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Questions and Answers
What is a common complication associated with marked thrombocytosis in primary myelofibrosis?
Which of the following mutations are tested for in the diagnosis of primary myelofibrosis?
Which classification identifies the prefibrotic and overtly fibrotic stages of primary myelofibrosis?
Which of the following is an uncommon symptom of primary myelofibrosis?
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What is one of the criteria included in the composite assessment for diagnosing primary myelofibrosis?
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What is a major criterion for diagnosing primary myelofibrosis in the overtly fibrotic stage?
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Which of the following is a minor criterion for both stages of primary myelofibrosis?
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How does the reticulin/collagen fibrosis differ between pre-fibrotic and overtly fibrotic stages of primary myelofibrosis?
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What laboratory finding characterizes the overtly fibrotic stage of primary myelofibrosis?
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Which mutation is associated with primary myelofibrosis?
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What describes the blood smear in pre-fibrotic primary myelofibrosis?
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Which condition is most likely to develop a PMF-like phenotype over time?
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What associated feature would be present in patients with overt primary myelofibrosis?
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What morphologic feature is characteristic of reticulocytosis and polychromatophilia?
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In the overt fibrotic stage, what is a common finding in the bone marrow?
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What is the role of a bone marrow biopsy in diagnosing these conditions?
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Which of the following findings indicates an increased level in regards to alkaline phosphatase in the prefibrotic stage?
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What pattern of megakaryocyte proliferation is typically seen in the prefibrotic stage?
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In the evaluation of reticulin fibrosis, which stain is primarily used?
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What does Grade 3 in Masson's trichrome stain indicate with regard to collagen fibers?
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What type of cellularity is commonly observed in the bone marrow aspirate of overt fibrotic stage patients?
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What is one of the most frequent cytogenetic abnormalities in primary myelofibrosis (PMF)?
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Which cytogenetic profile is classified as 'favorable' in myelofibrosis?
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Which of the following is an adverse effect on survival in patients with myelofibrosis?
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What is a characteristic feature linked to the diagnosis of chronic myeloid leukemia (CML)?
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Which of the following mutations is classified as a 'driver' mutation in myeloproliferative neoplasms?
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What is the function of cytogenetic studies in myelofibrosis?
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Which of the following is an example of a somatic mutation classified as 'other'?
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Which mutation is least likely to be involved in primary myelofibrosis causation?
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What should patients who fulfill the diagnostic criteria for PV be labeled as, despite substantial bone marrow fibrosis?
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What is a key morphological feature that distinguishes megakaryocytes in ET from those in prefibrotic PMF?
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Which condition should be suspected in the presence of dyserythropoiesis or dysgranulopoiesis?
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What is the median survival time for patients with primary myelofibrosis from onset?
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What additional factors does the dynamic prognostic model (DIPSS) incorporate that are independent of the initial prognostic scoring system (IPSS)?
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Which symptom is NOT typically associated with patients who have acute myeloid leukemia and acute myelofibrosis?
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What is a distinguishing characteristic of the clinical presentation of prefibrotic PMF compared to ET?
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What percentage of peripheral blood monocyte count is a potential indicator of Chronic Myelomonocytic Leukemia (CMML)?
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Study Notes
Primary Myelofibrosis (PMF)
- PMF is a rare, chronic myeloproliferative neoplasm (MPN) characterized by bone marrow fibrosis, extramedullary hematopoiesis (EMH), and splenomegaly.
- The median survival in primary myelofibrosis is 5 years from onset.
- The 2022 International Consensus Classification (ICC) defines PMF with three major and one minor criteria.
PMF Diagnosis Criteria
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Major Criteria:
- Megakaryocyte proliferation and atypia: Characterized by abnormal megakaryocyte growth and morphology in bone marrow.
- Reticulin/collagen fibrosis: Presence of excess fibrous tissue in the bone marrow.
- Presence of JAK2, CALR or MPL mutations: Genetic mutations often associated with PMF.
