Paper I
Question
A 60-year-old male develops fatiguability, weakness, weight loss and a dragging sensation in the abdomen. Blood examination reveals a total count exceeding 100,000 cells /cu mm. O/E massive splenomegaly. (
- (a) What is your provisional diagnosis. ( 2 mark(s)
- (b) Describe the peripheral smear and bone marrow findings. ( 8 mark(s)
- (c) Describe the pathogenesis and the further tests to be done. 5 mark(s)
Answer
(a) Provisional diagnosis
- Chronic Myeloid Leukaemia (CML) — the classic presentation of constitutional symptoms (fatiguability, weakness, weight loss), massive splenomegaly (causing the dragging abdominal sensation), and a markedly elevated total leucocyte count (>100,000/mm³) in an elderly patient is highly characteristic of CML
(b) Peripheral smear and bone marrow findings
Peripheral smear
- Marked leucocytosis with a full spectrum of granulocytic maturation stages — myeloblasts, promyelocytes, myelocytes, metamyelocytes, band forms, and mature neutrophils
- Absolute basophilia and eosinophilia (characteristic)
- Platelets often increased (thrombocytosis) in chronic phase
- Mild anaemia (normocytic normochromic)
Bone marrow findings
- Hypercellular marrow with markedly increased myeloid:erythroid ratio (>10:1, normal is 2-4:1)
- Granulocytic hyperplasia with all stages of maturation represented (left-shifted but orderly maturation, unlike acute leukaemia)
- Increased megakaryocytes, often small/hypolobated forms
- Pseudo-Gaucher cells and sea-blue histiocytes may be seen (due to increased cell turnover)
- Mild to moderate marrow fibrosis may be present
(c) Pathogenesis and further tests
Pathogenesis
- CML arises from a pluripotent haematopoietic stem cell carrying the characteristic reciprocal translocation t(9;22)(q34;q11) — the Philadelphia chromosome
- This translocation fuses the BCR gene (chromosome 22) with the ABL gene (chromosome 9), producing the BCR-ABL fusion gene
- The BCR-ABL fusion protein has constitutive, unregulated tyrosine kinase activity, driving uncontrolled proliferation of the myeloid lineage while retaining the capacity for terminal differentiation (distinguishing it from acute leukaemia)
- Untreated CML follows a triphasic course: chronic phase → accelerated phase → blast crisis (transformation to acute leukaemia)
Further tests
- Leukocyte alkaline phosphatase (LAP) score: Low/absent in CML (helps distinguish from leukemoid reaction, where it is elevated)
- Cytogenetics: Conventional karyotyping or FISH to demonstrate the Philadelphia chromosome
- Molecular testing (RT-PCR): Quantification of BCR-ABL transcript — used both for diagnosis and monitoring response to therapy (tyrosine kinase inhibitors, e.g., Imatinib)
- Bone marrow biopsy: To assess cellularity, fibrosis, and blast percentage (staging chronic vs. accelerated vs. blast phase)