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What is a common complication associated with marked thrombocytosis?
Which mutation tests are part of the diagnosis for Primary Myelofibrosis?
What are the two stages into which Primary Myelofibrosis is subclassified?
Which of the following is an uncommon symptom of Primary Myelofibrosis?
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Which classification includes Primary Myelofibrosis among myeloproliferative neoplasms?
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What is a defining characteristic of overtly fibrotic primary myelofibrosis?
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Which of the following is a minor criterion for both stages of primary myelofibrosis?
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Which mutation is relevant for diagnosing both overt and pre-fibrotic primary myelofibrosis?
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What blood count characteristic is associated with the pre-fibrotic stage of primary myelofibrosis?
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What condition can develop in about 15% of patients with essential thrombocythemia (ET) or polycythemia vera (PV)?
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Which criterion does NOT apply to the diagnosis of overtly fibrotic primary myelofibrosis?
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What findings can be observed on a peripheral blood smear in overt primary myelofibrosis?
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What is a common characteristic found in red blood cells of patients with primary myelofibrosis?
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What is the primary characteristic of primary myelofibrosis (PMF)?
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What percentage of PMF patients is estimated to have a mutated JAK2 gene?
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In which age group is primary myelofibrosis most commonly observed?
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Which of the following is NOT a common clinical feature of PMF?
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What is a characteristic morphological feature of reticulocytosis and polychromatophilia?
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Which cytokines are secreted by platelets and megakaryocytes during PMF?
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Which laboratory investigation is typically increased during the overt fibrotic stage?
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What is the most common presenting symptom of primary myelofibrosis?
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What is a rare subtype of primary myelofibrosis that lacks common mutations?
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In the prefibrotic stage, which of the following is observed in bone marrow examination?
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What is the primary purpose of performing a bone marrow biopsy in this context?
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Which mutation is associated with increased cytokine responsiveness of myeloid cells in PMF?
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What does increased reticulin staining indicate in bone marrow biopsies?
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In the overt fibrotic stage, which of the following descriptions is accurate regarding bone marrow structure?
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What does a grade 2 reticulin stain reveal about the collagen structure?
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Which of the following is a common finding in both prefibrotic and overt fibrotic stages regarding megakaryocytes?
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What should patients who fulfill the diagnostic criteria for PV be labeled as, even with substantial bone marrow fibrosis?
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What is a key distinguishing characteristic of megakaryocytes in Essential Thrombocythemia compared to prefibrotic Primary Myelofibrosis?
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What initial diagnosis should be considered in the presence of dyserythropoiesis or dysgranulopoiesis?
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In patients with acute Myelofibrosis, which symptom is likely to be present?
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What does the International Prognostic Scoring System (IPSS) for Primary Myelofibrosis use as predictors of inferior survival?
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What evolution did the IWG-MRT bring to prognostic modeling in PMF?
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How long is the median survival from the onset for patients diagnosed with primary Myelofibrosis?
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What is one of the DIPSS-independent risk factors considered in the prognostic model for PMF?
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Study Notes
Primary Myelofibrosis (PMF)
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Definition: A myeloproliferative neoplasm (MPN) characterized by stem cell-derived clonal myeloproliferation, often accompanied by JAK2, CALR, or MPL mutations.
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Key Features:
- Bone marrow reticulin/collagen fibrosis.
- Osteosclerosis.
- Aberrant inflammatory cytokine expression.
- Anemia.
- Hepatosplenomegaly
- Extramedullary hematopoiesis (EMH).
- Constitutional symptoms.
- Risk of leukemic progression.
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Incidence: 0.44-1.5 / 100,000 person-year, predominantly in the 60-70 year age group.
Pathophysiology of PMF
- Neoplastic transformation: Occurs in a pluripotent hematopoietic stem cell.
- JAK2/STAT5 signaling pathway mutation: Involved in signal transduction for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor (G-CSF).
- JAK2 mutation: Present in approximately 50-60% of patients, leading to increased cytokine responsiveness of myeloid cells.
- MPL and CALR gene mutations: Also involved in PMF development.
- Triple-negative primary myelofibrosis: Rare cases where none of the three mutations (JAK2, CALR, MPL) are present.
