Myelodysplastic Syndromes

Background

Myelodysplastic syndromes (MDS) are clonal hematopoietic malignancies characterized by ineffective hematopoiesis, cytopenia, unilineage or multilineage dysplasia and a susceptibility to leukemia, especially AML.

Epidemiology

Incidence
- 5/100,000 in the general population
- 22-45/100,000 in the elderly population (>70 years)
Age – median is 65-70
Sex – M>F

Classification

World Health Organization (WHO) classification of MDS

MDS Subtype	2008 WHO Classification
MDS Subtype	Blood	Bone Marrow
Refractory cytopenias with unilineage dysplasia (RCUD)	Unicytopenia or bicytopenia¹ No or rare blasts (<1%)²	Unilineage dysplasia ≥10 % of one cell line <5% blasts <15% of erythroid precursors are ring sideroblasts
Refractory anemia (RA)
Refractory neutropenia (RN)
Refractory thrombocytopenia (RT)
Refractory anemia with ring sideroblasts (RARS)	Anemia No blasts	≥15% erythroid precursors are ring sideroblasts Erythroid dysplasia only <5% blasts
Refractory cytopenia with multilineage dysplasia (RCMD)	Cytopenia(s) No or rare blasts (<1%) No Auer rods <1x10⁹/L monocytes	Dysplasia in ≥10% of cells in ≥2 myeloid lineages ±15% ring sideroblasts <5% blasts No Auer rods
Refractory anemia with excess blasts-1 (RAEB-1)	Cytopenia(s) <5% blasts No Auer rods <1x10⁹/L monocytes	Unilineage or multilineage dysplasia No Auer rods 5-9% blasts
Refractory anemia with excess blasts-2 (RAEB-2)	Cytopenia(s) 5-19% blasts Auer rods <1x10⁹/L monocytes	Unilineage or multilineage dysplasia Auer rods ± 10-19% blasts
Refractory anemia with excess blasts in transformation (RAEB-t)	subtype not used
Myelodysplastic syndrome, unclassified (MDS-U)	Cytopenias ≤1% blasts	Unequivocal dysplasia in <10% of cells in ≥1 myeloid cell lines when accompanied by a cytogenetic abnormality considered as presumptive evidence for a diagnosis of MDS <5% blasts
MDS associated with isolated del(5q)	Anemia Platelets normal or increased No or rare blasts (<1%)	Normal to increased megakaryocytes with hypolobated nuclei Isolated del(5q) <5% blasts No Auer rods
Chronic myelomonocytic leukemia (>1,000 monocytes/µL blood)	subtype not used
¹Bicytopenia may occasionally be observed; cases with pancytopenia = MDS-U ²If marrow myeloblasts <5% but 2-4% myeloblasts in blood = RAEB-1 ³Auer rods and <5% myeloblasts in blood and <10% in marrow = RAEB-2 Note: NCCN endorses using both the French-American-British (FAB) and WHO classification criteria for RAEB-t patients

Risk Factors

Increased age
Occupational exposures
- Benzene-containing products
- Pesticides
- Organic solvents
- Heavy metals (lead, arsenic)
Drug exposures
- Alkylating agents, other cytotoxic agents
- Azathioprine
- Mycophenolate
Therapy-related – 10-15% of MDS occurs following chemotherapy and radiation treatment
Genetic
- Fanconi anemia
- Familial myelodysplasia
- Diamond-Blackfan syndrome

Pathophysiology

Clonal expansion of the multipotential hematopoietic cell
Primary mechanism is defective maturation of marrow cells coupled with premature cell death

Clinical Presentation

May be asymptomatic
- Disease is generally indolent, with blood counts remaining relatively stable over several months or longer
Most common symptoms
- Anemia – pallor, weakness, exertional dyspnea
- Increased infection from neutropenia
- Bleeding/bruising from thrombocytopenia
Complications
- 25-30% progress to AML; incidence depends on MDS subtype
  - Lower response rate to standard therapy for patients >65 years with de novo AML
- Death from complications of cytopenia (neutropenia in particular)

Pediatrics

Clinical Background

Epidemiology

Incidence – 0.5-4/1,000,000 (rare)
Age – 6-8 years

Classification

Patients with 2-19% blasts in peripheral blood and/or 5-19% blasts in bone marrow may be classified using the adult schema provisional but excludes patients with Down syndrome
Additional pediatric entity of refractory cytopenia of childhood is recognized
- <2% blasts in peripheral blood and <5% blasts in bone marrow
- Bilineage dysplasia

