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What is a significant potential complication associated with marked thrombocytosis?
Which of the following tests is NOT part of the current diagnosis criteria for Primary Myelofibrosis (PMF)?
Which of the following classifications correctly describes the stages of Primary Myelofibrosis (PMF)?
What is a less common symptom associated with anemia as outlined?
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Which condition is classified as one of the JAK2 mutation-prevalent myeloproliferative neoplasms (MPN)?
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What is the primary characteristic of Primary Myelofibrosis (PMF)?
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Which of the following mutations is commonly associated with Primary Myelofibrosis?
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What percentage of patients with PMF are estimated to remain asymptomatic?
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Which clinical feature is most commonly reported in symptomatic patients with PMF?
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What is the incidence rate of Primary Myelofibrosis per 100,000 person-years?
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What role do platelets and megakaryocytes play in the pathophysiology of PMF?
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What secondary condition can occur due to extramedullary hematopoiesis in PMF?
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Which of the following symptoms is NOT typically associated with Primary Myelofibrosis?
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What morphological feature is characteristic of reticulocytosis and polychromatophilia?
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In the prefibrotic stage of bone marrow examination, which feature is observed?
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In overt fibrotic stage bone marrow, what can form tight clusters or sheets?
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What typically characterizes the bone marrow aspirate in the overt fibrotic stage?
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What is a significant finding in bone marrow biopsies for diagnosing reticulin fibrosis?
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Which stage of fibrosis shows extensive interconnected type I collagen fibers?
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What type of staining is particularly prominent in late stages of severe myeloproliferative diseases?
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What is frequently increased alongside lactate dehydrogenase in cases of overt reticulocytosis?
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What is a major criterion for the diagnosis of overt primary myelofibrosis?
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Which of the following best describes the fibrosis grading in pre-fibrotic primary myelofibrosis?
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What characteristic does NOT apply to the pre-fibrotic stage of primary myelofibrosis?
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Which minor criterion is common to both overt and pre-fibrotic primary myelofibrosis?
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What mutation is commonly associated with primary myelofibrosis?
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Which of the following abnormalities is typically seen in the blood smear of patients with overt primary myelofibrosis?
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Which statement is true regarding the blood counts in the pre-fibrotic stage of primary myelofibrosis?
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What clinical feature may develop in approximately 15% of patients with essential thrombocythemia or polycythemia vera over time?
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What is classified as an 'unfavorable' cytogenetic finding in primary myelofibrosis (PMF)?
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Which somatic mutation is categorized as a 'driver' mutation in myeloproliferative neoplasms?
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What type of cytogenetic analysis is important for excluding other myeloid neoplasms in PMF patients?
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What is the impact of an unfavorable cytogenetic profile on survival in PMF?
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Which abnormal finding would raise the suspicion of chronic myeloid leukemia (CML) in the context of myelofibrosis?
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Which of the following mutations has been identified as potential causative but occurs in fewer than 5% of patients with myelofibrosis?
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What role does lenalidomide therapy play in the treatment of myelofibrosis?
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Which of the following chromosomal abnormalities is the least frequent in patients with primary myelofibrosis?
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Study Notes
Primary Myelofibrosis (PMF)
- PMF is a myeloproliferative neoplasm (MPN) characterized by stem cell-derived clonal myeloproliferation often accompanied by JAK2, CALR, or MPL mutations.
- PMF features include bone marrow reticulin/collagen fibrosis, osteosclerosis, aberrant inflammatory cytokine expression, anemia, hepatosplenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, and risk of leukemic progression.
- The incidence of PMF is 0.44-1.5 / 100,000 person-year, predominantly affecting individuals between 60-70 years old.
Pathophysiology of PMF
- PMF results from neoplastic transformation of a pluripotent hematopoietic stem cell.
- Somatic mutation of the JAK2/STAT 5 signaling pathway, involved in signal transduction for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor (G-CSF), contributes to PMF development.
- Approximately 50-60% of PMF patients have a gain mutation in JAK2, leading to increased cytokine responsiveness of myeloid cells.
- Mutations in the thrombopoietin receptor gene (MPL) or calreticulin (CALR) gene can also be involved.
- Some rare cases of PMF are triple-negative, lacking all three mutations (JAK2, CALR, and MPL).
- Platelets, megakaryocytes, and monocytes secrete cytokines like platelet-derived growth factor (PDGF), IL-1, transforming growth factor beta (TGF beta), and basic fibroblast growth factor (BFGF), contributing to fibroblast formation and excessive collagen deposition.
Clinical Features of PMF
- Myelofibrosis can be asymptomatic in up to 30% of patients.
- The most common clinical features in symptomatic patients include:
- Splenomegaly (90%)
- Hepatomegaly (50%)
- Fatigue (the most common presenting symptom)
- Fever, night sweats, weight loss
- Anemia
- Leukocytosis or thrombocytosis (more common)
- Leukopenia or thrombocytopenia (less common)
- Gouty arthritis and renal stones
- Marked thrombocytosis can lead to thrombosis or hemorrhagic episodes.
- Uncommon symptoms include pruritus and pulmonary hypertension.
- Other disease complications include:
- Symptomatic portal hypertension, potentially causing variceal bleeding or ascites
- Non-hepatosplenic EMH, potentially causing cord compression, pleural effusion, pulmonary hypertension, or extremity pain.
Diagnosis of Primary Myelofibrosis
- The 2022 ICC criteria are used to diagnose PMF, based on a composite assessment of clinical and laboratory features.