- Cytokine secretion in platelets, megakaryocytes, and monocytes: PDGF, IL-1, TGF beta, and BFGF result in fibroblast formation and excessive collagen deposition.
Clinical Features of PMF
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Asymptomatic: Approximately 30% of patients are asymptomatic.
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Symptomatic: Most common clinical features include:
- Splenomegaly (90%).
- Hepatomegaly (50%).
- Constitutional symptoms: Fatigue (most common presenting symptom), fever, night sweats, weight loss, and Anemia.
- Leukocytosis or thrombocytosis (common).
- Leukopenia or thrombocytopenia (less common).
- Gouty arthritis and renal stones.
- Thrombosis and hemorrhagic episodes (due to marked thrombocytosis).
- Pruritus and pulmonary hypertension (uncommon).
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Disease Complications:
- Symptomatic portal hypertension (variceal bleeding, ascites).
- Non-hepatosplenic EMH (cord compression, pleural effusion, pulmonary hypertension, diffuse extremity pain).
Diagnosis of Primary Myelofibrosis
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International Consensus Classification (ICC) criteria (2022): A composite assessment of clinical and laboratory features.
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Diagnostic Procedures:
- Complete blood count (CBC) and peripheral blood smear.
- Bone marrow aspirate and biopsy.
- Testing for JAK2, CALR, and MPL mutations.
Classification of PMF
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2022 ICC category of myeloid neoplasms:
- PMF is one of four JAK2 mutation-prevalent MPNs (including Polycythemia vera (PV), Essential thrombocythemia (ET), and MPN unclassifiable (MPN-U)).
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Subclassifications:
- Prefibrotic (early stage).
- Overtly fibrotic (late stage).
International Consensus Classification (ICC) Diagnostic Criteria for Primary Myelofibrosis
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Table 1*:
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Primary Myelofibrosis (Overtly Fibrotic Stage)*
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Major Criteria:
- Megakaryocyte proliferation and atypia accompanied by ≥ grade 2 reticulin/collagen fibrosis.
- Presence of JAK2, CALR, or MPL mutations, or presence of other clonal markers, or absence of evidence for reactive bone marrow fibrosis.
- Not meeting ICC criteria for other myeloid neoplasms.
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Minor Criteria:
- Anemia not otherwise explained.
- Leukocytosis ≥11 × 10 /L.
- Palpable splenomegaly
- Increased serum lactate dehydrogenase
- A leukoerythroblastic blood smear.
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Primary Myelofibrosis (Prefibrotic/Early Stage)*
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Major Criteria:
- Megakaryocyte proliferation and atypia accompanied by ≤ grade 1 reticulin/collagen fibrosis, granulocyte proliferation/decreased erythropoiesis.
- Presence of JAK2, CALR, or MPL mutations, or presence of other clonal markers, or absence of evidence for reactive bone marrow fibrosis.
- Not meeting ICC criteria for other myeloid neoplasms.
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Minor Criteria:
- Anemia not otherwise explained.
- Leukocytosis ≥11 × 10 /L.
- Palpable splenomegaly.
- Increased serum lactate dehydrogenase.
Post-ET or Post-PV Myelofibrosis (MF)
- Approximately 15% of patients with ET or PV develop a PMF-like phenotype over time.
- Similar treatment and outcome to PMF.
Complete Blood Count/Peripheral Blood Smear
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Prefibrotic*
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Blood counts: Initially normal or increased.
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Mild neutrophilia: With a left shift.
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Thrombocytosis: Mild or moderate.
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Anemia: No or borderline.
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Myeloblasts: No or borderline.
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Leukoerythroblastosis: No or borderline.
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Overt*
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Thrombocytopenia: With bizarre abnormal large platelets with altered granulation, fragmented megakaryocytes.
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Leukoerythroblastosis and anemia: Present.
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Myeloblasts: Usually > 5%.
Red Blood Cell (RBC) Morphology
- Poikilocytosis: Present.
- Reticulocytosis and polychromatophilia: May be present.
- Teardrop-shaped RBCs (dacrocytes): Characteristic morphologic features.
- Nucleated RBCs and neutrophil precursors: Typically present in peripheral blood.