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Minor Criteria:
- Anemia: A deficiency in red blood cells.
- Leukocytosis: An increase in white blood cells.
- Palpable splenomegaly: An enlarged spleen.
- Increased serum lactate dehydrogenase: Elevated levels of lactate dehydrogenase enzyme in the blood.
Subclassifications of PMF
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Overtly Fibrotic Stage:
- Major Criteria: Megakaryocyte proliferation and atypia with ≥ grade 2 reticulin/collagen fibrosis, JAK2, CALR or MPL mutations, and no evidence of reactive bone marrow fibrosis.
- Minor Criteria: Anemia, leukocytosis ≥ 11 x 10/L, palpable splenomegaly, increased serum lactate dehydrogenase, leukoerythroblastic blood smear.
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Prefibrotic/Early Stage:
- Major Criteria: Megakaryocyte proliferation and atypia with ≤ grade 1 reticulin/collagen fibrosis, JAK2, CALR or MPL mutations, and no evidence of reactive bone marrow fibrosis.
- Minor Criteria: Anemia, leukocytosis ≥ 11 x 10/L, palpable splenomegaly, increased serum lactate dehydrogenase.
PMF Related Diseases
- Post-ET or post-PV myelofibrosis (MF): A PMF-like phenotype that develops in about 15% of patients with essential thrombocythemia (ET) or polycythemia vera (PV).
Complete Blood Count (CBC)/Peripheral Blood Smear Findings
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Prefibrotic PMF:
- Initially, normal or increased blood counts.
- Mild neutrophilia (an increase in neutrophils) with a left shift (immature neutrophils).
- Thrombocytosis (an increase in platelets).
- No or borderline anemia.
- No myeloblasts (immature white blood cells).
- No leukoerythroblastosis (presence of immature blood cells in the peripheral blood).
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Overt PMF:
- Thrombocytopenia (a decrease in platelets).
- Bizarre, abnormally large platelets with altered granulation.
- Fragmentation of megakaryocytes.
- Leukoerythroblastosis and anemia.
- Myeloblasts (usually >5%).
Red Blood Cell (RBC) Morphology
- Poikilocytosis: Abnormal shapes of red blood cells.
- Reticulocytosis: An increase in reticulocytes, immature red blood cells.
- Polychromatophilia: Red blood cells with a blue tinge.
- Teardrop-shaped RBCs (dacrocytes): Characteristic morphological features of PMF.
- Nucleated RBCs: Immature red blood cells with a nucleus.
- Neutrophil precursors: Immature white blood cells.
Laboratory Findings
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Lactate dehydrogenase (LDH):
- Prefibrotic PMF: Normal or borderline increased lactate dehydrogenase.
- Overt PMF: Increased lactate dehydrogenase.
- Increased alkaline phosphatase, uric acid, leukocyte alkaline phosphatase and vitamin B12.
Bone Marrow Examination
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Prefibrotic PMF:
- Hypercellular bone marrow with atypical megakaryocytic proliferations.
- Clustered (loose or tight) megakaryocytes with aberrant N:C ratios (nuclear-to-cytoplasmic ratios).
- Hyperchromatic, bulbous or irregularly folded nuclei.
- Often bare megakaryocytic nuclei.
- Erythropoiesis (red blood cell production) may be reduced with excess granulocyte production.
- Absent or only slight reticulin fibrosis.
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Overt Fibrotic Stage:
- Hypocellular bone marrow with alternating cellular and hypocellular regions.
- Atypical megakaryocytes form tight clusters or sheets.
- Bone marrow aspirate is often difficult (dry tap) in about 50% of patients.
- Marrow osteosclerosis (hardening of the bone marrow) with irregular, broad bony trabeculae.
- Markedly dilated sinuses.
Bone Marrow Biopsy
- Essential for confirming the diagnosis.
- Reticulin stain: Used to detect stromal structural fibres in bone marrow biopsy specimens.
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Trichrome stain: Used to detect collagen fibers in bone marrow biopsy specimens.
