Differentiating MDS from Essential Thrombocythemia
The key distinction is that MDS presents with cytopenias and dysplasia, while ET presents with isolated thrombocytosis (≥450 × 10⁹/L) without significant dysplasia or cytopenias. 1, 2
Critical Distinguishing Features
Blood Count Pattern
- MDS: Characterized by persistent cytopenias (anemia, neutropenia, and/or thrombocytopenia), typically with macrocytic anemia 3, 1
- ET: Isolated thrombocytosis ≥450 × 10⁹/L with normal or elevated hemoglobin and white blood cell counts 2
Bone Marrow Morphology
- Dysplasia in ≥10% of cells in one or more myeloid lineages
- Megaloblastoid erythropoiesis, nucleocytoplasmic asynchrony
- Small, hypolobated, or monolobated dysplastic megakaryocytes (often scattered, not clustered)
- Blast percentage may be increased (5-19% in higher-risk MDS)
- Increased number of mature-appearing megakaryocytes in loose clusters
- Large, mature megakaryocytes with deeply lobulated nuclei
- No significant dysplasia in other lineages
- Blasts <5%
- Marked hypercellularity is absent (unlike prefibrotic myelofibrosis)
Cytogenetics and Molecular Testing
- Specific chromosomal abnormalities: del(5q), del(7q), monosomy 7, trisomy 8, del(20q)
- Complex karyotype (≥3 abnormalities)
- Mutations in SF3B1 (associated with ring sideroblasts), TET2, ASXL1, RUNX1, TP53
ET-associated findings 2:
- Driver mutations in JAK2 (V617F,
60%), CALR (25%), or MPL (~5%) in mutually exclusive pattern - Approximately 80% harbor one of these three driver mutations
- Normal karyotype in >90% of cases
- Additional mutations in TET2 (9-11%), ASXL1 (7-20%), DNMT3A (7%), SF3B1 (5%)
Critical Diagnostic Pitfall: RARS-T (Refractory Anemia with Ring Sideroblasts and Thrombocytosis)
This provisional MDS/MPN overlap entity can mimic both conditions 6, 4:
- Presents with anemia, ring sideroblasts (≥15%), and thrombocytosis (≥450 × 10⁹/L)
- May harbor JAK2 V617F mutation (confusing with ET)
- Distinguished by presence of dyserythropoiesis and anemia (not seen in ET)
- Requires proliferation of large megakaryocytes resembling ET or myelofibrosis
- Remains classified as MDS/MPN, not pure ET 6
Diagnostic Algorithm
Step 1: Evaluate blood counts 1, 2
- Cytopenias present → Consider MDS
- Isolated thrombocytosis → Consider ET
Step 2: Bone marrow examination 3, 1
- Assess dysplasia (≥10% threshold for MDS diagnosis)
- Evaluate megakaryocyte morphology and distribution
- Determine blast percentage
- Assess for ring sideroblasts
Step 3: Cytogenetic analysis 1, 5
- MDS-specific abnormalities support MDS diagnosis
- Normal karyotype does not exclude either diagnosis
Step 4: Molecular testing 3, 2
- Test for JAK2/CALR/MPL mutations (supports ET if present with appropriate morphology)
- Test for MDS-associated mutations (SF3B1, TET2, ASXL1, RUNX1, TP53)
- Critical: JAK2 mutation alone does not confirm ET—must exclude MDS morphology
Step 5: Exclude other causes 1
- Rule out reactive thrombocytosis (infection, inflammation, iron deficiency, malignancy)
- Exclude chronic myeloid leukemia (BCR-ABL testing)
- Exclude prefibrotic myelofibrosis (requires careful morphologic assessment)
Common Diagnostic Errors to Avoid
Assuming JAK2 mutation = ET: JAK2 mutations can occur in RARS-T and other MDS/MPN overlap syndromes 6, 4
Overlooking subtle dysplasia: MDS requires only ≥10% dysplasia in one lineage, which can be subtle 3, 1
Misclassifying prefibrotic myelofibrosis as ET: Prefibrotic myelofibrosis presents with thrombocytosis but has different megakaryocyte morphology (aberrant nuclear features, tight clustering) and marked hypercellularity 4, 7
Ignoring ring sideroblasts with thrombocytosis: This combination suggests RARS-T (MDS/MPN overlap), not pure ET 6, 8
Relying solely on peripheral blood: Bone marrow examination is mandatory for definitive diagnosis 3, 1