelodysplastic syndromes (MDSs) occur in older patients (the mean age of onset is approximately 70 years).  Pediatric myelodysplasia is very rare and is strongly associated with congenital disorders (eg, Down syndrome, Fanconi anemia, and neurofibromatosis type 1).   In younger patients, including young adults, and in families with multiple cases of acute myeloid leukemia (AML), aplastic anemia, or MDS, an evaluation for inherited syndromes should be considered.  

Indications for Testing

MDS should be suspected in individuals with cytopenia(s) (values lower than standard values based on age, sex, ethnicity, and altitude of patient residence) that cannot otherwise be explained.   MDS may also be suspected if there is unexplained macrocytosis, peripheral blood dysplasia, blasts, or MDS-associated cytogenetic abnormalities.  

Classification

The diagnosis and classification of MDSs are based on clinical, morphologic, and cytogenetic criteria. Both bone marrow and peripheral blood tests are required to determine if patients fulfill these criteria.   In most cases, both cytopenia(s) and dysplasia(s) must be present. Classification follows the World Health Organization (WHO) scheme. 

WHO Classification of MDSs
MDS Subtype Blood Findings Bone Marrow Findings
MDS-SLD

Unicytopenia or bicytopenia

<1% blasts

Dysplasia in ≥10% of the cells in 1 myeloid lineage

<5% blasts

No Auer rods

MDS-RS

  • MDS-RS and single-lineage dysplasia
  • MDS-RS and multilineage dysplasia

Anemia

No blastsa

≥15% erythroid precursors are ring sideroblasts or ≥5% ring sideroblasts if SF3B1 mutation is present

<5% blasts

No Auer rods

MDS-MLD

Cytopenia(s)

<1% blasts

<1 x 109/L monocytes

Dysplasia in ≥10% of cells in ≥2 myeloid lineages

<15% ring sideroblasts or <5% ring sideroblasts if SF3B1 mutation is present

<5% blasts

No Auer rods

MDS-EB-1

Cytopenia(s)

<5% blasts

<1 x 109/L monocytes

Unilineage or multilineage dysplasia

5-9% blasts

No Auer rods

MDS-EB-2

Cytopenia(s)

5-19% blasts

<1 x 109/L monocytes

Unilineage or multilineage dysplasia

10-19% blasts with or without Auer rods

MDS-U

Cytopenia(s)

<1% blasts or 1% blasts on at least 2 occasions

Unilineage dysplasia or no dysplasia but characteristic MDS cytogenetics

<5% blasts

No Auer rods

MDS associated with isolated del(5q)

Anemia

Platelets normal or increased

<1% blasts

Unilineage erythroid dysplasia

Isolated del(5q) cytogenetic abnormality or del(5q) with 1 other abnormality except -7 or del(7q)

<5% blasts

No Auer rods

Provisional category: refractory cytopenia of childhood

Cytopenia(s)

<2% blasts

Dysplasia in 1-3 lineages

<5% blasts

MDS-EB-T

Cytopenias

5-19% blasts

Multilineage dysplasia

20-29% blasts

aWHO (2016) states that <1% blasts may be present.

MDS-EB-1, MDS with excess blasts-1; MDS-EB-2, MDS with excess blasts-2; MDS-EB-T, MDS with excess blasts in transformation; MDS-MLD, MDS with multilineage dysplasia; MDS-RS, MDS with ring sideroblasts; MDS-SLD, MDS with single-lineage dysplasia; MDS-U, MDS, unclassifiable; NCCN, National Comprehensive Cancer Network

Sources: NCCN, 2020 ; WHO, 2016 

In cases with only mild morphologic abnormalities in conjunction with persistent unexplained cytopenia(s), the condition may be referred to as an idiopathic cytopenia of uncertain significance (ICUS), although this term is not universally accepted.  Similarly, if dysplasia is present with no or mild cytopenia and a normal karyotype, the condition may be referred to as idiopathic dysplasia of unknown significance (IDUS), another term that is not universally accepted. 

