Neuroblastoma

Neuroblastoma is the commonest extracranial solid tumour of childhood. It arises from primitive neural crest cells of the sympathetic nervous system, most commonly in the adrenal medulla or along the sympathetic chain (paraspinal ganglia, extending from the neck through the pelvis).

It is a remarkably heterogeneous malignancy. Some tumours regress spontaneously without treatment, particularly a favourable pattern in infants. Others are highly aggressive, metastatic and carry a poor prognosis despite intensive multimodal treatment.

Risk stratification uses age, stage, and tumour biological and genetic features, most notably MYCN oncogene amplification status. It is the central framework guiding treatment intensity and prognosis.

Pathophysiology and risk stratification

• Neuroblastoma arises from incompletely differentiated neural crest cells that would normally mature into sympathetic ganglion cells or adrenal medullary chromaffin cells.
• The degree of tumour cell differentiation, together with molecular and genetic features, informs tumour behaviour and prognosis.
• MYCN oncogene amplification is the single most important adverse prognostic genetic marker. It is associated with aggressive biology, rapid progression and poor response to standard treatment, and it informs risk stratification and treatment intensity regardless of other staging factors.
• Age at diagnosis is a further critical prognostic factor. Infants (generally under eighteen months of age) have a substantially more favourable prognosis than older children with comparable disease.
• This reflects more favourable tumour biology in the younger age group and spontaneous regression, which can occur in a subset of infants with low-risk disease, including stage 4S disease.
• This is a distinct pattern of metastatic disease confined to skin, liver and limited bone marrow involvement in infants. Despite its metastatic classification it carries a paradoxically favourable prognosis, with substantial capacity for spontaneous regression.

• Presenting features vary with the primary tumour location and the extent of any metastatic disease.
• An abdominal mass, reflecting an adrenal or retroperitoneal primary tumour, is the commonest presentation. It is often the first feature identified, sometimes incidentally by a parent or on routine examination.
• Systemic symptoms are common additional features, including fever, weight loss and irritability.
• Bone pain reflects metastatic bony involvement. It is common at presentation because disease is often advanced at diagnosis, particularly in older children.
• Significant bone marrow infiltration causes pallor and bruising from cytopenias.
• Horner syndrome occurs with a cervical or upper thoracic sympathetic chain primary tumour.
• Spinal cord compression occurs when a paraspinal tumour extends through the neural foramina into the spinal canal. It is an oncological emergency requiring urgent recognition and treatment.
• In infants with stage 4S disease, characteristic features are hepatomegaly and bluish, non-tender subcutaneous nodules ("blueberry muffin" appearance) from cutaneous metastases.
• Opsoclonus-myoclonus-ataxia syndrome is a distinctive paraneoplastic presentation. This immune-mediated neurological syndrome produces rapid, chaotic eye movements with myoclonus and ataxia, and is associated with a generally low-risk, favourable tumour.
• The neurological syndrome itself can have significant, sometimes persistent long-term neurodevelopmental impact even after successful tumour treatment.
• Secretory diarrhoea is a further paraneoplastic presentation, reflecting vasoactive intestinal peptide secretion by the tumour.
• Catecholamine metabolite production by the tumour can cause hypertension and, occasionally, flushing or sweating episodes. This reflects the tumour's origin from sympathetic neural tissue and is directly relevant to the diagnostic biomarker.

• Elevated urinary catecholamine metabolites (vanillylmandelic acid and homovanillic acid) are a valuable, relatively non-invasive diagnostic biomarker. They are elevated in the substantial majority of confirmed cases and support both diagnosis and disease monitoring.
• Cross-sectional imaging (computed tomography or magnetic resonance imaging) characterises the primary tumour and its relationship to surrounding structures.
• Meta-iodobenzylguanidine (MIBG) scintigraphy is a valuable functional imaging modality, because the radiolabelled catecholamine analogue is selectively taken up by the substantial majority of neuroblastomas. It supports primary tumour characterisation and staging for metastatic disease.
• Tissue biopsy with histopathological and molecular genetic characterisation is an essential part of diagnosis and staging. It includes assessment of MYCN amplification status, which bears directly on risk stratification.
• Bone marrow aspiration and biopsy assess marrow involvement.
• Staging combines the imaging and bone marrow assessment with other investigations according to the clinical presentation. It supports formal risk stratification by stage, age and tumour biological features, which informs the individualised treatment approach.

• Treatment intensity is guided by formal risk stratification (low, intermediate or high risk, based on stage, age, MYCN amplification status and other factors).
• Low-risk disease is frequently managed with surgical resection alone. In selected infants with favourable, low-risk disease, including stage 4S presentation, observation alone is used because of the substantial capacity for spontaneous regression.
• Intermediate-risk disease is generally managed with surgical resection and a moderate-intensity chemotherapy regimen. Intensity and duration are individualised to the risk features present.
• High-risk disease requires intensive, multimodal treatment: induction chemotherapy, surgical resection of the primary tumour, high-dose chemotherapy with autologous stem cell rescue, and radiotherapy to the primary tumour site.
• Maintenance treatment is anti-GD2 monoclonal antibody immunotherapy (dinutuximab, targeting a ganglioside antigen expressed on neuroblastoma cells) combined with isotretinoin.
• This is a prolonged, intensive course, reflecting the less favourable prognosis of this risk category.
• Spinal cord compression at diagnosis is an oncological emergency requiring urgent treatment to prevent permanent neurological injury. Treatment is typically chemotherapy, because neuroblastoma responds rapidly, or in selected cases surgical decompression.
• Long-term follow up covers disease surveillance and the late effects of intensive treatment, including ototoxicity, endocrine dysfunction and secondary malignancy risk. These are particularly relevant after high-risk regimens.
• Psychosocial support for the child and family throughout the often prolonged treatment course underpins management of this diverse childhood malignancy.