Clinical Presentation

May be asymptomatic
Most common symptoms
- Anemia – pallor, weakness, exertional dyspnea
- Hepatomegaly/splenomegaly (5-10%)
- Arthralgias

Diagnosis

Refer to Diagnosis tab

Diagnosis

Indications for Testing

Abnormal CBC or peripheral smear – may see macrocytic anemia, other cytopenias, dysplastic cells in peripheral smear
For symptomatic anemia, consider HLA-DR15 typing

Laboratory Testing

Abnormal CBC should be evaluated for other obvious causes of cytopenias prior to bone marrow biopsy (eg, nutritional deficiency)

Diagnostic Criteria

International Consensus Working Group recommendation for minimal diagnostic prerequisites
- Stable cytopenia for at least 6 months
  - 2 months if accompanied by specific karyotype or bilineage dysplasia
- Exclusion of other potential disorders as a primary reason for dysplasia or cytopenia
- At least one MDS-related decisive criterion
  - Dysplasia (≥10% in 1-3 major bone marrow lineages)
  - Blast cell count of 5-19%
  - Specific MDS-associated karyotype [eg, del(5q), +8, -7/del(7q)]
- Co-criteria help confirm the diagnosis
  - Bone marrow histology and immunohistochemistry to detect fibrosis, dysplastic megakaryocytes, atypical localization of immature progenitors
  - Flow cytometric analysis to identify abnormal myeloid antigen patterns, abnormal CD34 expression in blasts
  - Molecular markers to detect myeloid clonality

Histology

Classification based on bone marrow histology, immunohistochemical features, flow cytometry and cytogenetic findings
- Bone marrow biopsy – diagnosis is almost exclusively made using marrow appearance
  - Criteria – dysplasia in at least 10% of myeloid lineage cells
- Cytogenetic testing for recurrent chromosome abnormalities consistent with MDS including 5q, 7q, 12p, 13q, and 20q deletions; trisomies 8, 9, 11, 19, and 21; structural abnormalities of chromosomes 3, 6, 9, 11, 16, and 17 (this list is not exhaustive, but represents the various abnormalities associated with MDS)
  - Most common are 5q and 7q deletions and trisomy 8
  - Therapy-related MDS
    - Monosomy 7 – observed in >50% of cases; associated with poor prognosis
    - Deletion 7q – observed in 5-10% of cases; associated with poor prognosis
    - Deletion 5q – associated with favorable prognosis if present as sole abnormality
    - 11q23 rearrangements involving MLL – often observed in MDS following treatment with anti-topomerase II (epidophyllotoxins); associated with poor prognosis
- Flow cytometry
  - Changes not specific for MDS; may be most useful in ruling out other neoplasms in patient with cytopenias
    - Absence of flow cytometric abnormalities does not exclude MDS
- Immunohistochemistry – CD117 (c-Kit); CD34 (QBEnd/10); myeloperoxidase (MPO) to identify abnormal localization of immature precursors and increased blasts

Prognosis

Dependent on karyotype, % of blasts, and number of cytopenias present
- Normal karyotype or deletion 5q or 20q – good prognosis (low risk)
- Three or more cytogenetic abnormalities or deletion 7 – poor prognosis (high-risk)
MDS International Prognostic Scoring System (IPSS)
- Combines information on bone marrow blast percentage, cytogenetic abnormalities and type(s) of cytopenia into low-, intermediate-, and high-risk disease
  - Low risk – normal karyotype, isolated del(5q), isolated del(20q), -Y, <5% cell blasts, 0-1 cytopenias (IPSS score = 0)
    - Median survival – 15.7 years
    - 25% will progress to AML in ~9 years
  - High risk – abnormalities of chromosome 7 or complex karyotype with three or more abnormalities; >10% cell blasts and two or more cytopenias (IPSS score ≥2.5)
    - Median survival – 0.4 years
    - 25% will progress to AML within 2-3 months
  - Intermediate risk – all other abnormalities
    - Median survival – 3.5 years
    - 25% will progress to AML in ~3 years
Newest prognostication from WHO classification-based scoring system incorporates transfusion burden
- Poor prognosis with RAEB or RAEB-t
  - Median survival 5-12 months
  - Disease transforms to AML in 40-50%
- Better prognosis with RA or RARS
  - Median survival 3-6 years
  - Disease transforms to AML in 5-15%