Classification of MDS-MPNa
Subtype Blood Bone Marrow
CMML 0

>1 x 109/L monocytes

≥10% monocytes

<2% blasts

Dysplasia in ≥1 hematopoietic line

<5% blasts

CMML 1

>1 x 109/L monocytes

≥10% monocytes

2-4% blasts

Dysplasia in ≥1 hematopoietic line

5-9% blasts

CMML 2

>1 x 109/L monocytes

≥10% monocytes

5-19% blasts or Auer rods

Dysplasia in ≥1 hematopoietic line

10-19% blasts or Auer rods

aCML, BCR-ABL1

WBCs >13 x 109/L

≥10% neutrophil precursors

<20% blasts

Dysgranulopoiesis

Hypercellular

<20% blasts

CNLb

WBCs ≥25 x 109/L

≥80% of WBCs are segmented neutrophils plus band forms

<1 x 109/L monocytes

Hypercellular

Increased neutrophil granulocytes

<5% blasts

JMML

>1 x 109/L monocytes

≥10% monocytes

<20% blasts

>1 x 109/L monocytes

<20% blasts

Ph negative

GM-CSF hypersensitive

MDS/MPN, unclassifiable (overlap syndrome)

Dysplasia

Myeloproliferative features

No previous MDS or MPN

Dysplasia

Myeloproliferative features

MDS/MPN with ring sideroblasts and thrombocytosis

Dysplasia

Myeloproliferative features

Platelets ≥450 x 109/L

≥15% ring sideroblasts

Dysplasia

Myeloproliferative features

aNCCN endorses using both the FAB  and WHO classification criteria for patients with refractory anemia with excess blasts in transformation (RAEB-t).

bWHO (2016) includes CNL with MPN classification.

aCML, atypical chronic myeloid leukemia; CNL, chronic neutrophilic leukemia; CMML, chronic myelomonocytic leukemia; FAB, French-American-British; GM-CSF, granulocyte-macrophage colony-stimulating factor; JMML, juvenile myelomonocytic leukemia; MPN, myeloproliferative neoplasm; WBC, white blood cell

Sources: NCCN, 2020 ; WHO, 2016 

Laboratory Testing

A complete history (including details about abnormal cytopenias, infections, bleeding episodes, and transfusions) and physical exam are the first steps in the evaluation of MDS.   This initial evaluation should be followed by peripheral blood and bone marrow tests.

Blood Tests

A CBC with differential, platelet count, and reticulocyte count is recommended to establish cell counts and determine whether cytopenias are present.   Anemia (typically hypoproductive macrocytic anemia) is generally present, with or without neutropenia and/or thrombocytopenia.   A peripheral smear with at least 200 cells is needed to evaluate dysplasia,   which is usually present in red blood cells (RBCs) and WBCs.

Anemia Investigation

An investigation of other possible causes of anemia, including kidney disease, gastrointestinal bleeding, hemolysis, and nutritional deficiency, is recommended.  RBC folate (or serum folate if RBC folate is unavailable, although serum folate does not necessarily reflect folate stores) and serum B12 tests are recommended to assess for vitamin deficiency.  Serum ferritin, iron, and total iron-binding capacity or transferrin saturation tests are recommended to assess for iron deficiency, with the caveat that serum ferritin may be elevated if inflammation is present.   Thyroid disease may result in anemia, so a thyroid-stimulating hormone (TSH) test is recommended.  Haptoglobin and creatinine tests are also useful for excluding other causes of anemia.  A lactate dehydrogenase (LDH) test is recommended both to exclude non-MDS causes of anemia and because elevated LDH at diagnosis predicts decreased survival.  

Additional Tests

Consider evaluation for copper deficiency if patient has malabsorption or malnutrition, has had gastric bypass surgery, or is taking zinc supplements.  HIV tests are recommended if clinically indicated.  Tests for erythropoietin concentration, paroxysmal nocturnal hemoglobinuria (PNH), Fanconi anemia, human leukocyte antigen (HLA) typing, cytomegalovirus, RBC phenotyping, and JAK2 variants may also be useful in some patients. 

Bone Marrow Tests

Morphology and Cytochemistry

Bone marrow aspiration is recommended to determine the percentage of marrow blasts and assess for the presence of morphologic dysplasia.   Up to 500 cells should be examined. 

Bone marrow biopsy may be useful if bone marrow aspiration fails to yield a satisfactory sample.  Bone marrow examination may also be useful to characterize hematopoietic cell maturation abnormalities and assess marrow cellularity.  Prussian blue staining for iron is recommended to detect ring sideroblasts.  Reticulin staining may be useful to assess bone marrow fibrosis.  

