Cytogenetics in Myeloproliferative Neoplasms

Cytogenetics and Molecular Analysis

• Analysis of BCR-ABL fusion gene is essential to rule out Chronic Myeloid Leukemia (CML).
• JAK2 mutations occur in approximately 60% of relevant cases.
• Abnormal platelet function tests show failure to aggregate with adrenaline.

Treatment Aims

• Treatment focuses on managing platelet counts and minimizing thrombotic risks.
• Hydroxyurea is utilized to control platelet counts (≥ 11 x 10^9/L).

Diagnosis Criteria for Primary Myelofibrosis (PMF)

• Diagnosis requires meeting all three major criteria and at least one minor criterion.

Clinical Features of PMF

• Insidious onset primarily in older patients, often with anemia symptoms.
• Symptoms associated with massive splenomegaly include abdominal discomfort and pain.
• Hypermetabolic symptoms such as weight loss, anorexia, fever, and night sweats can manifest.
• Additional features may include bleeding, bone pain, and gout.
• Splenomegaly is the most significant physical examination finding.

Laboratory Investigations for PMF

• Anemia is common; however, some patients may present with normal or elevated hemoglobin levels.
• White blood cell and platelet counts are often elevated at the start, leading to leukopenia and thrombocytopenia as the disease progresses.
• Characteristic leukoerythroblastic blood picture includes red cells with a "tear-drop" appearance.
• Bone marrow may be unobtainable via aspiration ("dry tap"), but biopsies reveal fibrotic, hypercellular marrow and frequent megakaryocytes.
• Myelosclerosis (increased bone density) is observed in 10% of cases via X-rays.
• Low serum and red cell folate, along with increased serum B12 levels, are notable findings.
• Normal NAP score is common; elevated uric acid and LDH levels reflect increased hematopoietic turnover.

WHO Criteria for Essential Thrombocythemia (ET)

• Major criteria include platelet count ≥ 450 x 10^9/L and bone marrow biopsy showing proliferation of megakaryocytes without significant left-shift in granulocyte or erythrocyte lineage.
• Absence of alternative diagnoses like CML, Polycythemia Vera (PV), PMF, or other myeloid neoplasms is required.
• JAK2, CALR, or MPL mutations must be present as part of diagnosis.
• Minor criteria include the presence of a clonal marker or absence of reactive thrombocytosis.

Reactive Thrombocytosis Causes

• Can stem from iron deficiency, acute or chronic blood loss, hyposplenism or splenectomy, chronic inflammation, various infections, and malignancies.
• Rebound thrombocytosis may occur after treatments like ITP or recovery from chemotherapy.

Clinical Features of ET

• Vasomotor symptoms may include headaches, visual disturbances, dizziness, and paresthesias.
• Thrombotic manifestations can affect arteries (e.g., TIA, CVA) and veins (e.g., deep vein thrombosis, mesenteric).
• Hemorrhagic events may occur in gastrointestinal and urogenital pathways.
• Obstetric complications include spontaneous abortion and premature delivery.
• Splenomegaly reported in about 50% of patients.

Laboratory Investigations for ET

• Blood films reveal abnormally large platelets and megakaryocyte fragments.
• Bone marrow trephine biopsy displays hypercellular marrow packed with abnormal megakaryocytes.

General Considerations for Myeloproliferative Neoplasms (MPNs)

• MPNs arise from acquired clonal abnormalities in hematopoietic stem cells.
• There are qualitative and quantitative changes in myeloid, erythroid, and platelet cell lines.
• These disorders often have overlapping clinical and laboratory features and can evolve from one type to another.
• Progression to Acute Myeloid Leukemia (AML) is a potential outcome of these conditions.
• Common pathogenic mechanism involves constitutive tyrosine kinase activation.
• The Philadelphia chromosome was the first identified cytogenetic abnormality in human malignancy linked to CML.
• Genetic advances have revealed mutations in genes like JAK2, MPL, CALR, and CSF3R among MPNs.

JAK2 Gene Function

• JAK2 gene encodes a protein that is instrumental in promoting cell growth and division.