Differential Diagnosis

Cytopenias
- Pancytopenia
  - Medication/toxin exposure
  - Bone marrow failure – anaplastic anemia
  - Hemophagocytic syndrome
  - Acute leukemias – AML
  - Alcohol abuse
  - Infections
  - Severe nutritional deficiency
Isolated anemia
- Parvovirus
- HIV
- Toxins
- Blood loss or hemolysis
- Vitamin deficiencies – B12, folate
Isolated neutropenia
- Acute leukemias (AML, ALL)
- Medications – sulfa antibiotics, ganciclovir
- HIV
- Hypersplenism
- Familial cyclic neutropenia
- Antineutrophil antibodies associated with autoimmunity or tumors
Isolated thrombocytopenia
- Idiopathic thrombocytopenic purpura
- Hypersplenism
Dyserythropoiesis
- Ring sideroblasts
  - Toxins – arsenic, zinc, lead
  - Deficiencies – copper, pyridoxine
  - Medications – tuberculosis treatment
- Congenital dyserythropoiesis
Other
- Paroxysmal nocturnal hemoglobinuria
- Myeloproliferative/myelodysplastic neoplasms

Tests

Tests generally appear in the order most useful for common clinical situations

Test name: Erythropoietin

ARUP #: 0050227

Methodology: Quantitative Chemiluminescent Immunoassay

Use:

Initial evaluation

Use prior to blood transfusion

Test name: Vitamin B₁₂ & Folate

ARUP #: 0070160

Methodology: Quantitative Chemiluminescent Immunoassay

Use:

Initial evaluation; identify nutrient deficiency in anemia

Test name: Ferritin

ARUP #: 0070065

Methodology: Quantitative Chemiluminescent Immunoassay

Use:

Initial evaluation

May be useful in differentiating iron deficiency anemia from anemia of chronic disease

Test name: Iron & Iron Binding Capacity

ARUP #: 0020420

Methodology: Quantitative Spectrophotometry/Calculation

Use:

Initial evaluation; identify iron deficiency as etiology of anemia

Test name: CBC with Platelet Count & Automated Differential

ARUP #: 0040003

Methodology: Automated Cell Count with Flow Cell Differential

Use:

Assess presence of cytopenias; identify presence of blasts

Test name: Chromosome Analysis, Bone Marrow

ARUP #: 2002292

Methodology: Giemsa-Band Analysis

Use:

Identify recurrent chromosome abnormalities consistent with MDS

Test name: Chromosome FISH, Interphase

ARUP #: 2002298

Methodology: Fluorescence in situ Hybridization

Use:

Monitor specific, previously identified abnormality

Specific FISH probes that must be requested with this test code and for this indication include 5q deletion, monosomy 7/7q deletion, +8, and 20q deletion

Indicate names of probes needed for testing

ARUP Oncology FISH Probes menu

Limitations:

Limit of detection is probe dependent; approximately 1-5% in interphase nuclei

Follow-up:

Repeat testing as clinically indicated to monitor disease progression

Test name: Myelodysplastic Syndrome (MDS) Panel by FISH

ARUP #: 2002709

Methodology: Fluorescence in situ Hybridization

Use:

Provides prognostic information for MDS

Use at time of diagnosis when no specific genetic abnormality is known

Monitor response to therapy or progression of disease

FISH probes include 5q deletion, monosomy 7/ 7q deletion, +8, and 20q deletion

AML may also include abnormalities detectable by this panel

Limitations:

Panel detects only the specific aberrations in chromosomes of interest for diagnosis and prognosis

Chromosome alterations outside probe region will not be detected

Order in conjunction with Chromosome Analysis, Bone Marrow

Test name: Acute Myelogenous Leukemia (AML) with Myelodysplastic Syndrome (MDS), or Therapy-Related AML, by FISH

ARUP #: 2002653

Methodology: Fluorescence in situ Hybridization

Use:

Provides prognostic information for patients with AML from previous MDS or patients with therapy-related MDS/AML

Monitor response to therapy or progression of disease

FISH probes include EGR1 (5q del), FRA7G (7q del/-7), and MLL

Limitations:

Chromosome alterations outside probe region will not be detected

Order in conjunction with Chromosome Analysis, Bone Marrow

Test name: CD117 (c-Kit) by Immunohistochemistry

ARUP #: 2003806

Methodology: Immunohistochemistry

Use:

Aid in histologic diagnosis of myelodysplastic syndromes; identify abnormal localization of immature precursors and increased blasts

Stained and returned to client pathologist; consultation available if needed

Test name: CD34, QBEnd/10 by Immunohistochemistry

ARUP #: 2003556

Methodology: Immunohistochemistry

Use:

Aid in histologic diagnosis of myelodysplastic syndromes; identify abnormal localization of immature precursors and increased blasts

Stained and returned to client pathologist; consultation available if needed

Test name: Myeloperoxidase (MPO) by Immunohistochemistry

ARUP #: 2004014

Methodology: Immunohistochemistry

Use:

