What is the difference in diagnosis and treatment between a leukemoid reaction and leukemia?

Differentiating Leukemoid Reaction from Leukemia

The key difference between leukemoid reaction and leukemia is that a leukemoid reaction is a reactive, non-neoplastic elevation of white blood cells (>50,000 cells/μL) in response to underlying conditions, while leukemia is a clonal proliferation of hematopoietic stem cells in the bone marrow.

Diagnostic Differences

Leukemoid Reaction

• Definition: Persistent neutrophilic leukocytosis >50,000 cells/μL not caused by leukemia 1
• Causes:
  • Severe infections (most common cause) 2
  • Malignancies (non-hematologic)
  • Severe hemorrhage
  • Acute hemolysis
  • Intoxications
  • Metabolic disorders (e.g., diabetic ketoacidosis) 3

Leukemia

• Definition: Clonal proliferation of hematopoietic stem cells in the bone marrow 4
• Diagnostic criteria for AML:
  • ≥20% blasts in bone marrow or peripheral blood 5
  • Exception: AML with t(8;21), inv(16), or t(15;17) can be diagnosed regardless of blast percentage 5

Key Diagnostic Tests

For Leukemoid Reaction:

1. Complete blood count with differential

   • Shows marked leukocytosis with left shift
   • Typically normal red blood cell and platelet counts
   • Absence of significant dysplasia 1

2. Peripheral blood smear

   • Predominance of mature and maturing neutrophils
   • Few or no blasts
   • Absence of Auer rods

3. Leukocyte alkaline phosphatase (LAP) score

   • Elevated in leukemoid reaction
   • Low in CML

4. Bone marrow examination

   • Hypercellular marrow with normal maturation
   • No increase in blasts
   • No significant dysplasia

5. Cytogenetic and molecular studies

   • Absence of Philadelphia chromosome or BCR-ABL fusion gene
   • No other clonal cytogenetic abnormalities

6. Identify underlying cause

   • Cultures for infection
   • Imaging for malignancy or other causes
   • Metabolic workup

For Leukemia:

1. Bone marrow aspirate and biopsy (mandatory)

   • ≥20% blasts for AML diagnosis
   • Morphologic examination with May-Grünwald-Giemsa or Wright-Giemsa stain 5
   • Count at least 500 nucleated cells

2. Cytochemistry

   • Myeloperoxidase (MPO) or Sudan Black B (SBB)
   • Nonspecific esterase (NSE)

3. Immunophenotyping (multiparameter flow cytometry)

   • AML markers: CD34, CD38, CD117, CD13, CD33, MPO
   • ALL markers: CD19, CD79a, CD10, CD3
   • CLL markers: CD5+, CD19+, CD20+ (low), CD23+ 6

4. Cytogenetics (mandatory)

   • Chromosome banding analysis (CBA) of marrow cells
   • Detection of specific translocations (e.g., t(9;22), t(8;21), inv(16))
   • Prognostic significance 5

5. Molecular studies

   • RT-PCR for fusion transcripts (e.g., BCR-ABL)
   • FLT3, NPM1, CEBPA mutations
   • MLL partial tandem duplications 5

Treatment Differences

Leukemoid Reaction:

• Treatment targets the underlying cause:
  • Antibiotics for infection
  • Treatment of primary malignancy
  • Correction of metabolic disorders
  • Resolution of the leukemoid reaction occurs with successful treatment of the underlying condition 3

Leukemia:

• Treatment depends on leukemia type, risk factors, and patient characteristics:
  • AML: Intensive induction chemotherapy, consolidation therapy, possibly stem cell transplantation 5
  • CML: Tyrosine kinase inhibitors (TKIs) targeting BCR-ABL 5
  • CLL: Watch and wait for asymptomatic patients; chemoimmunotherapy or targeted agents for symptomatic disease 6
  • ALL: Risk-adapted chemotherapy protocols, possibly with targeted agents and transplantation 5

Prognostic Differences

Leukemoid Reaction:

• Prognosis depends on the underlying cause
• Generally poor prognosis with high mortality, especially in paraneoplastic cases 2
• Resolution of leukocytosis follows treatment of underlying condition

Leukemia:

• Prognosis varies by leukemia type and risk factors:
  • AML: Cytogenetics is the most important prognostic factor 5
  • CML: Excellent prognosis with TKI therapy 5
  • CLL: Variable, with indolent course in many patients 6
  • ALL: Better outcomes in children than adults 5

Common Pitfalls

1. Misdiagnosis of metastatic carcinoma as lymphoma when Reed-Sternberg-like cells are present with a leukemoid reaction 7

2. Failure to perform cytogenetic studies to rule out CML in cases of marked leukocytosis

3. Premature diagnosis of leukemia without comprehensive evaluation including bone marrow examination and cytogenetics

4. Overlooking underlying causes of leukemoid reaction, particularly occult infections or malignancies

5. Initiating leukemia treatment before confirming diagnosis with appropriate testing

Clinical Pearls

• A leukemoid reaction with predominantly mature neutrophils suggests a reactive process
• The presence of >20% blasts strongly suggests acute leukemia
• Cytogenetic studies are essential to distinguish CML from a leukemoid reaction
• Consider leukemoid reaction when evaluating marked leukocytosis in a patient with severe infection, inflammation, or malignancy
• The LAP score is a useful but not definitive test to differentiate leukemoid reaction from CML