What is masked polycythemia vera?

Masked Polycythemia Vera

Masked polycythemia vera (PV) is a variant of PV where a true increase in red cell mass exists but is concealed by a concomitant increase in plasma volume, resulting in normal hemoglobin/hematocrit values despite the underlying myeloproliferative disorder. 1

Diagnostic Features of Masked PV

Masked PV can be identified by the following characteristics:

• JAK2 mutation positive (>90% have JAK2 V617F or JAK2 exon 12 mutations) 2
• Normal hemoglobin/hematocrit values that don't meet the WHO diagnostic thresholds for overt PV
• Increased red cell mass when measured directly
• Low serum erythropoietin levels
• Bone marrow showing hypercellularity with trilineage growth
• Often presents with higher platelet counts compared to overt PV 3
• May have lower JAK2V617F allele burden at diagnosis compared to overt PV 3
• May present with PV-related features despite normal hemoglobin/hematocrit:
  • Thrombocytosis
  • Leukocytosis
  • Microcytosis from iron deficiency
  • Splenomegaly
  • Aquagenic pruritus
  • Unusual thrombosis 2

Clinical Significance

Masked PV is clinically important for several reasons:

• It can lead to delayed or missed diagnosis, potentially worsening outcomes 4
• Patients with masked PV are at risk for the same complications as those with overt PV:
  • Arterial and venous thrombosis
  • Hemorrhagic events
  • Disease progression to myelofibrosis
  • Leukemic transformation 5

Diagnostic Approach

When masked PV is suspected:

1. First-line testing should include:

   • Complete blood count with peripheral blood smear
   • JAK2 V617F mutation testing
   • Serum erythropoietin level 2

2. Bone marrow biopsy and aspiration are critical for definitive diagnosis:

   • Evaluate megakaryocyte morphology and clustering
   • Assess for reticulin fibrosis
   • Perform cytogenetic studies to rule out other myeloid disorders 2

Treatment Considerations

Treatment of masked PV follows the same principles as overt PV:

• All patients should receive:

  • Therapeutic phlebotomy to maintain hematocrit <45%
  • Low-dose aspirin (81-100 mg daily) if no contraindications 2

• High-risk patients (age >60 years and/or history of thrombosis) require cytoreductive therapy:

  • Hydroxyurea (first-line)
  • Interferon-α
  • Ruxolitinib for those intolerant/resistant to hydroxyurea 2

Interestingly, patients with masked PV may:

• Need fewer phlebotomies
• Respond faster to hydroxyurea
• Achieve complete hematological response more frequently (79% vs. 58%) compared to overt PV 3

Common Pitfalls in Diagnosis

• Iron deficiency masking PV: Iron deficiency can normalize hemoglobin levels in PV patients, further "masking" the condition 2
• Attributing findings solely to inflammation: Persistent abnormalities warrant hematologic evaluation 2
• Neglecting bone marrow examination: Essential for definitive diagnosis in cases with suspicious blood findings 2
• Overlooking secondary causes of polycythemia when JAK2 mutation is absent 2
• Confusing with relative polycythemia: Caused by dehydration, diuretics use, or smoker's polycythemia 2

Monitoring

Regular monitoring is essential:

• CBC every 2-3 months during initial management
• CBC every 3-6 months once stable
• Evaluation for signs of disease progression, thrombotic and bleeding complications, and transformation to myelofibrosis or acute leukemia 2

Despite the differences in presentation between masked and overt PV, studies have shown similar overall survival, rates of thrombosis and major bleeding, and probability of transformation between the two forms 3.