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Questions and Answers
What is a common complication associated with marked thrombocytosis?
What is a common complication associated with marked thrombocytosis?
Which of the following is NOT typically utilized in the diagnosis of Primary Myelofibrosis?
Which of the following is NOT typically utilized in the diagnosis of Primary Myelofibrosis?
Which JAK2 mutation-prevalent myeloproliferative neoplasm is classified along with Primary Myelofibrosis?
Which JAK2 mutation-prevalent myeloproliferative neoplasm is classified along with Primary Myelofibrosis?
In the International Consensus Classification (ICC), how is Primary Myelofibrosis subclassified?
In the International Consensus Classification (ICC), how is Primary Myelofibrosis subclassified?
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Which symptom is considered uncommon in patients with Primary Myelofibrosis?
Which symptom is considered uncommon in patients with Primary Myelofibrosis?
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What is the most common mutation found in patients with primary myelofibrosis (PMF)?
What is the most common mutation found in patients with primary myelofibrosis (PMF)?
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Which of the following is NOT a common clinical feature of primary myelofibrosis (PMF)?
Which of the following is NOT a common clinical feature of primary myelofibrosis (PMF)?
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In what age group is primary myelofibrosis (PMF) most commonly diagnosed?
In what age group is primary myelofibrosis (PMF) most commonly diagnosed?
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What percentage of patients with PMF are asymptomatic?
What percentage of patients with PMF are asymptomatic?
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What role do megakaryocytes play in primary myelofibrosis (PMF)?
What role do megakaryocytes play in primary myelofibrosis (PMF)?
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Which cytokine is involved in the signaling pathway affected by mutations in primary myelofibrosis (PMF)?
Which cytokine is involved in the signaling pathway affected by mutations in primary myelofibrosis (PMF)?
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What is a rare form of primary myelofibrosis characterized by the absence of common mutations?
What is a rare form of primary myelofibrosis characterized by the absence of common mutations?
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Which of the following symptoms is considered the most common presenting symptom in primary myelofibrosis (PMF)?
Which of the following symptoms is considered the most common presenting symptom in primary myelofibrosis (PMF)?
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What is a major criterion distinguishing primary myelofibrosis in the overtly fibrotic stage?
What is a major criterion distinguishing primary myelofibrosis in the overtly fibrotic stage?
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Which laboratory finding is consistent with the pre-fibrotic stage of primary myelofibrosis?
Which laboratory finding is consistent with the pre-fibrotic stage of primary myelofibrosis?
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Which of the following is included in the minor criteria for diagnosing both stages of primary myelofibrosis?
Which of the following is included in the minor criteria for diagnosing both stages of primary myelofibrosis?
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What is indicative of post-ET or post-PV myelofibrosis?
What is indicative of post-ET or post-PV myelofibrosis?
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What abnormal finding can be seen in the overt stage of primary myelofibrosis?
What abnormal finding can be seen in the overt stage of primary myelofibrosis?
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Which of the following counts would indicate leukocytosis as a minor criterion in both stages of primary myelofibrosis?
Which of the following counts would indicate leukocytosis as a minor criterion in both stages of primary myelofibrosis?
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What histological feature may be seen in a blood smear during the overtly fibrotic stage?
What histological feature may be seen in a blood smear during the overtly fibrotic stage?
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Which mutation must be present to meet the criteria for both stages of primary myelofibrosis?
Which mutation must be present to meet the criteria for both stages of primary myelofibrosis?
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What shape are teardrop-shaped RBCs characteristic of?
What shape are teardrop-shaped RBCs characteristic of?
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In the prefibrotic stage, which of the following is typically observed in bone marrow?
In the prefibrotic stage, which of the following is typically observed in bone marrow?
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Which enzyme's levels increase in the overt stage of bone marrow disease?
Which enzyme's levels increase in the overt stage of bone marrow disease?
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Which condition is characterized by hypocellular bone marrow with alternating cellular and hypocellular regions?
Which condition is characterized by hypocellular bone marrow with alternating cellular and hypocellular regions?
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What is the significance of increased reticulin staining in bone marrow examinations?
What is the significance of increased reticulin staining in bone marrow examinations?
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Which type of collagen is prominent in Grade 3 bone marrow biopsies?
Which type of collagen is prominent in Grade 3 bone marrow biopsies?
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Which feature is typical of the bone marrow aspirate in overt fibrosis?
Which feature is typical of the bone marrow aspirate in overt fibrosis?
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What staining method is used to identify stromal structural fibers in bone marrow biopsy specimens?
What staining method is used to identify stromal structural fibers in bone marrow biopsy specimens?
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What is the significance of labeling patients with PV even in the presence of substantial bone marrow fibrosis?
What is the significance of labeling patients with PV even in the presence of substantial bone marrow fibrosis?
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Which morphological feature distinguishes megakaryocytes in ET from those in prefibrotic PMF?
Which morphological feature distinguishes megakaryocytes in ET from those in prefibrotic PMF?
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What condition should be suspected in the presence of dyserythropoiesis or dysgranulopoiesis?
