What is a Myeloproliferative Neoplasm (MPN)?

What is a Myeloproliferative Neoplasm (MPN)?

A myeloproliferative neoplasm (MPN) is a heterogeneous group of clonal hematopoietic stem cell disorders characterized by excessive proliferation of one or more myeloid cell lineages in the bone marrow. 1

Core Definition and Pathophysiology

MPNs arise from acquired genetic driver mutations in bone marrow stem cells, leading to uncontrolled production of red blood cells, white blood cells, or platelets. 2 The nomenclature was changed from "chronic myeloproliferative disease" to "myeloproliferative neoplasms" in the 2008 WHO classification to accurately reflect their neoplastic nature. 1

WHO Classification of MPNs

The current WHO classification divides MPNs into several major categories: 1

Philadelphia Chromosome-Positive MPN

• Chronic Myeloid Leukemia (CML): Distinguished by the BCR-ABL1 fusion gene resulting from the Philadelphia chromosome t(9;22)(q34;q11.2) 3

Philadelphia Chromosome-Negative Classical MPNs

These represent the most common subtypes: 4, 3

• Polycythemia Vera (PV): Characterized by excessive red blood cell production, with hemoglobin >18.5 g/dL in men or >16.5 g/dL in women 1
• Essential Thrombocythemia (ET): Defined by sustained platelet count ≥450 × 10⁹/L with megakaryocytic proliferation 1, 3
• Primary Myelofibrosis (PMF): Characterized by megakaryocyte proliferation and atypia with reticulin and/or collagen fibrosis 3

Non-Classical Philadelphia-Negative MPNs

• Chronic Neutrophilic Leukemia (CNL): Rare MPN with persistent neutrophilia 1, 3
• Chronic Eosinophilic Leukemia (CEL): Persistent eosinophilia with clonal markers 3
• Mastocytosis 1

MPN, Unclassifiable (MPN-U)

Cases with clinical-pathological findings not fulfilling diagnostic criteria for any specific entity. 5

Key Molecular Features

The diagnosis of Philadelphia-negative MPNs relies heavily on molecular testing for driver mutations: 1

• JAK2 V617F mutation: Present in approximately 95% of PV cases and 50-60% of ET and PMF cases 1, 3
• CALR mutations: Found in 20-25% of ET and PMF cases, generally conferring better prognosis than JAK2 mutations 1, 4
• MPL mutations: Present in 3-8% of ET and PMF cases 1
• "Triple-negative" cases: Lack all three driver mutations, associated with inferior outcomes 1, 4

Clinical Significance and Complications

MPNs carry substantial morbidity and mortality risks: 1, 2

• Thrombotic complications: Arterial and venous thrombosis, including splanchnic vein thrombosis (PV accounts for 40-49% of Budd-Chiari syndrome cases) 3
• Hemorrhagic events: Paradoxical bleeding despite elevated cell counts 1
• Constitutional symptoms: Fatigue, pruritus, weight loss, night sweats, and splenomegaly-related symptoms 1
• Leukemic transformation: 2-10% risk of progression to acute myeloid leukemia, particularly in cases with specific cytogenetic abnormalities 1
• Progression to myelofibrosis: Post-PV or post-ET myelofibrosis can occur 1

Diagnostic Approach

For suspected MPN, the diagnostic workup must include: 1

• Complete blood count with differential and peripheral blood smear examination
• Bone marrow aspirate and biopsy with reticulin staining
• BCR-ABL1 testing by FISH or RT-PCR to exclude CML (mandatory first step) 1
• Molecular testing for JAK2 V617F; if negative, test for CALR and MPL mutations 1
• Bone marrow cytogenetics (karyotype ± FISH)
• Serum erythropoietin level (for PV evaluation) 1

Prognosis and Survival

Survival varies significantly by MPN subtype. Patients with MPN have substantially inferior survival compared to matched controls, with myelofibrosis having the worst prognosis among the classical MPNs. 1 The median survival for low-risk PV or ET patients can be 3-6 years or longer, while high-risk myelofibrosis patients may have median survival of only 5-12 months without treatment. 1

Common Pitfalls in Diagnosis

• Failing to exclude BCR-ABL1: CML must always be ruled out first, as it requires different treatment 1
• Overlooking triple-negative cases: Approximately 10-15% of ET and PMF cases lack JAK2, CALR, and MPL mutations but are still clonal MPNs 1
• Confusing reactive conditions with MPN: Reactive thrombocytosis or erythrocytosis can mimic MPN; clonal markers are essential for diagnosis 1
• Missing cryptic BCR-ABL1 rearrangements: FISH is mandatory when karyotype is normal or insufficient metaphases are obtained 1