Additional Investigations
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Prefibrotic*
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Lactate dehydrogenase (LDH): Normal or borderline increased.
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Overt*
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Lactate dehydrogenase (LDH): Increased.
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Increased levels: Alkaline phosphatase, uric acid, leukocyte alkaline phosphatase and vitamin B12.
Bone Marrow Examination
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Prefibrotic Stage*
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Hypercellular bone marrow: With atypical megakaryocytic proliferations.
- Megakaryocytes clustered (loose or tight), aberrant N:C ratios.
- Hyperchromatic, bulbous, or irregularly folded nuclei.
- Often bare megakaryocytic nuclei.
- Erythropoiesis may be reduced with excess granulocytes.
- Absent or only slight reticulin fibrosis.
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Overt Fibrotic Stage*
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Hypocellular bone marrow: With usually alternating cellular and hypocellular regions
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Atypical megakaryocytes: May form tight clusters or sheets.
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Bone marrow aspirate: Often dry tap (difficult to obtain) in approximately 50% of patients.
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Marrow osteosclerosis: With irregular, broad bony trabeculae.
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Significantly dilated sinuses: Present.
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Bone marrow biopsy: Essential for confirming diagnosis.
Reticulin and Trichrome Staining
- Reticulin staining: Detects stromal structural fibers. Increased staining associated with benign and malignant conditions.
- Trichrome staining: Detects collagen fibrosis. Increased staining prominent in late stages of severe myeloproliferative diseases or following tumor metastasis to the bone marrow.
Reticulin Stain Grades
- Grade 0: Normal bone marrow with only perivascular type I collagen.
- Grade 1: Minimal presence of type I collagen in the central of bone marrow.
- Grade 2: Paratrabecular and prominent central deposition with interconnecting collagen fibers.
- Grade 3: Extensive interconnected type I collagen fibers.
Polycythemia Vera (PV) Considerations
- Patients meeting PV diagnostic criteria should be labeled as "PV" even if substantial bone marrow fibrosis is present.
Distinguishing Prefibrotic PMF from Essential Thrombocythemia (ET)
- Prefibrotic PMF and ET can resemble each other in presentation and mutation profile.
- Megakaryocytes in ET: Loose clusters, large, mature-appearing.
- Megakaryocytes in Prefibrotic PMF: Tight clusters, abnormal maturation with hyperchromatic and irregularly folded nuclei.
- Prognostic relevance: Distinction between ET and pre-fibrotic PMF is important for prognosis.
Considerations for Other Myeloid Neoplasms
- MDS or MDS/MPN: Suspect in the presence of dyserythropoiesis or dysgranulopoiesis.
- CMML: Consider in the presence of peripheral blood monocyte count ≥0.5 × 109/L and monocyte percentage ≥10%.
- Acute MF: Acute panmyelosis with MF or acute megakaryoblastic leukemia, characterized by severe constitutional symptoms, pancytopenia, mild or no splenomegaly, and increased circulating blasts.
Risk Stratification of PMF
- Median survival: 5 years from PMF onset, but wide variability.
- Rapidly progressive disorder: Short survival due to development of acute myeloid leukemia.
- Indolent course: Most patients have a slower disease progression.
International Prognostic Scoring System (IPSS)
- Developed in 2009.
- Used at time of initial diagnosis.
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Five independent predictors of inferior survival:
- Age > 65 years.
- Hemoglobin < 10 g/dL.
- White blood cell count > 25 × 109/L.
- Circulating blasts ≥ 1%.
- Presence of constitutional symptoms.
Dynamic International Prognostic Scoring System (DIPSS)
- Subsequent to IPSS.
- Dynamic model: Applicable at any time during the disease course.
- Same prognostic variables as IPSS.
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Three additional risk factors:
- Platelet count < 100 × 109/L.
- Serum LDH > 1.5 times the upper limit of normal.
- Presence of constitutional symptoms at diagnosis.
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Description
This quiz covers the essential aspects of Primary Myelofibrosis (PMF), including its definition, key features, incidence, and pathophysiology. Explore the mutations involved and how they affect hematopoietic stem cells, impacting patient outcomes and treatment strategies.
