A 50y old male complains of dragging sensation in abdomen. Physical examination revealed pallor and massive spleenomegaly. There is no lymphadenopathy. Total leucocyte count is 1,60,000 cell/mm³ and platelet count is 2 Lakhs/mm³. M a) What is the probable diagnosis? b) Describe cytogenetic change in this case? c) Enumerate peripheral blood smear findings?
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Clinical Case Analysis
50-year-old male | Dragging abdominal sensation | Pallor | Massive splenomegaly | No lymphadenopathy | TLC 1,60,000/mm³ | Platelets 2 Lakhs/mm³
a) Probable Diagnosis: Chronic Myeloid Leukemia (CML) - Chronic Phase
The clinical triad strongly points to CML:
| Feature | This Case | Significance |
|---|---|---|
| Age/sex | 50-year-old male | Peak incidence 5th-6th decade |
| Dragging sensation in abdomen | Present | Caused by massive splenomegaly |
| Massive splenomegaly | Present | Extramedullary hematopoiesis |
| Pallor | Present | Mild-to-moderate anemia |
| No lymphadenopathy | Absent | Distinguishes from lymphoma/CLL |
| TLC 1,60,000/mm³ (1,60,000 cells/mm³) | Markedly elevated | Leukocytosis often exceeds 1,00,000/µL in CML |
| Platelets 2 Lakhs | Normal-slightly elevated | Typical of CML chronic phase |
As Robbins & Kumar Pathologic Basis of Disease explicitly states: "Sometimes the first symptom is a dragging sensation in the abdomen caused by splenomegaly." CML is primarily a disease of adults with peak incidence in the fifth to sixth decades of life.
The absence of lymphadenopathy is a key feature distinguishing CML from lymphoma/CLL, as CML splenomegaly results from extramedullary hematopoiesis - not lymphoid infiltration.
b) Cytogenetic Change: The Philadelphia Chromosome - t(9;22)(q34;q11)
The Philadelphia (Ph) Chromosome
The hallmark cytogenetic change in CML is the reciprocal translocation between chromosomes 9 and 22: t(9;22)(q34;q11)
Fig: Pathogenesis of CML - BCR::ABL fusion gene creation and downstream signaling (Robbins & Kumar Pathologic Basis of Disease)
Mechanistic cascade:
- DNA breakage occurs at chromosome 22q11 (BCR gene) and chromosome 9q34 (ABL gene)
- Reciprocal translocation fuses BCR sequences from chromosome 22 with ABL sequences from chromosome 9
- This creates the chimeric BCR::ABL fusion gene on the derivative (shortened) chromosome 22 - the Philadelphia chromosome
- The fusion gene is transcribed into BCR::ABL fusion mRNA
- Translated into a 210 kDa BCR-ABL fusion protein (p210)
- The BCR moiety contains a dimerization domain that causes self-association, leading to constitutive (always "on") ABL tyrosine kinase activity
- The activated kinase phosphorylates downstream proteins activating RAS, JAK/STAT, and AKT pathways - driving growth-factor-independent proliferation and survival
- Net result: increased mature granulocytes and platelets in peripheral blood (differentiation remains intact, unlike acute leukemia)
Key cytogenetic facts:
- Present in >90% of CML cases by karyotype
- The remaining cases have cryptic (karyotypically invisible) BCR-ABL rearrangements detectable only by FISH or PCR
- There is NO BCR-ABL-negative CML - if BCR-ABL is absent by all methods, it is a different disease entity (e.g., atypical CML, chronic neutrophilic leukemia)
- The Ph chromosome results in an elongated chromosome 9 and a shortened chromosome 22
- The cell of origin is a pluripotent hematopoietic stem cell (explaining why blast crisis can be myeloid or lymphoid)
c) Peripheral Blood Smear Findings in CML
Fig: CML peripheral blood smear showing mature neutrophils, metamyelocytes, and a myelocyte (Robbins & Kumar Pathologic Basis of Disease)
The peripheral blood smear in CML shows a characteristic "left shift" - increased granulocytes at all stages of maturation:
| Finding | Details |
|---|---|
| Leukocytosis | Often >1,00,000 cells/µL; predominantly granulocytic |
| Neutrophilia | Mature neutrophils predominate |
| Band forms | Increased band neutrophils |
| Metamyelocytes | Present in increased numbers |
| Myelocytes | Present - classically myelocytes > metamyelocytes (opposite of leukemoid reaction) |
| Promyelocytes | May be present |
| Blasts | Usually <10% in chronic phase |
| Basophilia | Characteristically increased - a distinguishing feature |
| Eosinophilia | Present |
| Thrombocytosis | Platelets often increased, sometimes markedly |
| Anemia | Mild to moderate normocytic normochromic anemia |
Distinguishing CML from Leukemoid Reaction on smear:
| Feature | CML | Leukemoid Reaction |
|---|---|---|
| Myelocyte:metamyelocyte ratio | Myelocytes > metamyelocytes | Metamyelocytes > myelocytes |
| Basophilia | Present | Absent |
| Eosinophilia | Present | Absent |
| Anemia | Present | Absent |
| Thrombocytosis | Present | Absent |
| LAP (Leukocyte Alkaline Phosphatase) score | Low/absent | High |
| Philadelphia chromosome | Present | Absent |
Sources:
- Robbins, Cotran & Kumar - Pathologic Basis of Disease, Ch. 13 (Chronic Myeloid Leukemia)
- Robbins & Kumar - Basic Pathology
- Goldman-Cecil Medicine - Chronic Myelogenous Leukemia chapter
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