Myeloproliferative Neoplasms : Part 1 PDF

# MYELOPROLIFERATIVE NEOPLASMS : PART 1 ## Overview ### PHYSIOLOGY - Common myeloid Progenitor (CMP) - Terminal myeloid Cells - RBC - Platelets - Neutrophils - Monocytes - Eosinophils - Basophils ### PATHOLOGY - Myeloproliferative neoplasms (M...

# MYELOPROLIFERATIVE NEOPLASMS : PART 1 ## Overview ### PHYSIOLOGY - Common myeloid Progenitor (CMP) - Terminal myeloid Cells - RBC - Platelets - Neutrophils - Monocytes - Eosinophils - Basophils ### PATHOLOGY - Myeloproliferative neoplasms (MPN): Slow proliferation of terminal myeloid cells (mature cells) of multiple lineages. - No dysplastic or immature cells seen. ## CLASSIFICATION (WHO 5TH EDITION) | Phenotypic heterogeneity | mutation | |---|---| | 1. Polycythemia rubra vera (PCRV): m/c | JAK-2 mutation: Deletion on chr 9p | | 2. Primary myelofibrosis (PMF) | BCR-ABL translocation: t(9;22) | | 3. Essential thrombocytosis/thrombocythemia (ET) | BCR-ABL negative | | 4. Chronic myeloid leukemia (CML) | | | 5. Chronic neutrophilic leukemia (CNL): CSF3R mutation | | | 6. Chronic eosinophilic leukemia (CEL): PDGFRA mutation | | | 7. Juvenile myelomonocytic Leukemia (JMML)| | | 8. MPN, not otherwise specified | | **Note:** - 2° myelofibrosis (myelophthisis): Bone marrow failure. - Systemic mastocytosis (mast cell disease): c-kit mutation (Excluded from MPN). ## CLINICAL FEATURES - Extramedullary hematopoiesis: Spleen (m/c), skin, liver etc. - Splenomegaly - Massive: CML, PMF - Moderate: PCRV - Mild: ET - Hyperviscosity symptoms: D/t ↑ WBC - Headache, vertigo, tinnitus. - Cytokine release: Fatigue, thrombosis, cytokine related endothelial injury. - Classical & symptoms: In 20% (Fever, night sweats, weight loss). **Note:** - In acute leukemia: Proliferation of single immature cell. - Rapid turnover → No symptoms of extramedullary proliferation, cytokine, hyperviscosity, classical & symptoms. - MPN can transform into each other or AML. - MDS/MPN overlap included in WHO 5th edition classification. - Myelodysplastic syndrome (MDS): Ineffective proliferation of terminal myeloid cells → Pancytopenia. ## Polycythemia | | Hb (gm%) | PCV | |---|---|---| | Male | 216.5 | 49 | | Female | 216 | 48 | **Types:** Relative, absolute. ### RELATIVE POLYCYTHEMIA (GAISBOCK’S SYNDROME) **Etiopathogenesis:** - ↓ plasma volume (Dehydration) → ↑ Hb%. - Post viral: - Dengue: D/t capillary leak → ↓ intravascular volume. **Investigations:** - RBC mass: Normal. - ↑ Hb. - Total leukocyte count (TC): Normal. - Platelet count (exc): Normal. ## ABSOLUTE POLYCYTHEMIA - RBC mass: Increased | Types: | Primary (PCRV) | Secondary | |---|---|---| | ερο (4-10 μιυ) | Normal to low | Increased | | TC | Increased | Normal | | PLC | Increased | Normal | **EPO:** Erythropoietin. **Note:** Erythropoietin is produced by peritubular interstitial fibroblasts (In cortex and outer medulla of kidney). ### SECONDARY POLYCYTHEMIA **Etiology:** **L Hypoxia:** - COPD. - OSAS (Obstructive Sleep Apnea Syndrome). - High altitude. - CO intoxication. - Hepatopulmonary syndrome. **2. Renal artery stenosis.** **3. Paraneoplastic:** - Renal carcinoma (Hypernephroma). - Cerebellar hemangioblastoma (a/w von Hippel-Lindau syndrome). - Meningioma. - Pheochromocytoma. - Uterine fibroids. - Hepatoma. **Note:** Presence of pallor in pheochromocytoma indicates malignancy. ### management: - No symptoms → Hydration (3-4 L) daily x 3-4 weeks. - Repeat Investigations: Abnormal → Evaluate further. ## Primary myelofibrosis **Etiology:** - JAK-2 mutation: 50%. - Calreticulin (CALR): 30-40%. - MPL gene mutation (Codes for thrombopoietin): 10-20%. - Triple negative PMF : Absence of above mutations (Poor prognosis). - Deletion 13q. **Pathogenesis:** - Myeloproliferation (Hypercellular marrow) - Dysplastic megakaryocytes (Lack CXCR, receptors) - TGF-B (most potent pathogenic fibrogenic cytokine) - PDGF (Platelet derived growth factor) - Marrow fibrosis (↑ in type-III collagen). - Pancytopenia - Release of premature cells - Leukoerythroblastosis in peripheral smear. **Clinical features:** - Most cases present in fibrotic stage. - Age: 760 years. - Gender: male = female. - Thrombosis (↑ risk in PCRV > ET > PMF). - B-symptoms (In 20%): Fever, night sweats, weight loss - Pancytopenia: - Anemia: Fatigue (m/c symptom). - Bleeding. - Gout: During proliferation stage. - Extramedullary hematopoiesis. - Osteosclerosis. - Skin: Febrile neutrophilic dermatosis (Sweet syndrome). - Massive splenomegaly (75%). - Hepatomegaly (Portal hypertension). **Note:** Febrile neutrophilic dermatosis is characteristic of AML. **Diagnosis:** WHO criteria 3 major (or) a major + I minor criteria. **Major criteria:** - Hb: 7165 g/dL in men and >16 g/dL in women. - Bone marrow: Hypercellularity. - JAK-2 mutation. **Minor criteria:** Subnormal serum erythropoietin level. **Management:** | Treatment | Low risk | High risk | |---|---|---| | | <60 years | 760yrs, h/o thrombosis | | Phlebotomy | Weekly (maintain Hb 13-14 g/dL) | + Phlebotomy | | Aspirin | | + Aspirin 75 mg | | | | + JAK inhibitor: Ruxolitinib 10 mg BD (or) | | | | + Hydroxyurea: 0.5-2 g/day. | **Note:** - ↓ MCV (To conserve MCH) - No rouleaux formation. - Hypoxia. - Thalassemia. - PCRV. ## Essential thrombocytosis (ET) - Benign disease: Good prognosis. - **Etiology:** - JAK-2 mutation (50-60%). - CALR mutation (30-40%). - MPL mutation (10-20%). - **Clinical features:** - Mild splenomegaly. - Thrombosis (D/t hyperplasia) > Bleeding (D/t dysplastic cells). - Gender: Female > male - Age: 50-60 years. - **Investigations:** - RBC: Normal. - WBC: Normal. - PLC: 74.5 Lakhs. - Bone marrow biopsy: megakaryocytes show - Hyperplasia (Few dysplastic). - Staghorn cells : Giant cells with mature cytoplasm, hyperlobulated nuclei. - **Complications:** - Least risk of conversion to: - Myelofibrosis. - AML (PCRV > PMF > ET). - **Investigations:** - Peripheral smear: - Leukoerythroblastosis (Immature myeloid cells CD34+', nucleated red cells). - Anisopoikilocytosis with teardrop red cells/dacryocyte. - Thrombocytosis: Cloud-like megakaryocytes. - Serum type-III procollagen peptide: Increased. - Bone marrow aspirate: Dry tap. - Bone marrow biopsy: - Silver impregnation: Reticulin fibrosis & collagen fibrosis. - Fibrosis with hypercellular marrow. **Note:** megakaryocytes in peripheral smear. - Staghorn: ET. - Dwarf: CML. - Giant: ITP. - **Management:** - Median survival of 5 years. - **Medical Treatment:** - Oral Ruxolitinib: In JAK-2 mutation. - Lenalidomide. - **Definitive Treatment:** - Allogenic hematopoietic stem cell transplant (AHSCT). - **Limitations:** - Complete match required. - ↑ risk of infection. ## Primary polycythemia (Polycythemia rubra vera): - m/c MPN. - Age: 50-60 years - Gender: Female > male. **Etiology:** - JAK-2 mutation (Seen in 100% patients): - Exon 14 mutation (95%): V617F mutation. - Exon 12 mutation (5%). **Clinical features:** - **Erythrocytosis:** - Hyperviscosity symptoms. - Thrombosis: Arterial > venous. - Arterial: Stroke in young. - Venous: Budd-Chiari syndrome, Deep vein thrombosis. - Microvascular: Erythromelalgia (Burning pain of hands and feet). - Hypertension. - **Granulocytosis:** - Neutrophilia. - Basophilia (mast cell → Histamine): Aquagenic pruritus (Pruritus after bath). - Mature granulocytes: ↑ transcobalamin-1 → ↑ vit B12 binding capacity. - **Thrombocytosis (↑ dysfunctional platelets):** - Bleeding (Epistaxis): Acquired von Willebrand disease. - **Erythromelalgia (Burning pain of hand and feet):** - D/t microvascular thrombosis. - **Moderate splenomegaly.** - **Hyperuricemia: D/t ↑ turnover of cells.** - **Investigations:** - RBC: Increased - ↓ mcv, normal MCH. - ESR: Low (↓ rouleaux formation). - Peripheral smear (PS): microcytosis with erythrocytosis. - Leukocyte alkaline phosphatase (LAP from mature neutrophils): High. - Vit B12 binding capacity: Increased. - **Evaluation:** - **Diagnosis by exclusion:** - Sustained platelet count 74.5 lakhs. - Rule out reactive thrombocytosis (Response to inflammation) - (Normal RBC and WBC) - Marrow: I, staghorn megakaryocyte - JAK-2 mutation, Calretinin, MPL. - Rule out other MPN/MDS - ET - **Management:** | Treatment | Low risk | High risk | |---|---|---| | | <60yrs | 760yrs, H/o thrombosis, platelets 71.5 x 10^9 | | Aspirin 75mg/day | | + Aspirin | | | | + Hydroxyurea > interferon > anagrelide |