What condition should be suspected in the presence of dyserythropoiesis or dysgranulopoiesis?
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Which of the following presents with severe constitutional symptoms and increased circulating blasts?
Which of the following presents with severe constitutional symptoms and increased circulating blasts?
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What is the median survival time for primary myelofibrosis from onset?
What is the median survival time for primary myelofibrosis from onset?
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What does the International Prognostic Scoring System (IPSS) utilize for assessing PMF prognosis?
What does the International Prognostic Scoring System (IPSS) utilize for assessing PMF prognosis?
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What does the DIPSS model incorporate that the IPSS does not?
What does the DIPSS model incorporate that the IPSS does not?
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What is a common mutation profile seen in both essential thrombocythemia (ET) and prefibrotic PMF?
What is a common mutation profile seen in both essential thrombocythemia (ET) and prefibrotic PMF?
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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 also involves bone marrow reticulin/collagen fibrosis, osteosclerosis, aberrant inflammatory cytokine expression, anemia, hepatosplenomegaly, extramedullary hematopoiesis (EMH), constitutional symptoms, and a risk of leukemic progression.
- The incidence of PMF is 0.44-1.5 per 100,000 person-years, predominantly affecting individuals aged 60-70.
Pathophysiology of PMF
- PMF originates from the neoplastic transformation of a pluripotent hematopoietic stem cell.
- Somatic mutations in the Janus kinase/signal transducer and activator of transcription (JAK2/STAT 5) signaling pathway are implicated. This pathway is involved in signal transduction for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor (G-CSF).
- 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 contribute.
- Rare cases of triple-negative PMF exist, lacking all three mutations.
- Platelets, megakaryocytes, and monocytes release various cytokines, such as platelet-derived growth factor (PDGF), IL-1, transforming growth factor beta (TGF beta), and basic fibroblast growth factor (BFGF), resulting in fibroblast formation and excessive collagen deposition.
Clinical Features of PMF
- Myelofibrosis can be asymptomatic in about 30% of patients.
- The most common clinical features of symptomatic PMF include:
- Splenomegaly (90%)
- Hepatomegaly (50%)
- Constitutional symptoms such as fatigue (most common), fever, night sweats, and weight loss.
- Anemia
- Leukocytosis or thrombocytosis, with less frequent leukopenia or thrombocytopenia.
- Gouty arthritis and renal stones.
- Thrombosis or hemorrhagic episodes may arise from marked thrombocytosis.
- Uncommon symptoms: pruritus and pulmonary hypertension.
- Other disease complications include symptomatic portal hypertension leading to variceal bleeding or ascites, and non-hepatosplenic EMH potentially causing cord compression, pleural effusion, pulmonary hypertension, or diffuse extremity pain.
Diagnosis of Primary Myelofibrosis
- Current PMF diagnosis relies on the 2022 International Consensus Classification (ICC) criteria, encompassing clinical and laboratory features.
- Key diagnostic components:
- 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 categorized as one of four JAK2 mutation-prevalent MPNs, including polycythemia vera (PV), essential thrombocythemia (ET), and MPN unclassifiable (MPN-U).
- MPNs are included within the 2022 ICC category of myeloid neoplasms, which also encompasses acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
- The ICC subcategorizes PMF into “prefibrotic” and “overtly fibrotic” stages.
- Diagnostic criteria:
-
Overtly fibrotic stage:
- Megakaryocyte proliferation and atypia, accompanied by ≥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.
-
Pre-fibrotic/early stage:
- Megakaryocyte proliferation and atypia, accompanied by ≤grade 1 reticulin/collagen fibrosis, granulocyte proliferation/decreased erythropoiesis.
- 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.
-
Overtly fibrotic stage:
Risk Stratification of PMF
- The median survival in PMF is 5 years from onset, but significant variability exists.
- Prognostic models:
-
International Prognostic Scoring System (IPSS) (2009):
- Utilizes five independent predictors of inferior survival:
- Age > 65 years.
- Hemoglobin <10 g/dL.
- Platelet count > 25 × 109/L.
- Circulating blasts ≥1%.
- Presence of constitutional symptoms.
- Utilizes five independent predictors of inferior survival:
-
Dynamic International Prognostic Scoring System (DIPSS):
- Based on IPSS variables but applicable at any stage during the disease course.
- Incorporates three additional DIPSS-independent risk factors:
- Platelet count > 100 × 109/L.
- Anemia requiring transfusion.
- Presence of constitutional symptoms.
-
DIPSS-Plus:
- Incorporates a 5th prognostic category:
- Intermediate-2, which includes patients with a lower risk of death and transformation to acute leukemia but higher risk than low-risk patients.
- Incorporates a 5th prognostic category:
-
International Prognostic Scoring System (IPSS) (2009):
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Description
Explore the key aspects of Primary Myelofibrosis (PMF), a type of myeloproliferative neoplasm (MPN) characterized by specific mutations and complications. This quiz covers its pathophysiology, symptoms, and demographic impacts, highlighting the underlying genetic factors contributing to the disease. Test your knowledge on PMF and its clinical implications.
