Definition/General
Introduction:
Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm characterized by the presence of BCR-ABL1 fusion gene
It represents 15% of all leukemias in adults
CML arises from a pluripotent hematopoietic stem cell
The disease is driven by constitutive tyrosine kinase activity of the BCR-ABL1 protein.
Origin:
Originates from the reciprocal translocation t(9;22)(q34;q11.2) creating the Philadelphia chromosome
This translocation fuses the BCR gene on chromosome 22 with the ABL1 gene on chromosome 9
The resulting BCR-ABL1 fusion protein has enhanced tyrosine kinase activity
This leads to uncontrolled cell proliferation and resistance to apoptosis.
Classification:
WHO classification recognizes CML as a distinct entity under myeloproliferative neoplasms
CML has three phases: Chronic phase (85-90% at diagnosis)
Accelerated phase (transformation stage)
Blast crisis (acute leukemia-like phase)
Each phase has specific morphologic and genetic criteria.
Epidemiology:
Peak incidence in 5th-6th decades of life
Male to female ratio 1.4:1
Annual incidence 1-2 per 100,000 population
In India, median age at diagnosis is 40-45 years (younger than Western populations)
Associated with ionizing radiation exposure
No clear genetic predisposition identified.
Clinical Features
Presentation:
Often asymptomatic at diagnosis (40-50% cases)
Splenomegaly (most common physical finding - 90% cases)
Fatigue and weakness (60-70% cases)
Abdominal fullness due to splenomegaly
Weight loss (30-40% cases)
Night sweats (20-30% cases)
Easy bleeding or bruising.
Symptoms:
B-symptoms (fever, night sweats, weight loss) in 25% cases
Left upper quadrant pain (splenic infarction)
Early satiety (massive splenomegaly)
Gout due to hyperuricemia
Visual disturbances (hyperviscosity)
Priapism (rare, due to leukostasis).
Risk Factors:
Ionizing radiation exposure (atomic bomb survivors, medical radiation)
Advanced age (>60 years)
Male gender
No clear genetic predisposition
No association with alkylating agents
Not hereditary
Occupational benzene exposure (weak association).
Screening:
No routine screening recommendations
Suspect in patients with unexplained leukocytosis
Consider in patients with splenomegaly of unknown cause
Complete blood count as initial test
Cytogenetic analysis for Philadelphia chromosome
BCR-ABL1 quantitative PCR for molecular diagnosis.
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Gross Description
Appearance:
Splenomegaly is the most prominent gross finding (present in 90% cases)
Spleen weight can reach 1000-3000 grams (normal 150-200g)
Hepatomegaly in 50-60% cases
Lymph node enlargement is uncommon in chronic phase
Bone marrow hypercellularity on biopsy specimens.
Characteristics:
Spleen shows red pulp expansion with loss of white pulp architecture
Splenic infarcts may be present due to massive size
Liver shows sinusoidal infiltration by leukemic cells
Bone marrow appears hypercellular and fibrotic in advanced cases.
Size Location:
Spleen enlargement extends 5-15 cm below left costal margin
Liver enlargement typically 2-6 cm below right costal margin
Bone marrow cellularity approaches 90-100% (normal 40-60%)
Extramedullary hematopoiesis in spleen and liver.
Multifocality:
Systemic disease involving bone marrow, spleen, and liver
Leukemic infiltration can occur in any organ
Central nervous system involvement rare in chronic phase
Chloromas (granulocytic sarcomas) may develop in blast crisis.
Microscopic Description
Histological Features:
Bone marrow shows marked hypercellularity with granulocytic hyperplasia
Left shift in granulocytic maturation with increased myelocytes and metamyelocytes
Basophilia and eosinophilia are characteristic
Decreased erythropoiesis and normal to increased megakaryopoiesis
Reticulin fibrosis may be present.
Cellular Characteristics:
Peripheral blood shows leukocytosis (typically >25,000/μL)
Complete maturation spectrum from myeloblasts to neutrophils
Basophils >2% and eosinophils >4% are characteristic
Low leukocyte alkaline phosphatase (LAP) score
Platelets may be normal, increased, or decreased.
Architectural Patterns:
Granulocytic hyperplasia with maintained maturation
Sea-blue histiocytes may be present in bone marrow
Spleen shows extramedullary hematopoiesis in red pulp
Megakaryocyte clustering and dysplasia in accelerated phase.
Grading Criteria:
Chronic phase: Blasts <10% in bone marrow and <5% in blood
Accelerated phase: Blasts 10-19% or specific cytogenetic abnormalities
Blast crisis: Blasts ≥20% in bone marrow or blood
Additional criteria include increasing spleen size, thrombocytopenia, and new cytogenetic abnormalities.
