Myelodysplastic Syndromes

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
    • FISH – does not add substantially for cytogenetically normal cases
    • Microarray – identification of MDS-associated imbalances and loss of heterozygosity in ~20% of cases with normal cytogenetic chromosome analysis
  • 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

Clinical 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
  	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

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Leukemia/Lymphoma Phenotyping (Comprehensive - Miscellaneous) 0095243 Method: Flow Cytometry	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
Leukemia/Lymphoma Phenotyping (Comprehensive - Whole Blood) 0096299 Method: Flow Cytometry	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
Leukemia/Lymphoma Phenotyping (Comprehensive - Bone Marrow) 0095244 Method: Flow Cytometry	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