In a child with a 2‑month history of lethargy, pallor, low‑grade fever and persistent lymphadenopathy, what is the first investigation to confirm a suspected hematologic malignancy?

Initial Investigation for Suspected Hematologic Malignancy in a Child

A peripheral blood film is the appropriate initial investigation to confirm the diagnosis in this child with lethargy, pallor, low-grade fever, and lymphadenopathy for 2 months.

Rationale for Blood Film as First-Line Investigation

The clinical presentation—chronic constitutional symptoms (lethargy, pallor, fever) combined with lymphadenopathy—strongly suggests acute lymphoblastic leukemia (ALL) or lymphoma, the most common pediatric hematologic malignancies 1. The NCCN Guidelines for Pediatric ALL explicitly state that peripheral blood may be substituted for bone marrow when there is a significant amount of circulating disease, with ≥1,000 circulating lymphoblasts per microliter or ≥20% lymphoblasts 1.

Why Blood Film First:

• Most children with ALL present with circulating blasts detectable on peripheral blood film 1. In fact, 34% of pediatric ALL patients present with white cell counts >50,000/mm³, making peripheral blood highly diagnostic 2.

• Blood film examination is rapid, minimally invasive, and immediately available, allowing prompt diagnosis without the need for sedation or procedural risk 1.

• The NCCN recommends complete blood count with differential and peripheral blood smear as foundational screening tests to identify cytopenias, abnormal white blood cell counts, or circulating blasts 3.

• Common laboratory findings in pediatric ALL include anemia (86%), thrombocytopenia (33% with platelets <20,000), and abnormal white cell counts 2. These abnormalities, combined with blast cells on blood film, establish the diagnosis 1.

When Bone Marrow Examination is Required

Bone marrow aspirate and biopsy become necessary only when:

• Peripheral blood shows insufficient circulating disease (<1,000 lymphoblasts/μL or <20% lymphoblasts) to establish diagnosis 1

• Definitive diagnosis requires ≥20% bone marrow lymphoblasts on hematopathology review, though ≥25% is often used in treatment protocols 1

• Comprehensive immunophenotyping, cytogenetics, and molecular characterization are needed for risk stratification and treatment planning 1

• Clinical situations preclude bone marrow sampling initially (e.g., hyperleukocytosis ≥100,000/μL, mediastinal mass causing respiratory compromise) 1

Why Not Virology Screening First

Virology screening is not the initial diagnostic test because:

• The 2-month duration of symptoms with progressive lymphadenopathy, pallor, and constitutional symptoms is inconsistent with typical viral infections 1

• While infections can coexist with malignancy, the presence of infection does not exclude hematologic malignancy 1

• Viral testing does not establish or exclude the diagnosis of leukemia/lymphoma, which requires demonstration of malignant cells 1

Algorithmic Approach to This Clinical Scenario

Step 1: Immediate Laboratory Evaluation

• Complete blood count with differential and peripheral blood film examination 3
• Lactate dehydrogenase (LDH) as both diagnostic marker and prognostic indicator 3
• Comprehensive metabolic panel including uric acid, calcium, phosphorus, potassium to assess for tumor lysis syndrome 3

Step 2: Interpretation of Blood Film

• If ≥1,000 circulating lymphoblasts/μL or ≥20% lymphoblasts are present: diagnosis can be established from peripheral blood alone 1
• If circulating blasts are present but insufficient for diagnosis: proceed to bone marrow examination 1
• If no blasts but significant cytopenias with high clinical suspicion: proceed to bone marrow examination 1

Step 3: Confirmatory Testing (Once Malignancy Identified)

• Bone marrow aspirate and biopsy with flow cytometry, cytogenetics, and molecular testing for complete characterization 1
• Immunophenotyping panel including CD20, CD3, CD5, CD10, CD19, CD79a, and others for accurate subtyping 3
• Chest X-ray to evaluate for mediastinal mass (common in T-cell lymphoblastic lymphoma) 3

Critical Clinical Pitfalls to Avoid

• Do not delay blood film examination in favor of bone marrow biopsy when peripheral blood may be diagnostic, especially in a sick child 1

• Do not assume normal or near-normal blood counts exclude leukemia—blood examinations can sometimes be subtle or within normal limits, particularly early in disease 4

• Do not attribute chronic lymphadenopathy and constitutional symptoms to viral infection without first excluding malignancy with blood film 1, 3

• Recognize that 6% of children with ALL are asymptomatic at diagnosis, but this child has clear symptoms warranting immediate evaluation 5

• Multiple symptoms occurring together (pallor, fever, lymphadenopathy, lethargy) should heighten suspicion for hematologic malignancy 5