What is the recommended initial diagnostic workup for a child suspected of having neuroblastoma?

Neuroblastoma Initial Diagnostic Workup

For a child suspected of having neuroblastoma, obtain tissue diagnosis via surgical resection (when localized without image-defined risk factors) or core biopsy (minimum 10 cores), bilateral bone marrow aspirates and trephine biopsies, urine catecholamines, complete blood count, comprehensive metabolic panel, cross-sectional imaging (MRI or CT with contrast), and 123I-MIBG scintigraphy. 1, 2

Diagnostic Criteria

A definitive diagnosis requires meeting one of two pathways 1, 2:

• Unequivocal pathologic diagnosis from tumor tissue by light microscopy, OR
• Bone marrow aspirate/trephine biopsy showing unequivocal tumor cells (syncytia or immunocytologically positive clumps) PLUS elevated urinary catecholamine metabolites 1, 2

Tissue Sampling Strategy

Prioritize surgical resection when feasible, particularly for localized disease without image-defined risk factors 1, 2. This approach provides both diagnosis and potential cure in one procedure.

When biopsy is indicated instead of upfront resection 1, 2:

• Obtain at least 10 core biopsies or incisional biopsy >1 cm³ to ensure adequate tissue for histologic and molecular evaluation 2
• Consider open biopsy if minimally invasive techniques cannot obtain sufficient tissue 1
• Have an experienced pathologist review frozen sections immediately to confirm specimen adequacy, as samples may be necrotic 1
• Avoid fine-needle aspiration—it is inadequate 1

Essential Laboratory Testing

Obtain the following baseline studies 1, 2:

• Complete blood count with differential (assess for pancytopenia, anemia)
• Comprehensive metabolic panel (evaluate renal function, electrolytes, liver function)
• Urine catecholamines (homovanillic acid and vanillylmandelic acid)—elevated in most cases and required for diagnosis when tissue is unavailable

Bone Marrow Evaluation

Bilateral bone marrow aspirates and trephine biopsies are mandatory for initial staging 1. This bilateral approach is critical because:

• Bone marrow involvement is a hallmark of aggressive high-risk disease 1
• The International Neuroblastoma Risk Group Staging System defines ≥10% tumor cell infiltration as the threshold distinguishing metastatic disease stages 1
• Bone marrow can serve as the sole diagnostic tissue source when combined with elevated urine catecholamines 1, 2

Imaging Protocol

Primary Tumor Evaluation 1, 2

• MRI with/without contrast OR CT with contrast to evaluate soft tissue disease and define image-defined risk factors
• MRI spine with/without contrast for all paraspinal tumors (assess for intraspinal extension)
• MRI brain with/without contrast OR CT skull/orbits with contrast if neurologic symptoms present

Metastatic Disease Assessment 1, 2, 3

123I-MIBG scintigraphy is the primary metastatic imaging modality with high specificity and sensitivity for neuroblastoma 2, 3. This nuclear medicine study:

• Detects bone and soft tissue metastases with superior sensitivity compared to conventional imaging 3
• Serves as baseline for monitoring treatment response 3
• Should be performed in all cases except rare MIBG-negative tumors 3

Molecular and Histologic Characterization

Before initiating therapy, obtain 1, 2:

• Histologic classification per International Neuroblastoma Pathology Classification
• MYCN amplification status (critical prognostic factor associated with aggressive disease)
• Segmental chromosomal aberrations (1p deletion, 11q aberration)
• ALK mutation status
• Tumor ploidy (DNA index)

These molecular markers are essential for risk stratification and treatment selection 1, 2, 4.

Clinical Presentation Clues

Children typically present with 1:

• Abdominal mass or distension (most common)
• Constitutional symptoms: loss of appetite, weight loss, irritability, fever
• Metastatic manifestations: bone pain, bruising/swelling around eyes (periorbital ecchymoses), pancytopenia
• Paraspinal tumors: paralysis, constipation
• Paraneoplastic syndrome: opsoclonus-myoclonus-ataxia (rapid eye movements, ataxia, irritability)

Critical Pitfalls to Avoid

• Do not rely on fine-needle aspiration—it provides insufficient tissue for complete evaluation 1
• Do not perform unilateral bone marrow sampling—bilateral aspirates and biopsies are required 1
• Do not delay molecular testing—MYCN status and chromosomal aberrations are essential for risk classification and cannot be added later if tissue is inadequate 1, 2
• Do not skip 123I-MIBG scintigraphy—it is more sensitive than conventional imaging for detecting metastases 2, 3

Next Steps After Diagnosis

Once diagnosis is confirmed 2:

• Apply International Neuroblastoma Risk Group Staging System before treatment initiation
• Complete risk classification using age, stage, histology, MYCN status, and chromosomal aberrations to determine treatment intensity 2, 4
• Risk groups (low, intermediate, high) guide whether observation, chemotherapy, or intensive multimodal therapy is appropriate 4