What is Primary Myelofibrosis (PMF), a type of Myeloproliferative Neoplasm (MPN)?

What is Primary Myelofibrosis (PMF)?

Primary myelofibrosis is a BCR-ABL1-negative myeloproliferative neoplasm characterized by clonal stem cell proliferation with abnormal megakaryocyte and granulocyte expansion, bone marrow fibrosis (though not always present at diagnosis), and driver mutations in JAK2, CALR, or MPL in approximately 90% of cases. 1, 2, 3

Core Disease Features

PMF is defined by several cardinal characteristics that distinguish it from other myeloid disorders:

• Clonal myeloproliferation originating from hematopoietic stem cells, with JAK2 V617F mutation present in >90% of polycythemia vera cases but only approximately 50% of PMF cases 1, 2
• Megakaryocyte proliferation and atypia is the morphologic hallmark, featuring small to large megakaryocytes with aberrant nuclear/cytoplasmic ratios, hyperchromatic, bulbous, or irregularly folded nuclei, and dense clustering 1
• Bone marrow fibrosis with reticulin and/or collagen deposition is characteristic but not required for diagnosis, particularly in prefibrotic disease 1
• Granulocytic proliferation with left-shifted forms accompanies the megakaryocyte changes and helps distinguish PMF from essential thrombocythemia 1

Diagnostic Criteria (WHO 2016/2008)

Diagnosis requires meeting all 3 major criteria and at least 2 of 4 minor criteria 1:

Major Criteria:

1. Megakaryocyte proliferation and atypia, usually with reticulin/collagen fibrosis OR in the absence of significant fibrosis, increased bone marrow cellularity with granulocytic proliferation and decreased erythropoiesis (prefibrotic cellular-phase disease) 1
2. Exclusion of other WHO-defined myeloid neoplasms including polycythemia vera, BCR-ABL1-positive CML, and myelodysplastic syndromes 1
3. Demonstration of JAK2 V617F, CALR, or MPL mutation (present in ~90% of cases), OR in triple-negative cases, absence of evidence that fibrosis is secondary to infection, autoimmune disorder, lymphoid neoplasm, metastatic malignancy, or toxic myelopathies 1

Minor Criteria:

1. Leukoerythroblastosis (immature white and red blood cells in peripheral blood) 1
2. Elevated serum lactate dehydrogenase level 1
3. Anemia not attributed to other comorbid conditions 1
4. Palpable splenomegaly 1

Clinical Manifestations

The disease presents with a constellation of features that reflect both the clonal proliferation and the inflammatory cytokine dysregulation:

• Bone marrow failure manifesting as anemia, which develops in most patients and is a minor diagnostic criterion 1, 2, 3
• Splenomegaly from extramedullary hematopoiesis, often massive and symptomatic 2, 3, 4
• Hepatomegaly due to extramedullary hematopoiesis in the liver 2, 3
• Constitutional symptoms including fatigue, night sweats, fever, and weight loss driven by aberrant cytokine expression 2, 3, 4
• Cachexia in advanced disease 2, 3
• Leukemic transformation occurs in a subset of patients, representing disease progression 2, 3, 4

Molecular Landscape

Understanding the genetic drivers is essential for diagnosis and has prognostic implications:

• JAK2 V617F mutation is found in approximately 50% of PMF patients, compared to >90% in polycythemia vera 1, 2
• CALR mutations (calreticulin) are present in many JAK2-negative cases and are now included as major diagnostic criteria in the 2016 WHO classification 1, 2
• MPL mutations (thrombopoietin receptor, codon 515) occur in 5-8% of PMF patients 1, 2
• Triple-negative cases (lacking JAK2, CALR, or MPL mutations) comprise approximately 10% of patients 2, 3, 4
• High-risk mutations including ASXL1, SRSF2, and U2AF1-Q157 predict inferior survival independent of other risk factors 3, 4
• Type 1/like CALR mutations are associated with superior survival compared to other driver mutations 2, 4

