How to diagnose myelodysplastic syndrome?

Diagnosis of Myelodysplastic Syndrome (MDS)

The diagnosis of myelodysplastic syndrome requires a comprehensive bone marrow examination including both aspirate and biopsy, along with cytogenetic analysis, as these are mandatory components of the diagnostic workup. 1

Initial Evaluation for Suspected MDS

Clinical Presentation

• Persistent unexplained cytopenias (anemia, neutropenia, thrombocytopenia)
• Symptoms related to cytopenias: fatigue, infections, bleeding
• Typically affects older individuals (though can occur at any age)
• History of prior chemotherapy, radiation exposure, or benzene exposure

Initial Laboratory Workup

• Complete blood count with differential
• Peripheral blood smear examination for:
  • Anisocytosis, poikilocytosis, basophilic stippling in RBCs
  • Hypolobated neutrophils (pseudo Pelger-Huët anomaly)
  • Hypogranulated neutrophils
  • Giant or abnormal platelets
• Biochemical tests to exclude other causes:
  • Iron studies (iron, TIBC, ferritin)
  • Vitamin B12 and folate levels
  • Liver and kidney function tests
  • LDH, bilirubin, haptoglobin
• Viral studies (HIV, hepatitis, parvovirus B19, CMV)
• Testing for paroxysmal nocturnal hemoglobinuria (PNH) clone

Definitive Diagnostic Approach

Bone Marrow Examination

The following procedures are mandatory for MDS diagnosis 1:

1. Bone marrow aspirate to evaluate:

   • Dysplasia in one or more hematopoietic cell lines (>10% of cells)
   • Blast percentage
   • Ring sideroblasts
   • Cellularity assessment

2. Bone marrow biopsy to assess:

   • Marrow architecture
   • Cellularity
   • Fibrosis
   • Topography
   • Spatial relationships between cells

3. Cytogenetic analysis to detect:

   • Clonal chromosomal abnormalities (particularly del(5q), monosomy 7, trisomy 8)
   • Important for both diagnosis and prognosis

Recommended Additional Studies

• Flow cytometry immunophenotyping to detect abnormalities in:

  • Erythroid lineage
  • Immature myeloid cells
  • Maturing granulocytes
  • Monocytes
  • Lymphoid compartments

• FISH (Fluorescence In Situ Hybridization) when:

  • Standard cytogenetics fails
  • Targeting specific chromosomal abnormalities

Suggested Advanced Studies

• Mutation analysis of candidate genes (e.g., TET2, ASXL1, SF3B1, SRSF2, TP53)
• SNP array for high-resolution detection of chromosomal defects

Diagnostic Criteria

MDS diagnosis requires:

1. Persistent cytopenia(s) in one or more cell lines
2. Morphologic dysplasia in ≥10% of cells in one or more cell lines
3. Exclusion of other causes of cytopenia/dysplasia
4. At least one of the following:
   • Increased blasts (≥5% in bone marrow or ≥1% in peripheral blood)
   • Specific chromosomal abnormality
   • Ring sideroblasts ≥15% of erythroid precursors

Challenging Diagnostic Cases

For cases with unilineage dysplasia, normal karyotype, no excess blasts, and <15% ring sideroblasts:

• Observation period of 6 months is recommended
• Repeat bone marrow investigation after this period
• These patients typically present with mild cytopenia and slow disease progression 1

Morphological Features of Dysplasia

Erythroid Dysplasia

• Binuclearity
• Irregular nuclear edges
• Megaloblastoid changes
• Ring sideroblasts
• Cytoplasmic inclusions

Myeloid Dysplasia

• Bizarre nuclear shapes
• Nuclear hypolobation (pseudo Pelger-Huët)
• Nuclear hypersegmentation
• Cytoplasmic hypogranulation/degranulation

Megakaryocytic Dysplasia

• Large monolobular forms
• Small binucleated elements
• Micromegakaryocytes

Pitfalls and Caveats

1. Diagnostic challenges:

   • MDS can mimic other conditions causing cytopenia
   • Dysplastic changes can be seen in vitamin deficiencies, drug toxicity, and viral infections
   • Repeated bone marrow examinations may be necessary over time

2. Procedural considerations:

   • Perform trephine biopsy first or at a different site from aspiration to avoid artifactual hypocellularity 2
   • In cases of "dry tap" (failed aspiration), trephine biopsy becomes essential

3. Interpretation challenges:

   • The concordance rate between bone marrow aspiration and trephine biopsy is only about 72.4%, highlighting the importance of performing both procedures 2
   • Diagnosis may be difficult in patients with normal karyotype without robust morphologic markers

4. Follow-up recommendations:

   • For borderline cases, follow-up bone marrow examination after 6 months is essential
   • Monitor for disease progression, especially in patients with mild cytopenia

By following this systematic diagnostic approach, clinicians can accurately identify MDS and distinguish it from other causes of cytopenia, leading to appropriate treatment decisions that can impact morbidity and mortality.