Immunohistochemistry
Positive Markers:
Myeloperoxidase (positive in granulocytic cells)
CD13 and CD33 (myeloid markers)
CD34 (increased blasts in accelerated/blast phase)
CD117 (c-kit, positive in myeloid precursors)
Lysozyme (positive in monocytic cells)
CD68 (macrophages and some blasts).
Negative Markers:
Terminal deoxynucleotidyl transferase (TdT) typically negative
CD10 usually negative (unlike ALL)
CD19, CD20 (B-cell markers) negative in myeloid blast crisis
CD3, CD7 (T-cell markers) negative unless lymphoid blast crisis.
Diagnostic Utility:
Immunophenotyping crucial for blast crisis classification
Myeloid blast crisis: CD13+, CD33+, MPO+
Lymphoid blast crisis: CD19+, CD10+, TdT+ (B-cell) or CD3+, CD7+ (T-cell)
Mixed lineage blast crisis can occur
Flow cytometry essential for accurate lineage assignment.
Molecular Subtypes:
Major BCR-ABL1 (p210) in 95% of CML cases
Minor BCR-ABL1 (p190) more common in ALL
Micro BCR-ABL1 (p230) rare, associated with neutrophilic-CML
Different transcript sizes correlate with clinical phenotype and prognosis.
Molecular/Genetic
Genetic Mutations:
BCR-ABL1 fusion is pathognomonic (>95% cases)
t(9;22)(q34;q11.2) Philadelphia chromosome in 90-95% cases
Cryptic rearrangements in 5-10% (normal karyotype but BCR-ABL1 positive)
Additional mutations in progression: TP53 (20-30%), RUNX1 (10-15%), ASXL1 (15-20%).
Molecular Markers:
BCR-ABL1 transcript levels monitored by quantitative RT-PCR
Major molecular response (MMR): 3-log reduction from baseline
Deep molecular response: 4-log or greater reduction
Treatment-free remission possible with sustained deep molecular response.
Prognostic Significance:
Sokal score predicts outcome in chronic phase (age, spleen size, blasts, platelets)
EUTOS score for patients on tyrosine kinase inhibitors
Additional cytogenetic abnormalities indicate accelerated phase
Complex karyotype associated with poor prognosis in blast crisis.
Therapeutic Targets:
BCR-ABL1 tyrosine kinase targeted by imatinib (Gleevec)
Second-generation TKIs: dasatinib, nilotinib for resistance
Third-generation TKIs: ponatinib for T315I mutation
Resistance mutations guide TKI selection
Allogeneic stem cell transplant for blast crisis or TKI failure.
Differential Diagnosis
Similar Entities:
Chronic Neutrophilic Leukemia (CNL): CSF3R mutated, no BCR-ABL1
Chronic Myelomonocytic Leukemia (CMML): monocytosis, dysplasia
Primary Myelofibrosis: JAK2/CALR/MPL mutations, fibrosis
Essential Thrombocythemia: thrombocytosis, JAK2/CALR mutations
Polycythemia Vera: erythrocytosis, JAK2 V617F.
Distinguishing Features:
CML: BCR-ABL1 positive, basophilia, low LAP score
CNL: CSF3R mutations, no BCR-ABL1, normal LAP
CMML: monocytosis >1000/μL, dysplastic changes
PMF: bone marrow fibrosis, teardrop cells, JAK2/CALR/MPL mutations
ET: thrombocytosis >450,000/μL, no BCR-ABL1.
Diagnostic Challenges:
Differentiating from reactive leukocytosis (infection, inflammation)
Atypical CML (BCR-ABL1 negative) versus CML
Chronic phase versus accelerated phase distinction
Lymphoid versus myeloid blast crisis classification
Treatment-related changes versus disease progression.
Rare Variants:
Neutrophilic-CML with p230 BCR-ABL1 transcript
CML with t(9;22) variants involving third chromosome
Ph-negative CML with cryptic BCR-ABL1 rearrangement
CML in children (rare, often p190 transcript)
Chronic eosinophilic leukemia BCR-ABL1 positive (very rare).
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Bone marrow aspirate and biopsy, [site], [date collected]
Peripheral Blood Findings
WBC: [count]/μL, with left shift and [X]% basophils
Bone Marrow Morphology
Hypercellular bone marrow ([X]% cellularity) with granulocytic hyperplasia
Blast Count
Blasts comprise [X]% of bone marrow cells and [X]% of peripheral blood
Cytogenetic Analysis
[karyotype], including t(9;22)(q34;q11.2) in [X]% of metaphases
Molecular Studies
BCR-ABL1 fusion detected, [transcript type], quantitative level [X]%
Disease Phase
Chronic myeloid leukemia, [chronic/accelerated/blast crisis] phase
Additional Studies
Flow cytometry: [if performed, results]
Immunohistochemistry: [if performed, results]
[other studies]: [results]
Final Diagnosis
Chronic myeloid leukemia, BCR-ABL1 positive, [phase]