Prefibrotic vs. Overt PMF

The WHO classification distinguishes two phases with important prognostic and diagnostic implications:

Prefibrotic PMF (Pre-PMF):

• Megakaryocyte proliferation and atypia without significant reticulin fibrosis (grade 0-1) 1
• Marked bone marrow hypercellularity with granulocytic proliferation and decreased erythropoiesis 1
• Can mimic essential thrombocythemia clinically, making bone marrow examination critical for distinction 1
• Mild or absent leukoerythroblastosis and dacrocytes (teardrop cells) in peripheral blood 1

Overt (Fibrotic) PMF:

• Megakaryocyte proliferation with reticulin fibrosis grade 2-3 or collagen fibrosis 1
• Leukoerythroblastosis in peripheral blood 1
• More pronounced splenomegaly and constitutional symptoms 1

Critical Distinguishing Features from Other Disorders

PMF vs. Essential Thrombocythemia (ET):

• PMF shows marked bone marrow hypercellularity with prominent granulocytic proliferation and left-shifted forms, which are absent in ET 1
• Megakaryocytes in PMF are small to large with aberrant nuclear features and dense clustering, whereas ET shows giant, mature-appearing megakaryocytes with deeply lobulated nuclei 1
• ET lacks significant reticulin fibrosis, leukoerythroblastosis, or the marked hypercellularity seen in prefibrotic PMF 1

PMF vs. Myelodysplastic Syndrome (MDS) with Fibrosis:

• PMF megakaryocytes form sizable loose to tight clusters with hyperchromatic, bulbous, or irregularly folded nuclei 1
• MDS shows classic dysmyelopoietic features with small megakaryocytes having monolobated, hypolobated, or widely dispersed nuclei that are not usually clustered 1
• PMF requires absence of dyserythropoiesis and dysgranulopoiesis 1

PMF vs. Reactive Myelofibrosis:

• Demonstration of clonal markers (JAK2, CALR, MPL mutations or cytogenetic abnormalities) establishes clonality and excludes reactive processes 1
• Reactive fibrosis from infection, autoimmune disorders, hairy cell leukemia, metastatic malignancy, or toxic myelopathies must be excluded 1
• Critical caveat: Patients with conditions causing reactive myelofibrosis are not immune to developing PMF, and diagnosis should still be considered if other criteria are met 1

Prognosis and Risk Stratification

Contemporary prognostic systems integrate clinical, molecular, and cytogenetic features:

• DIPSS-plus uses eight predictors including age >65 years, hemoglobin <10 g/dL, leukocytes >25×10⁹/L, circulating blasts ≥1%, constitutional symptoms, transfusion dependency, platelets <100×10⁹/L, and unfavorable karyotype 2
• Very high-risk cytogenetic abnormalities include -7, inv(3), i(17q), +21, +19, 12p-, and 11q- 3, 4
• GIPSS (genetically-inspired prognostic scoring system) is based exclusively on mutations and karyotype 3, 4
• MIPSSv2 (mutation and karyotype-enhanced international prognostic scoring system) includes clinical risk factors in addition to genetic features 3, 4

Common Diagnostic Pitfalls

• Failing to perform bone marrow examination in patients with thrombocytosis can lead to misdiagnosis of ET when prefibrotic PMF is present, which has significant prognostic implications 1
• Overlooking the requirement for all 3 major criteria before diagnosis; presence of JAK2 mutation alone is insufficient as it occurs in multiple MPNs 1
• Misinterpreting minimal reticulin fibrosis as excluding PMF diagnosis, when prefibrotic disease is characterized by megakaryocyte changes without significant fibrosis 1
• Not recognizing triple-negative cases (10% of patients) where diagnosis relies on morphology, cytogenetics, and exclusion of reactive causes 2, 3
• Confusing post-PV/ET myelofibrosis with primary myelofibrosis; approximately 15% of ET or PV patients progress to a PMF-like phenotype requiring different diagnostic criteria 1, 3, 4