4.2 Neuroblastoma

Neuroblastoma is the most common extracranial solid tumor of childhood. It arises from neural-crest cells of the adrenal medulla or the sympathetic chain—paraspinal abdomen, thorax, neck, or pelvis. Peak incidence is infancy and the toddler years, with many diagnoses before age 2. CPHON items test the strange presentations, the catecholamine and metaiodobenzylguanidine (MIBG) workup, International Neuroblastoma Risk Group (INRG) assignment, and the high-risk modality sequence. Do not treat one cooperative-group protocol acronym as if it were the only 2026 law; teach the order of modalities.

How the tumor announces itself

A toddler’s abdominal mass may be found in the bath. Thoracic tumors cause cough, respiratory distress, or Horner syndrome (ptosis, miosis, anhidrosis) when the cervical-thoracic chain is involved. Paraspinal dumbbell tumors grow through neural foramina and cause spinal cord compression: a toddler who stops walking, develops a sensory level, or cannot empty the bladder needs emergency MRI and cord-directed therapy, not a wait-until-Monday clinic slot.

Metastatic signs are exam classics. Raccoon-eye periorbital ecchymoses reflect orbital bony metastases and are not just a fall when an abdominal mass is present. Blueberry-muffin lesions are dermal metastases, more often in infants. Opsoclonus-myoclonus syndrome (OMS)—chaotic dancing eyes, myoclonic jerks, and ataxia—is a paraneoplastic syndrome. The primary tumor may be small, but the neurologic injury can be lasting, so treat OMS as both an oncologic and a neuroinflammatory emergency. Vasoactive intestinal peptide (VIP) secretion causes watery secretory diarrhea and hypokalemia. Catecholamine effects can include hypertension and flushing, but VIP diarrhea is the board-style gastrointestinal clue.

A 15-month-old with raccoon eyes, a hard abdominal flank mass, and darting eyes is metastatic neuroblastoma until the workup says otherwise. Do not close the chart as isolated trauma when the belly is full, and do not call it Wilms tumor: Wilms does not produce raccoon-eye marrow-and-bone metastases as its signature.

Workup that assigns risk

Send urine homovanillic acid (HVA) and vanillylmandelic acid (VMA)—catecholamine metabolites. Image the primary with MRI or computed tomography, then stage with MIBG scan (neuroblastoma cells take up this norepinephrine analog), bilateral bone marrow aspirate and biopsy, and a tissue biopsy for histology, MYCN status, ploidy, and other biologic features. MIBG-negative disease needs an alternative functional study per team practice, often fluorodeoxyglucose positron-emission tomography. Do not skip marrow: cortical bone and marrow metastases define high-stage disease.

INRG risk: what actually changes treatment

INRG staging uses image-defined risk factors to label L1 (localized, no image-defined risk factors), L2 (locoregional with risk factors), M (distant metastatic), and MS (metastatic disease in children younger than 18 months limited to skin, liver, and/or limited marrow—the group formerly called 4S). Risk assignment then layers age, stage, MYCN amplification, histology (International Neuroblastoma Pathology Classification), and ploidy. MYCN-amplified tumors are treated as high-risk even when the scan looks localized. Infants with MS disease and favorable biology can do remarkably well; the same metastatic pattern in a 4-year-old with MYCN amplification is a different disease.

Localized versus metastatic is not the whole story. A perinatal infant with a small adrenal mass and favorable biology may be a candidate for observation. A preschooler with marrow and bone metastases is on a high-risk pathway. Teach families that stage without age and MYCN is an incomplete sentence.

Treatment as a sequence of modalities

Observation is appropriate for selected perinatal adrenal neuroblastomas with favorable features; serial ultrasound and urine catecholamines replace immediate resection for that carefully chosen group.

Surgery is local control for L1 and selected L2 tumors and is cytoreduction after induction in high-risk disease. Cord compression may need urgent chemotherapy, laminotomy or laminectomy, or both.

Chemotherapy is the backbone of intermediate- and high-risk treatment. Induction typically uses combinations that may include cyclophosphamide, doxorubicin, vincristine, cisplatin, and etoposide—generic names, protocol-dependent.

High-risk disease then moves to consolidation. Contemporary Children’s Oncology Group (COG)–style high-risk approaches have used tandem autologous hematopoietic stem cell transplantation (HSCT) or other intensified consolidations. After consolidation, local radiation to residual primary and selected metastatic sites is common.

Dinutuximab, a monoclonal anti-GD2 antibody, plus cytokines (granulocyte-macrophage colony-stimulating factor is the cytokine most consistently paired in current practice; interleukin-2 was used historically and is more toxic) is immunotherapy after high-risk consolidation, often with oral isotretinoin as a differentiating agent. Iodine-131 metaiodobenzylguanidine (I-131-MIBG) is a targeted radiopharmaceutical for MIBG-avid refractory or relapsed disease, not first-line therapy for a tiny perinatal L1 adrenal mass.

Anti-GD2 nursing is a CPHON skill

GD2 is expressed on neuroblastoma and on peripheral nerve. Dinutuximab therefore causes neuropathic pain during the infusion. Plan a standing opioid infusion and adjuncts per protocol; do not wait for the child to prove pain, and do not withhold analgesia because pain means it is working. Capillary leak produces edema, rapid weight gain, hypoxia, and a rising oxygen requirement. Hypotension is expected enough that blood pressure is a vital sign, not an afterthought; have fluid-bolus orders and hold parameters ready. Fever, urticaria, and true hypersensitivity also occur. Premedication, slow titration, and intensive-care-capable monitoring during early doses are standard in many centers.

I-131-MIBG adds radiation isolation, thyroid blockade so free iodide does not irradiate the thyroid, caregiver film-badge teaching, and myelosuppression that can require stem-cell backup.

A 3-week-old with a 2-cm adrenal mass and a 3-year-old with MYCN-amplified marrow disease should not leave the teaching session sounding like the same protocol. Observation versus induction, consolidation, then anti-GD2—plus pain and leak precautions for dinutuximab—is the CPHON distinction.