Probable Diagnosis: Chronic Myeloid Leukemia (CML)

• 50-year-old male (peak incidence is 5th-6th decade)
• Dragging sensation in abdomen - classic symptom of massive splenomegaly in CML
• Massive splenomegaly without lymphadenopathy - hallmark distinguishing CML from lymphoproliferative disorders
• TLC = 1,60,000/mm³ (markedly elevated, typical of CML chronic phase, often 1,00,000-4,00,000/mm³)
• Platelets = 2 Lakhs/mm³ - normal to elevated (thrombocytosis is characteristic; contrast with acute leukemia where platelets are low)
• Pallor due to anemia from marrow infiltration and splenic sequestration

"Sometimes the first symptom is a dragging sensation in the abdomen caused by splenomegaly... CML is best differentiated from other myeloproliferative neoplasms by detection of the BCR::ABL fusion gene." - Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 583

a) Probable Diagnosis

• Marked leukocytosis (1,60,000/mm³) without lymphadenopathy
• Massive splenomegaly
• Normal/elevated platelets
• Middle-aged male ...is the classic triad pointing to CML rather than ALL/AML/CLL or lymphoma.

b) Cytogenetic Changes

The Philadelphia (Ph) Chromosome

1. DNA breakage and reciprocal translocation between chromosomes 9 and 22
2. BCR sequences from chr. 22 fuse with ABL tyrosine kinase sequences from chr. 9
3. This creates the BCR::ABL fusion gene on the derivative (shortened) chromosome 22
4. The 210 kDa BCR-ABL protein has constitutive, ligand-independent tyrosine kinase activity
5. It activates downstream pathways - RAS, STAT, AKT - causing growth factor-independent proliferation while preserving normal differentiation (hence mature granulocytes in blood, not blasts)

"In more than 90% of cases, BCR::ABL is created by a reciprocal (9;22)(q34;q11) translocation (the so-called Philadelphia chromosome [Ph])." - Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 583

• Trisomy 8 (+8)
• Isochromosome 17q [i(17q)]
• Duplication of the Ph chromosome (+Ph)
• These signal transformation toward blast crisis

c) Peripheral Blood Smear Findings

Enumerated Peripheral Blood Smear Findings in CML (Chronic Phase):

1. Leukocytosis - WBC typically 1,00,000-3,00,000/mm³; composed predominantly of granulocytes at various stages of maturation
2. "Myelocyte bulge" (Myelocyte peak) - The entire myeloid maturation series is represented:
   • Myeloblasts (< 2%)
   • Promyelocytes
   • Myelocytes (predominant immature form - the "bulge") - most conspicuous immature cell
   • Metamyelocytes
   • Band forms (stab cells)
   • Mature segmented neutrophils (predominant cell)
3. Basophilia - Absolute increase in basophils; a very characteristic and diagnostically important finding. Increasing basophilia signals disease progression/accelerated phase.
4. Eosinophilia - Mild increase in eosinophils
5. Thrombocytosis - Platelet count normal to elevated (as in this case, 2 Lakhs/mm³); large/abnormal platelet forms may be seen
6. Normochromic normocytic anemia - Pallor on smear, mild to moderate reduction in RBCs
7. Nucleated RBCs (NRBCs) - May be present occasionally
8. Reduced/absent toxic granulation and Döhle bodies - In contrast to reactive leukocytosis (leukemoid reaction)
9. Low Leukocyte Alkaline Phosphatase (LAP) score - A key distinguishing feature from leukemoid reaction (in which LAP is high). Note: LAP score is a cytochemical stain result reported with the smear.
10. No significant lymphocytosis - Differentiates from CLL

"Peripheral blood smear shows many mature neutrophils, some metamyelocytes, and a myelocyte." - Robbins, Cotran & Kumar Pathologic Basis of Disease, Fig. 13.35

Summary Table: Key Differentiating Features

a) Probable Diagnosis: Chronic Myeloid Leukemia (CML) - Chronic Phase

"Sometimes the first symptom is a dragging sensation in the abdomen caused by splenomegaly... The onset is insidious. Mild-to-moderate anemia and hypermetabolism due to increased cell turnover lead to fatigability, weakness, weight loss, and anorexia." - Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 583

b) Cytogenetic Change: The Philadelphia (Ph) Chromosome

Fig. 13.34 - Robbins Pathology: Pathogenesis of CML - BCR::ABL fusion gene formation and downstream signaling

The Translocation: t(9;22)(q34;q11)

Chromosome 9 (q34):  ABL proto-oncogene (Abelson tyrosine kinase)
         +
Chromosome 22 (q11): BCR gene (Breakpoint Cluster Region)
         ↓
BCR::ABL fusion gene on the shortened derivative chromosome 22
= Philadelphia (Ph) chromosome

Key Details:

Why the Protein is Oncogenic:

In the ~5-10% Ph-negative cases:

Additional cytogenetic abnormalities (disease progression signals):

• Trisomy 8 (+8)
• Isochromosome 17q [i(17q)]
• Duplication of Ph chromosome (+Ph)
• These emerge in the accelerated/blast phase

"In more than 90% of cases, BCR::ABL is created by a reciprocal (9;22)(q34;q11) translocation (the so-called Philadelphia chromosome). The cell of origin is a pluripotent HSC." - Robbins, Cotran & Kumar Pathologic Basis of Disease, p. 583

c) Peripheral Blood Smear Findings in CML

Fig. 13.35 - Robbins Pathology: CML peripheral blood smear - mature neutrophils, metamyelocytes, and myelocytes (Dr. Robert W. McKenna, UT Southwestern)

Enumerated Findings:

• WBC typically 1,00,000-4,00,000/mm³ at presentation
• Composed overwhelmingly of granulocytes at all maturation stages

• Increased basophils - a very characteristic and diagnostically important feature
• Rising basophilia signals progression to accelerated phase

• Mild-to-moderate increase in eosinophils

• Platelets often elevated (as in this case - 2 Lakhs/mm³)
• Large, abnormal platelet morphology may be seen
• Thrombocytopenia in late/accelerated phase signals disease progression

• Mild-to-moderate; reflects marrow replacement and splenic sequestration

• Leukoerythroblastic picture in some cases

• CML neutrophils have markedly reduced LAP (score 0-10; normal 20-100)
• This is the key cytochemical distinction from a leukemoid reaction (which has very high LAP)

• Distinguishes from CMML (high monocytes) and CLL (lymphocytes)

• These reactive features seen in infective leukocytosis are absent, reflecting a neoplastic rather than reactive process

Summary: CML vs. Leukemoid Reaction