Flow Cytometry

Flow cytometry, specifically to measure the cell surface expression of CD34, may be considered to determine the percentage of blast cells in the bone marrow,   although it is not a substitute for morphologic evaluation to determine blast percentage.  Expanded flow cytometry may be helpful to investigate abnormal antigen expression and/or differentiation patterns in myeloid or progenitor cells.  These findings can be used to exclude other diagnoses, confirm the diagnosis of MDS if the diagnosis is uncertain, and for prognosis.  The diagnosis of MDS requires the presence of multiple abnormalities.  Flow cytometry may also be useful to evaluate for large granular lymphocytes (LGL) and PNH. 

Cytogenetics

Karyotyping

Depending on the MDS subtype and origin (ie, de novo versus chemo/radiotherapy disease), clonal chromosome abnormalities can be detected in 30% to >80% of patients. Common chromosome abnormalities in MDS include deletions within 5q, 7q, and 20q; monosomy 7; and trisomy 8, among others. Each abnormality is associated with different cytogenetic prognostic subgroups.   Chromosome banding analysis (karyotyping) is thus recommended on bone marrow collected as part of the initial evaluation for patients with suspected MDSs.  

A standard karyotype study analyzes 20 or more dividing metaphase cells from independent cultures; abnormal clones are defined by the presence of two or more metaphase cells with structural abnormalities and/or chromosome gains, or three or more metaphase cells with the loss of the same chromosome.  Complex karyotypes are defined as those having three or more independent chromosome abnormalities detected in at least two metaphase cells.  In cases with a poor mitotic index (ie, fewer than 20 metaphase cells available for analysis), 10-20 metaphase cells can be analyzed and reported if an abnormal clone is present. Apparently normal samples with a poor mitotic index can be further analyzed with chromosomal microarray (CMA) or fluorescence in situ hybridization (FISH). 

Chromosomal Microarray and Fluorescence in situ Hybridization

If standard karyotype analysis of 20 or more metaphase cells cannot be performed, chromosomal microarray analysis (also referred to as cytogenomic single nucleotide polymorphism [SNP] microarray, SNP-A, or CMA) or an MDS-related FISH panel should be performed.  FISH panels should include probes targeting 5q31, 7q31, cen7, cen8, TP53, 20q, and cenY (cen refers to centromere probes). 

For patients with normal karyotype results, CMA analysis should be considered.  CMA technology has the capability of detecting submicroscopic chromosome copy number variants and copy-neutral loss of heterozygosity (CN-LOH), which can provide relevant diagnostic and prognostic information in 10% to 80% of patients with a normal karyotype.  Of note, CMA analysis can detect both somatic and germline variants. 

Comparison of Cytogenetic Techniques in MDSs
  Conventional Cytogenetics (Karyotyping) FISH CMA
Suggested use Diagnosis, prognosis

May increase diagnostic sensitivity in MDS if metaphase cytogenetic study is suboptimal (<20 normal metaphases) or fails

Use to establish and/or monitor abnormal clone

Complements conventional cytogenetic methods

Detects copy number alterations (loss/gain of DNA) and CN-LOH

Only method that can identify MDS-associated LOH (some clinically relevant CN-LOH includes regions 7q, 11q, and 17p)

A more comprehensive analysis of myeloid-associated genomic alterations may be obtained through combined analysis of copy number, CN-LOH, and somatic mutations using CMA combined with next generation sequencing

Limitations

G-banded metaphase chromosome analysis has limited resolution (3-5 Mb), so it may fail to identify subtle abnormalities

Cannot identify cryptic (sequence level) alterations or CN-LOH

Complex rearrangements or uncertainty of additional genomic material may require further clarification by CMA

Success rate depends on growth of tumor cells in culture

Standard MDS FISH panels are unlikely to increase diagnostic sensitivity when complete metaphase cytogenetic study (with ≥20 cells) is normal

Chromosome alterations outside FISH probe region are not detected

Cannot detect LOH

Microarray will detect only copy number alterations and CN-LOH

Microarray technology cannot detect balanced genomic rearrangements such as translocations, inversions, or balanced insertions, and may not detect low-level mosaicism (<15%-20%)

Somatic Variants

Consideration of genetic testing for somatic variants in genes associated with MDSs is recommended and may aid in diagnosis and prognostication.  Bone marrow (obtained for histology purposes) or peripheral blood cells should be tested for MDS-associated driver mutations using panels that include TET2, DNMT3A, ASXL1, EZH2, SF3B1, SRSF2, U2AF1, ZRSR2, RUNX1, TP53, STAG2, NRAS, and CBL.  Correlation of somatic variant(s) with clinical findings, hematologic parameters, and cytogenetic findings is recommended for definitive diagnosis.

