What is the initial investigation to confirm the diagnosis in a child presenting with lethargy, pallor, low‑grade fever, and persistent lymphadenopathy for two months?

Bone Marrow Examination to Confirm Diagnosis

Bone marrow aspiration and biopsy is the initial investigation to confirm the diagnosis in this child with a 2-month history of lethargy, pallor, low-grade fever, and lymphadenopathy. 1

Rationale for Bone Marrow as the Confirmatory Test

The clinical presentation—chronic constitutional symptoms (lethargy, fever), cytopenias (pallor), and lymphadenopathy persisting for 2 months—strongly suggests acute lymphoblastic leukemia (ALL) or another hematologic malignancy requiring definitive marrow-based diagnosis. 1, 2

• ALL diagnosis requires ≥20% bone marrow lymphoblasts on hematopathology review of bone marrow aspirate and biopsy, which is the gold standard confirmatory threshold. 1
• The 2-month duration with progressive symptoms indicates a marrow-based process rather than isolated lymphoma, making bone marrow examination the most direct path to diagnosis. 2, 3
• Bone marrow evaluation provides comprehensive diagnostic information including morphology, immunophenotyping, cytogenetics, and molecular studies essential for risk stratification and treatment planning. 1, 3

Why Not Blood Film Alone (Option A)

While peripheral blood film is an important initial screening test, it is insufficient to confirm the diagnosis in most cases:

• Blood film can suggest leukemia when circulating blasts are present, but peripheral blood alone can only substitute for bone marrow when there is ≥1,000 circulating lymphoblasts per microliter or ≥20% lymphoblasts with significant circulating disease. 1, 2
• Many children with ALL present with cytopenias without significant circulating blasts, requiring bone marrow examination for definitive diagnosis. 2, 3
• The chronic presentation (2 months) with pallor suggests possible marrow infiltration that may not be fully reflected in peripheral blood. 2, 4

Why Not Virology Screening (Option B)

Virology screening is not a confirmatory diagnostic test for the suspected hematologic malignancy:

• Viral testing (EBV, CMV) is targeted for specific scenarios such as post-transplant lymphoproliferative disorder or immunocompromised patients, not for initial diagnosis of suspected leukemia. 2
• The clinical picture of progressive pallor, lymphadenopathy, and constitutional symptoms over 2 months points to malignancy rather than viral infection. 1, 4
• Hepatitis B screening is performed before treatment initiation if chemotherapy is planned, not as a diagnostic test. 2

Diagnostic Algorithm for This Clinical Scenario

Step 1 – Initial Blood Work:

• Obtain complete blood count with differential, peripheral blood smear, lactate dehydrogenase, and comprehensive metabolic panel. 2, 3
• If blood shows very high white cell count with abundant circulating lymphoblasts meeting the threshold criteria, diagnosis may be established from blood alone. 1, 2

Step 2 – Proceed Directly to Bone Marrow:

• In this case with chronic symptoms and likely cytopenias (pallor), bone marrow aspiration and biopsy should be performed immediately to achieve definitive diagnosis. 1, 2, 3
• Bone marrow evaluation must include morphology with cytochemistry, comprehensive immunophenotyping with flow cytometry, cytogenetic analysis (karyotyping and/or FISH), and molecular genetics. 1

Step 3 – Additional Staging:

• Lumbar puncture to evaluate for CNS involvement should be performed at diagnosis (unless contraindicated by coagulopathy or severe thrombocytopenia). 1
• Lymph node biopsy is reserved only for cases where bone marrow shows <20% blasts yet clinical suspicion for lymphoma remains high. 1, 2

Critical Pitfalls to Avoid

• Do not delay bone marrow examination in favor of lymph node biopsy when hepatosplenomegaly and constitutional symptoms point toward leukemia rather than isolated lymphoma. 2
• Do not rely solely on peripheral blood film unless the specific criteria of very high white cell count with abundant circulating blasts are definitively met. 1, 2
• Do not perform lumbar puncture if the patient has severe thrombocytopenia or coagulopathy until the bleeding risk is corrected. 1
• Be aware that normal or near-normal blood counts do not exclude leukemia—some children present with subtle hematologic abnormalities that evolve over time, requiring bone marrow examination for diagnosis. 5, 6