What is the best initial screening test for myeloproliferative (bone marrow) disorders?

Best Screening Test for Myeloproliferative Disorders

The best initial screening test for myeloproliferative disorders is molecular testing for JAK2, CALR, and MPL mutations, which are the characteristic driver mutations in BCR-ABL1-negative myeloproliferative neoplasms. 1, 2, 3

Understanding Myeloproliferative Disorders

Myeloproliferative disorders (MPDs), now called myeloproliferative neoplasms (MPNs), are clonal hematopoietic stem cell diseases characterized by proliferation of one or more myeloid lineages. The main BCR-ABL1-negative MPNs include:

• Polycythemia vera (PV)
• Essential thrombocythemia (ET)
• Primary myelofibrosis (PMF)

Diagnostic Approach

Step 1: Initial Laboratory Evaluation

• Complete blood count (CBC) with differential
• Peripheral blood smear examination
• Basic chemistry profile including LDH, creatinine, and uric acid

Step 2: Molecular Testing (Primary Screening)

• JAK2 V617F mutation: Present in approximately 95% of PV cases and 60% of ET and PMF cases 2
• CALR mutation: Present in approximately 20-25% of ET and PMF cases (not found in PV) 1
• MPL mutation: Present in approximately 3-7% of ET and PMF cases 2

These mutations are mutually exclusive and collectively account for >90% of BCR-ABL1-negative MPNs, making molecular testing the most efficient initial screening approach.

Step 3: Additional Testing Based on Results

If molecular testing is positive:

• Bone marrow biopsy and aspiration to confirm diagnosis and classify the specific MPN
• Cytogenetic analysis to identify additional chromosomal abnormalities

If molecular testing is negative but clinical suspicion remains high:

• Bone marrow examination to evaluate for morphologic features
• Cytogenetic analysis
• Additional molecular testing for less common mutations

Specific Diagnostic Criteria by MPN Type

Polycythemia Vera (PV)

Diagnosis requires either all 3 major criteria or the first 2 major criteria plus the minor criterion 1:

• Major criteria:
  1. Elevated hemoglobin (>16.5 g/dL in men, >16.0 g/dL in women) OR elevated hematocrit (>49% in men, >48% in women) OR increased red cell mass
  2. Bone marrow biopsy showing hypercellularity with trilineage growth
  3. Presence of JAK2 V617F or JAK2 exon 12 mutation
• Minor criterion: Subnormal serum erythropoietin level

Essential Thrombocythemia (ET)

Diagnosis requires all 4 major criteria or the first 3 major criteria plus the minor criterion 1:

• Major criteria:
  1. Platelet count ≥450 × 10^9/L
  2. Bone marrow biopsy showing proliferation mainly of megakaryocytes
  3. Not meeting WHO criteria for other myeloid neoplasms
  4. Presence of JAK2, CALR, or MPL mutation
• Minor criterion: Presence of a clonal marker or absence of evidence for reactive thrombocytosis

Primary Myelofibrosis (PMF)

Diagnosis requires meeting both major criteria and at least one minor criterion:

• Major criteria:
  1. Bone marrow fibrosis
  2. Not meeting WHO criteria for other myeloid neoplasms
• Minor criteria include presence of JAK2, CALR, or MPL mutation

Common Pitfalls to Avoid

1. Failing to exclude secondary causes: Always rule out reactive causes of cytosis before pursuing MPN workup

   • Secondary erythrocytosis (hypoxia, smoking, high altitude)
   • Secondary thrombocytosis (inflammation, infection, iron deficiency)

2. Relying solely on blood counts: Blood counts alone are insufficient for diagnosis; molecular testing is essential

3. Missing atypical presentations: Some patients may have normal or near-normal blood counts despite having an MPN

4. Overlooking bone marrow examination: While molecular testing is an excellent screening tool, bone marrow examination remains essential for definitive diagnosis and classification

5. Confusing MDS with MPN: Myelodysplastic syndromes (MDS) can sometimes present with features that overlap with MPNs; molecular testing helps distinguish between these entities

In conclusion, molecular testing for JAK2, CALR, and MPL mutations provides the highest diagnostic yield as an initial screening test for myeloproliferative disorders, with subsequent bone marrow examination required for confirmation and classification.