Hereditary Syndromes/Germline Variants

Genetic testing for hereditary hematologic malignancy predisposition and other congenital syndromes (eg, Down syndrome, Fanconi anemia, and neurofibromatosis type 1) is recommended in specific patients, particularly younger patients, with MDSs.  Such conditions may account for cytopenias with or without MDS.  Further testing for the syndrome in question can facilitate diagnosis.  For a complete discussion of germline variants and conditions associated with MDSs, see the NCCN Clinical Practice Guidelines in Oncology, Myelodysplastic Syndromes. 

Prognosis and Risk Assessment

Results from the CBC and cytogenetic studies (karyotyping, CMA, and/or FISH) are frequently used in prognosis and risk assessment.  Serum ferritin and LDH tests may also have some prognostic value. 

Prognostic Scoring Systems

Several scoring systems are available for prognostication in MDSs.

Commonly Used Prognostic Scoring Systems in MDSs
Scoring System Factors Use
IPSS-R

Cytogenetics

Marrow blast percentage

Hemoglobin

Platelet count

Accurate risk stratification

May be useful in therapeutic decision-making

WPSS

WHO morphologic category

Karyotype (IPSS cytogenetic categories)

Severe anemia

Prognostication at multiple timepoints over the course of MDS

LR-PSS

Cytogenetics (IPSS cytogenetic categories)

Age

Hemoglobin

Platelet count

Percentage of bone marrow blasts

Identification of patients with lower-risk disease with poor prognosis

IPSS-R, Revised International Prognostic Scoring System; LR-PSS, Lower-Risk Prognostic Scoring System; WPSS, WHO Classification-Based Prognostic Scoring System

Source: NCCN, 2020 

Treatment Planning and Monitoring

Treatment Planning

Cytomegalovirus testing and full HLA typing should be performed in both the patient and potential donors if the patient is a candidate for hematopoietic stem cell transplantation.  Serum erythropoietin should be measured before transfusion to assist in determining whether to treat with erythropoiesis-stimulating agents.   Screening for PNH or STAT3-mutant cytotoxic T-cells may be useful to determine potential responsiveness to immunosuppressive therapy. 

Monitoring

Regular blood counts should be performed for routine follow-up.  If cytopenias worsen or a change in peripheral blasts occurs, bone marrow examination (with or without karyotyping) can be performed.  Additional follow-up should be performed as indicated for the specific treatment being used. 

ARUP Laboratory Tests

Chromosome Analysis

Use for diagnosis, prognosis, and monitoring of hematopoietic neoplasms

Chromosome Microarray

Use to detect important genomic abnormalities and monitor disease progression and response to therapy

Fluorescence in situ Hybridization

Use in conjunction with karyotype analysis for diagnosis, prognosis, and monitoring of MDS

Probes include del(5q), -7/del(7q), + 8, del(20q)

Use in conjunction with karyotype analysis for diagnosis, prognosis, and monitoring in therapy-related MDS or AML associated with MDS

Probes include -5/del(5q), -7/del(7q), 3q26, CBFB, KMT2A, and t(8;21) rearrangements

If FISH panel tests are not desired, individual probes can be selected; see the ARUP Oncology FISH Probes menu for additional information

Somatic Variant Panels

Use to assess for single gene variants that may have diagnostic, prognostic, and/or therapeutic significance in MDS and MDS/MPN overlap disorders

Refer to the Laboratory Test Directory for a complete list of variants tested

Germline Variant Panel

Use to assess for inherited/germline DNA variants associated with familial myeloid dysplasias and malignancies

Components: ANKRD26, ATM, BLM, CBL, CEBPA, DDX41, ELANE, ETV6, GATA1, GATA2, KRAS, NBN, PTPN11, RUNX1, SAMD9, SAMD9L, SRP72, TERC, TERT, TP53

Medical Experts

Contributor

Patel

Jay L. Patel, MD, MBA
Associate Professor of Pathology (Clinical), University of Utah
Executive Director, Clinical Trials and PharmaDx, ARUP Laboratories
Medical Director, Molecular Oncology and Hematopathology, ARUP Laboratories
Contributor

References