What is the next step in diagnosis and management for a patient with hypercellular bone marrow, myeloid preponderance, and borderline dysmyelopoiesis, with normal cytogenetic results and negative FISH for BCR/ABL?

Next Step in Diagnosis and Management

The immediate next step is to perform molecular testing for mutations associated with myeloproliferative neoplasms (MPNs) and myelodysplastic syndromes (MDS), specifically JAK2 V617F, CALR, MPL, and a comprehensive myeloid mutation panel including SF3B1, TET2, ASXL1, SRSF2, and TP53. 1

Rationale for Molecular Testing

Since BCR::ABL1 fusion has been excluded by FISH, the differential diagnosis narrows to BCR::ABL1-negative MPNs versus MDS/MPN overlap syndromes. 1 The NCCN MPN Guidelines explicitly state that molecular testing for variants associated with other myeloproliferative conditions is required for the diagnosis of MPNs and MDS/MPNs when BCR::ABL1 fusion is negative. 1

Priority Molecular Tests

First-tier testing (mandatory):

• JAK2 V617F mutation - found in most patients with polycythemia vera, essential thrombocythemia, or primary myelofibrosis and serves as a clonal marker 1
• CALR mutations - particularly important in the diagnostic workup of MPNs 1
• MPL mutations - part of the diagnostic triad for BCR::ABL1-negative MPNs 1

Second-tier testing (strongly recommended):

• Comprehensive myeloid mutation panel including SF3B1 (25-30% frequency in MDS), TET2 (20-25%), SRSF2 (10-15%), ASXL1 (10-15%), and TP53 (5-10%) 1, 2, 3
• These mutations provide both diagnostic clarification and prognostic information 1

Additional Diagnostic Considerations

Flow Cytometry Immunophenotyping

Flow cytometry is recommended (not mandatory but strongly advised) to detect abnormalities in erythroid, immature myeloid, maturing granulocytes, and monocyte compartments. 1 This can help identify aberrant immunophenotypic patterns suggestive of clonal disease even when morphologic dysplasia is borderline. 1

Peripheral Blood Evaluation

Complete blood count with differential is essential to assess:

• Monocyte count - absolute monocytosis >1×10⁹/L would suggest chronic myelomonocytic leukemia (CMML), a common MDS/MPN overlap syndrome 1, 3
• White blood cell count - WBC ≥13×10⁹/L distinguishes proliferative from dysplastic variants 1
• Presence of circulating blasts or immature cells 1, 4

Clinical Correlation Required

Exclude secondary causes of myeloid proliferation:

• Infectious diseases (particularly chronic infections) 1
• Solid tumors 1
• Autoimmune conditions 1
• Prior chemotherapy or radiation exposure 1
• Benzene or occupational exposures 1

Diagnostic Algorithm

Step 1: Obtain molecular testing panel (JAK2, CALR, MPL + comprehensive myeloid mutations) 1

Step 2: Review peripheral blood smear for monocytosis, dysplastic features, and circulating blasts 4, 3

Step 3: Consider flow cytometry immunophenotyping if not already performed 1

Step 4: Based on molecular results:

• If JAK2/CALR/MPL positive → Diagnose as BCR::ABL1-negative MPN (specific subtype depends on clinical/morphologic features) 1
• If SF3B1 mutated with thrombocytosis → Consider MDS/MPN with SF3B1 mutation and thrombocytosis 3, 5
• If multiple mutations without driver mutations → Likely MDS/MPN unclassified or MDS 1, 3
• If all molecular testing negative → May require observation period of 6 months with repeat bone marrow examination 1

Critical Pitfalls to Avoid

Normal karyotype does not exclude hematologic malignancy. The cytogenetics report correctly notes that many hematologic malignancies show normal chromosomes, and molecular testing is essential. 1

Borderline dysplasia requires molecular confirmation. When dysplasia is not robust (as in this case with "borderline dysmyelopoiesis"), molecular markers become critical for establishing clonality. 1

Only 7 metaphases analyzed is suboptimal. Standard recommendations call for analysis of at least 20 metaphases when possible, though 7 cells may be acceptable if that's all that was obtainable. 1 The limited cell count increases the importance of molecular testing.

Prognostic Implications

Once molecular results are available, risk stratification should be performed:

• For MDS: Use IPSS-R scoring system incorporating cytogenetics and molecular data 1
• For MPN: Use disease-specific scoring (DIPSS-plus for myelofibrosis, etc.) 1
• For MDS/MPN: Use CMML-specific prognostic scores if monocytosis present 3, 5

TP53 mutations, if detected, confer particularly poor prognosis and may influence treatment decisions, including consideration for early allogeneic stem cell transplantation in appropriate candidates. 1