- Increased reticulin staining: Associated with many benign and malignant conditions.
- Increased trichrome staining: Prominent in late stages of severe myeloproliferative diseases.
Reticulin Fibrosis Grading
- Grade 0: Normal bone marrow with only perivascular type I collagen.
- Grade 1: Minimal presence of type I collagen in the center of the bone marrow.
- Grade 2: Paratrabecular and prominent central deposition of interconnecting collagen fibers.
- Grade 3: Extensive interconnected type I collagen fibers.
Cytogenetics and Molecular Findings
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Cytogenetic abnormalities: Present in approximately one-third of patients.
- Most common: del(20q), del(13q), trisomy 8 and 9, and abnormalities of chromosome 1 including duplication 1q.
- Less frequent: -7/del(7q), del(5q), del(12p), +21 and der(6)t(1;6)(q21;p21.3).
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Cytogenetic findings classified as 'favorable' or 'unfavorable' based on prognostic effect:
- Favorable: Normal karyotype or isolated del(20q) or del(13q).
- Unfavorable: All other abnormalities.
- Unfavorable cytogenetic profile: Associated with higher JAK2V617F mutational frequency and an independent adverse effect on survival.
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Somatic mutations:
- Driver mutations: JAK2, CALR and MPL.
- Other mutations: ASXL1, SRSF2, U2AF1.
- Potential MF causative mutations: NRAS, KRAS, PTPN11, GATA2, TP53, and RUNX1 in less than 5% of patients.
Differential Diagnosis: PMF vs. other Myeloid Neoplasms
- Chronic myeloid leukemia (CML): Presence of dwarf megakaryocytes raises the possibility of CML and should be investigated with BCR-ABL1 cytogenetic or molecular testing.
- Polycythemia vera (PV): Patients who fulfill the diagnostic criteria for PV should be labeled as “PV” even if they display substantial bone marrow fibrosis.
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Essential thrombocythemia (ET): Prefibrotic PMF with thrombocytosis can mimic ET in its presentation and mutation profile; careful morphologic examination is needed for differentiation.
- Megakaryocytes in ET: Distributed in loose clusters and are large and mature-appearing.
- Megakaryocytes in prefibrotic PMF: Display tight clusters, abnormal maturation with hyperchromatic and irregularly folded nuclei.
- Myelodysplastic syndromes (MDS) or MDS/MPN: Suspect in the presence of dyserythropoiesis (abnormal red blood cell production) or dysgranulopoiesis (abnormal white blood cell production).
- Chronic myelomonocytic leukemia (CMML): A possibility in the presence of peripheral blood monocyte count ≥0.5 x 109/L and monocyte percentage ≥10%.
- Acute MF (acute panmyelosis with MF or acute megakaryoblastic leukemia): Usually presents with severe constitutional symptoms, pancytopenia (a deficiency of all blood cells), mild or no splenomegaly, and increased circulating blasts (immature white blood cells).
Risk Stratification of PMF
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International Prognostic Scoring System (IPSS): Developed in 2009, uses five independent predictors of inferior survival:
- Age > 65 years
- Hemoglobin < 10 g/dL
- Platelet count < 100 x 109/L
- White blood cell count ≥ 25 x 109/L
- Circulating blasts ≥ 1%
- Presence of constitutional symptoms.
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Dynamic International Prognostic Scoring System (DIPSS): A dynamic prognostic model developed by the International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT).
- Utilizes the same prognostic variables as IPSS but can be applied at any time during the disease course.
- Incorporates three additional DIPSS-independent risk factors:
- Platelet count < 50 x 109/L (favorable)
- Splenomegaly (unfavorable)
- Constitutional symptoms: Fever, weight loss, night sweats, fatigue, bone pain, and abdominal fullness.
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Test your knowledge on primary myelofibrosis with this quiz. Explore common complications associated with marked thrombocytosis and mutations that are essential for diagnosis. Enhance your understanding of this hematological condition.
