How to diagnose Myelodysplastic Syndromes (MDS) in a patient with anemia?

Diagnosing MDS in Patients with Anemia

The diagnosis of Myelodysplastic Syndromes (MDS) in patients with anemia requires a comprehensive diagnostic approach including peripheral blood smear, bone marrow aspiration with biopsy, and cytogenetic analysis as mandatory procedures. 1

Initial Evaluation

Required Laboratory Tests

• Complete blood count (CBC) with platelets and differential
• Reticulocyte count
• Peripheral blood smear examination
• Bone marrow aspiration with iron stain and biopsy
• Cytogenetic analysis
• Serum erythropoietin level (prior to RBC transfusion)
• Iron studies (serum ferritin, iron, total iron-binding capacity)
• RBC folate and serum B12
• Biochemistry panel including:
  • Lactate dehydrogenase (LDH)
  • Bilirubin
  • Haptoglobin 1

Peripheral Blood Evaluation

• Look for specific dysplastic features:
  • Erythroid: Anisocytosis, poikilocytosis, basophilic stippling
  • Myeloid: Granulocyte nuclear hypolobation (pseudo Pelger-Huët), hypogranulation
  • Megakaryocytic: Platelet anisocytosis, giant platelets 1

Bone Marrow Assessment

1. Bone marrow aspirate (mandatory):

   • Evaluate dysplasia in ≥10% of cells in one or more hematopoietic cell lines
   • Count blasts (critical for prognosis)
   • Enumerate ring sideroblasts
   • Assess cellularity and CD34+ cells

2. Bone marrow biopsy (mandatory):

   • Assess marrow cellularity
   • Evaluate fibrosis
   • Assess topography 1

Diagnostic Criteria

MDS diagnosis requires:

• Persistent cytopenia(s) for at least 4 months (if no definitive cytogenetic/molecular markers)
• Exclusion of other causes of cytopenia and dysplasia
• Presence of at least one of the following:
  1. Dysplasia in ≥10% of cells in one or more myeloid lineages
  2. 5-19% blasts in bone marrow
  3. Specific MDS-defining cytogenetic abnormalities 1

Cytogenetic and Molecular Analysis

• Cytogenetic analysis (mandatory): Detects clonal chromosomal abnormalities that confirm diagnosis and provide prognostic information
• FISH analysis (recommended): For targeted chromosomal abnormalities when standard cytogenetics fails
• Flow cytometry immunophenotyping (recommended): Detects abnormalities in various cell compartments
• Mutation analysis (suggested): Detection of somatic mutations (e.g., SF3B1, TET2, ASXL1, TP53) 1

Diagnostic Challenges and Pitfalls

When Diagnosis is Uncertain

• If only unilineage dysplasia is present
• No increase in blasts
• Ring sideroblasts <15% of erythroid precursors
• No recurrent cytogenetic abnormalities

In these cases, observation for 6 months with repeat bone marrow investigation is recommended before making a definitive MDS diagnosis. 1

Differential Diagnoses to Exclude

• Iron deficiency anemia
• Megaloblastic anemia (B12, folate deficiency)
• Hemolytic anemia
• Renal anemia
• Anemia of chronic disease
• Aplastic anemia
• Paroxysmal nocturnal hemoglobinuria (PNH)
• Autoimmune disorders
• Viral infections (HIV, CMV, parvovirus B19) 1

Special Considerations

Borderline Conditions

Be aware of entities that may represent early or uncertain forms of MDS:

• ICUS (Idiopathic Cytopenia of Uncertain Significance): Persistent cytopenia without significant dysplasia or clonal markers
• IDUS (Idiopathic Dysplasia of Unknown Significance): Dysplasia without significant cytopenias
• CCUS (Clonal Cytopenia of Uncertain Significance): Cytopenia with clonal markers but insufficient dysplasia 1

Diagnostic Algorithm for Anemia of Uncertain Etiology

1. Screen for anemia and/or macrocytosis
2. Exclude known causes of anemia
3. Perform peripheral blood smear and additional testing (iron, B12, folate, thyroid)
4. If still unexplained, proceed with bone marrow evaluation 2

Key Points to Remember

• MDS diagnosis requires exclusion of other causes of cytopenia
• Dysplastic features must be present in ≥10% of cells in at least one cell line
• Cytogenetic abnormalities can provide definitive diagnosis even with minimal dysplasia
• Repeated bone marrow examinations may be necessary in borderline cases
• Molecular testing is increasingly important for diagnosis and prognosis

By following this systematic approach, clinicians can accurately diagnose MDS in patients presenting with anemia, leading to appropriate treatment and improved outcomes.