JAK2 Negativity in Polycythemia Vera
Polycythemia vera (PV) is JAK2 negative in only approximately 3-5% of cases, with virtually all patients having some form of JAK2 mutation. 1
Molecular Profile of PV
JAK2 Mutation Status
- JAK2 V617F mutation is present in >95% of PV cases 1, 2
- In JAK2 V617F-negative PV cases (3-5%), most harbor JAK2 exon 12 mutations 3
- Specifically, 2-4% of PV patients have JAK2 exon 12 mutations 1
- After accounting for misdiagnosis and treatment effects, >95% of PV patients have some form of JAK2 mutation 3
JAK2 Exon 12 Mutations
- In a European collaborative study of 106 JAK2 V617F-negative PV patients, 17 different exon 12 mutations were identified 4
- Common exon 12 mutations include F537-K539delinsL and N542-E543del 3
- These mutations are functionally similar to the JAK2 V617F mutation but result in a somewhat different clinical presentation 5
Clinical Differences Between JAK2 V617F and Exon 12 Mutations
JAK2 Exon 12-Positive PV
- Two-thirds of patients present with isolated erythrocytosis 4
- Significantly higher hemoglobin levels at diagnosis 4
- Lower platelet and leukocyte counts at diagnosis 4
- Bone marrow shows hypercellularity with erythroid hyperplasia 5
- Megakaryocytes are typically small and atypical, with abnormal lobation and chromatin distribution 5
- Rare clusters of megakaryocytes may be present but are usually subtle 5
JAK2 V617F-Positive PV
- More likely to present with panmyelosis (elevated red cells, white cells, and platelets) 4
- More pronounced megakaryocytic abnormalities 5
- Classic myeloproliferative morphologic features are more evident 5
Diagnostic Implications
- World Health Organization (WHO) criteria include JAK2 mutations (both V617F and exon 12) as major diagnostic criteria for PV 2
- The National Comprehensive Cancer Network recommends testing for JAK2 V617F mutation first, and if negative, testing for JAK2 exon 12 mutations in patients suspected of having PV 2
- Clinically suspected PV with low serum erythropoietin and absent JAK2 V617F should prompt evaluation for exon 12 mutations 5
Prognostic Implications
Despite phenotypic differences, long-term outcomes appear similar between JAK2 V617F and exon 12 mutation carriers:
- Similar incidences of thrombosis, progression to myelofibrosis, leukemic transformation, and death 4
- Age >60 years and prior thrombosis remain the main predictors of thrombotic events in both groups 4
Clinical Approach to JAK2-Negative Erythrocytosis
When faced with suspected PV that is JAK2 V617F negative:
- Test for JAK2 exon 12 mutations
- If exon 12 mutations are negative, reconsider the diagnosis
- Evaluate for other causes of erythrocytosis (congenital, secondary causes)
- Consider bone marrow examination for morphologic assessment
Management Considerations
Management remains the same regardless of mutation type:
- Phlebotomy to maintain hematocrit <45%
- Low-dose aspirin (81-100 mg/day)
- Cytoreductive therapy for high-risk patients (age >60 years or history of thrombosis)
Pitfalls and Caveats
- JAK2 exon 12-positive PV may be misdiagnosed as idiopathic erythrocytosis due to the isolated erythrocytosis and subtle bone marrow findings 5
- Testing peripheral blood for exon 12 mutations is reliable and can avoid the need for bone marrow examination in some cases 3
- The presence of erythroid hyperplasia with subtle megakaryocytic atypia should raise suspicion for exon 12 mutations even when classic myeloproliferative features are absent 5