- Diagnosis involves:
- Complete blood count (CBC) and peripheral blood smear
- Bone marrow aspirate and biopsy
- Testing for JAK2, CALR, and MPL mutations
Classification of PMF
- PMF is one of four JAK2 mutation-prevalent MPNs, also including polycythemia vera (PV), essential thrombocythemia (ET), and MPN unclassifiable (MPN-U).
- The 2022 ICC classifies PMF into "prefibrotic" and "overtly fibrotic" stages:
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Prefibrotic/Early Stage PMF: Requires all 3 major criteria and 1 minor criterion.
- Major criteria: Megakaryocyte proliferation and atypia with ≤ grade 1 reticulin/collagen fibrosis, granulocyte proliferation/decreased erythropoiesis.
- Minor criteria: Anemia not otherwise explained, Leukocytosis ≥ 11 × 109/L, Palpable splenomegaly, Increased serum lactate dehydrogenase, A leukoerythroblastic blood smear.
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Overtly Fibrotic Stage PMF: Requires all 3 major criteria and 1 minor criterion.
- Major criteria: Megakaryocyte proliferation and atypia with ≥ grade 2 reticulin/collagen fibrosis, presence of JAK2, CALR, or MPL mutations (or other clonal markers or absence of evidence for reactive bone marrow fibrosis), not meeting ICC criteria for other myeloid neoplasms.
- Minor criteria: Anemia not otherwise explained, Leukocytosis ≥ 11 × 109/L, Palpable splenomegaly, Increased serum lactate dehydrogenase, A leukoerythroblastic blood smear.
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Prefibrotic/Early Stage PMF: Requires all 3 major criteria and 1 minor criterion.
Complete Blood Count/Peripheral Blood Smear
- Prefibrotic stage: Initially normal or increased blood counts, mild neutrophilia with left shift, thrombocytosis (mild/moderate), no or borderline anemia, no or myeloblasts, no or leukoerythroblastosis.
- Overt stage: Thrombocytopenia with bizarre, abnormal, large platelets with altered granulation, fragmented megakaryocytes, leukoerythroblastosis, anemia, myeloblasts (usually > 5%).
Red Blood Cells (RBCs)
- Prefibrotic and overt stages: Poikilocytosis, reticulocytosis, and polychromatophilia, teardrop-shaped RBCs (dacrocytes) are characteristic.
- Prefibrotic and overt stages: Nucleated RBCs and neutrophil precursors are present in peripheral blood.
Additional Investigations
- Prefibrotic stage: Normal or borderline increased lactate dehydrogenase.
- Overt stage: Increased lactate dehydrogenase.
- Elevated alkaline phosphatase, uric acid, leukocyte alkaline phosphatase, and vitamin B12 levels.
Bone Marrow Examination
- Prefibrotic Stage: Hypercellular bone marrow with atypical megakaryocytic proliferations (clustered megakaryocytes, aberrant N:C ratios, hyperchromatic, bulbous or irregularly folded nuclei, often bare megakaryocytic nuclei), reduced erythropoiesis with excess granulocytes, absent or only slight reticulin fibrosis.
- Overt Fibrotic Stage: Hypocellular bone marrow with alternating cellular and hypocellular regions, atypical megakaryocytes forming tight clusters or sheets, difficult bone marrow aspirate (dry tap) in approximately 50% of patients, marrow osteosclerosis with irregular, broad bony trabeculae, markedly dilated sinuses.
- Essential for diagnosis: Bone marrow biopsy to confirm diagnosis.
- Reticulin and trichrome stains: Used to detect stromal structural fibers in bone marrow biopsy specimens.
- Increased reticulin staining (reticulin fibrosis): Associated with many benign and malignant conditions.
- Increased trichrome staining (collagen fibrosis): Particularly prominent in late stages of severe myeloproliferative diseases or following tumor metastasis to the bone marrow.
Cytogenetic/Molecular
- Approximately one-third of PMF patients present with cytogenetic abnormalities: Most frequent include del(20q), del(13q), trisomy 8 and 9, and abnormalities of chromosome 1 (including duplication 1q).
- Less frequent lesions: -7/del(7q), del(5q), del(12p), +21, and der(6)t(1;6)(q21;p21.3).
- Prognostic significance: Cytogenetic findings are classified as "favorable" (normal karyotype or isolated del(20q) or del(13q)) or "unfavorable" (all other abnormalities).
- Unfavorable cytogenetic profile: Associated with independent adverse effect on survival, higher JAK2V617F mutational frequency.
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Value of cytogenetic studies:
- Prognostication
- Diagnostic exclusion of other myeloid neoplasms associated with bone marrow fibrosis (e.g., BCR-ABL1-positive or PDGFRB-rearranged)
- Specific treatment selection (e.g., lenalidomide therapy for del(5q) associated MF).
- Somatic mutations in MPNs: Operationally classified as "driver" mutations (essential for MPN phenotype, include JAK2, CALR, MPL) and "other" mutations (contribute to disease progression and leukemic transformation, potentially preceding the 3 primary genetic drivers).
- Other potential MF causative mutations: NRAS, KRAS, PTPN11, GATA2, TP53, and RUNX1 (in less than 5% of patients).
Differential Diagnosis of PMF
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Distinction from other closely related myeloid neoplasms:
- Chronic myeloid leukemia (CML) - presence of dwarf megakaryocytes suggests CML, requiring BCR-ABL1 cytogenetic or molecular testing.
- PV, ET, MDS, chronic myelomonocytic leukemia (CMML), "acute myelofibrosis."
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Description
This quiz explores Primary Myelofibrosis (PMF), a type of myeloproliferative neoplasm characterized by specific mutations and symptoms. Learn about its pathophysiology, incidence, and the role of JAK2 mutations in its development. Perfect for those studying hematology and related disciplines.