Aid in histologic diagnosis of myelodysplastic syndromes; identify abnormal localization of immature precursors and increased blasts

Stained and returned to client pathologist; consultation available if needed

Additional Tests Available

Test name: Leukemia/Lymphoma Phenotyping (Comprehensive - Miscellaneous)

ARUP #: 0095243

Methodology: Flow Cytometry

Comments:

Identify blasts and aberrant antigen expression patterns associated with MPN in bone marrow specimen

Available myeloid antigens: CD11b, CD13, CD14 (Mo2), CD14 (MY4), CD15, CD33, CD64, CD117, myeloperoxidase

Test name: Leukemia/Lymphoma Phenotyping (Comprehensive - Whole Blood)

ARUP #: 0096299

Methodology: Flow Cytometry

Comments:

Identify blasts and aberrant antigen expression patterns associated with MPN in bone marrow specimen

Available myeloid antigens: CD11b, CD13, CD14 (Mo2), CD14 (MY4), CD15, CD33, CD64, CD117, myeloperoxidase

Test name: Leukemia/Lymphoma Phenotyping (Comprehensive - Bone Marrow)

ARUP #: 0095244

Methodology: Flow Cytometry

Comments:

Identify blasts and aberrant antigen expression patterns associated with MPN in bone marrow specimen

Available myeloid antigens: CD11b, CD13, CD14 (Mo2), CD14 (MY4), CD15, CD33, CD64, CD117, myeloperoxidase

References

Guidelines

General

Barzi A, Sekeres MA. Myelodysplastic syndromes: a practical approach to diagnosis and treatment. Cleve Clin J Med. 2010; 77 (1) :37-44.PubMed
Cazzola M, Malcovati L. Prognostic classification and risk assessment in myelodysplastic syndromes. Hematol Oncol Clin North Am. 2010; 24 (2) :459-468.PubMed
Craig FE, Foon KA. Flow cytometric immunophenotyping for hematologic neoplasms. Blood. 2008; 111 (8) :3941-3967.PubMed
Elghetany MT. Myelodysplastic syndromes in children: a critical review of issues in the diagnosis and classification of 887 cases from 13 published series. Arch Pathol Lab Med. 2007; 131 (7) :1110-1116.PubMed
Khan AM, Komrokji RS, Haddad RY. Myelodysplastic syndromes: what a primary care physician needs to know. Dis Mon. 2010; 56 (8) :468-478.PubMed
Komrokji RS, Zhang L, Bennett JM. Myelodysplastic syndromes classification and risk stratification. Hematol Oncol Clin North Am. 2010; 24 (2) :443-457.PubMed
Naeem RC. Cytogenetics of Hematologic Neoplasms. In Gersen SL, Keagle MB, eds. The Principles of Clinical Cytogenetics. Totowa, New Jersey: Humana Press Inc, 2005. pp. 365-420.
Nimer SD. Myelodysplastic syndromes. Blood. 2008; 111 (10) :4841-4851.PubMed
Ogata K. Diagnostic flow cytometry for low-grade myelodysplastic syndromes. Hematol Oncol. 2008; 26 (4) :193-198.PubMed
Orazi A, Czader MB. Myelodysplastic syndromes. Am J Clin Pathol. 2009; 132 (2) :290-305.PubMed
Scott BL, Deeg HJ. Myelodysplastic syndromes. Annu Rev Med. 2010; 61 :345-358.PubMed
Stetler-Stevenson M, Yuan CM. Myelodysplastic syndromes: the role of flow cytometry in diagnosis and prognosis. Int J Lab Hematol. 2009; 31 (5) :479-483.PubMed
Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Harald S, Thiele J, Vardiman JW. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4th ed. Lyon: International Agency for Research on Cancer, 2008. pp. 1-439.
Tefferi A, Vardiman JW. Myelodysplastic syndromes. N Engl J Med. 2009; 361 (19) :1872-1885.PubMed
Valent P, Wieser R. Update on genetic and molecular markers associated with myelodysplastic syndromes. Leuk Lymphoma. 2009; 50 (3) :341-348.PubMed

ARUP Institute for Clinical and Experimental Pathology®

Dunphy CH, O'Malley DP, Perkins SL, Chang CC. Analysis of immunohistochemical markers in bone marrow sections to evaluate for myelodysplastic syndromes and acute myeloid leukemias. Appl Immunohistochem Mol Morphol. 2007; 15 (2) :154-159.PubMed

Medical Reviewers

Comprehensive Review: May 2011
Last Update: May 2011