Neuroblastomas

What is a neuroblastoma?¹

Neuroblastoma is a cancer that arises in cells derived from the neural crest, and tumours can develop at any site in the sympathetic nervous system. Neuroblastoma is an embryonal neoplasm that is predominantly a disease of early childhood.

Neuroblastoma is the most common extracranial solid tumour in children. Most children are diagnosed under the age of 5 years, with a median age at diagnosis of 17 months.

The neuroblastoma originates most commonly in the adrenal or paraspinal sites. Metastases are present in approximately 60% at the time of diagnosis.

How common are neuroblastomas? (Epidemiology)

• Fewer than 100 children are diagnosed with neuroblastoma each year in the UK. However, neuroblastomas are the most common extracranial solid tumour of childhood.²

• Neuroblastoma is the third most common paediatric cancer. Although neuroblastoma accounts for 7% of paediatric malignancies, it is responsible for more than 10% of childhood cancer-related deaths.³

• 90% of those diagnosed are under the age of 5, with a peak age of incidence of 2-3.⁴

• The aetiology is unknown. Several genes have been shown to be associated with familial neuroblastoma.⁵

• Neuroblastoma is occasionally diagnosed prenatally on ultrasound scan.

Pathogenesis

Chromosomal and molecular abnormalities have been identified in patients with neuroblastoma. These markers are used to assess prognosis and have been included into the strategies used for a risk group staging system - see below. The most important of these is the oncogene MYCN. Amplification of the MYC family member (MYCN) is found in about 25% of cases and correlates with high-risk disease and poor prognosis. MYCN is the most established genetic marker of risk in neuroblastoma.²

Symptoms of neuroblastomas (presentation)¹

Presentation is usually quite late and the majority of symptoms and signs occur either due to the mass effect of the tumour or as a result of metastases.

Clinical symptoms vary depending on the location of the primary tumour, and may include an abdominal mass, abdominal pain, respiratory distress, or neurological symptoms from spinal cord involvement.

Children with metastatic disease often appear ill at diagnosis, with fever, bone pain, and weight loss.

While in some cases of neuroblastoma, lesions may regress spontaneously, in others, the disease may behave aggressively, with many patients having recurrent/refractory metastatic disease.

Symptoms

• Loss of appetite.

• Occasionally watery diarrhoea due to vaso-active intestinal polypeptide (VIP) secretion.

• Vomiting.

• Weight loss.

• Fatigue.

• Bruising due to pancytopenia as a result of marrow infiltration.

• Periorbital bruising - 'racoon eyes' (due to metastatic disease in the orbits).

• Weakness, limping, paralysis and bladder and bowel dysfunction due to spinal cord compression from paraspinal sympathetic tumours.

• Bone pain (due to bone metastases).

• Permanent cognitive deficits - rare.

Signs

• Mild fever.

• Abdominal distension due to enlarged liver.

• Hypertension - due to pressure on the renal artery.

• Horner's syndrome due to thoracic lesion.

• Primary cervical neuroblastoma is rare but may result in a mass in the neck.

• 'Blueberry muffin baby' - occurs in neonates; metastases cause severe skin involvement, resulting in a characteristic appearance.

Opsoclonus myoclonus syndrome (dancing eye syndrome) is characterised by opsoclonus, myoclonus and ataxia, usually with behavioural difficulties. It is rare but is associated with neuroblastomas in children.⁶

Differential diagnosis

Tumours of early childhood such as:

• Rhabdomyosarcoma.

• Lymphoma.

• Neuroectodermal tumour.

• Wilms' tumour.

Other conditions that may need to be considered include:

• Osteomyelitis.

• Rheumatoid arthritis.

• Disseminated bone disease.

• Primary neurological disease.

• Inflammatory bowel disease

Diagnosing neuroblastomas (investigations)⁷

Diagnosis can usually be confirmed by urine catecholamines and imaging. However, biopsy of the primary site (or bone marrow for staging purposes) is required to establish biology and risk stratification.⁸

Initial laboratory tests

• FBC - may detect anaemia.

• ESR may be raised.

• Coagulation tests:
  

  • Prothrombin time and partial thromboplastin time may be abnormal once liver involvement occurs.

  • Thrombocytopenia may occur if deposits overwhelm the bone marrow.

  • Catecholamine by-products can be detected in the urine of patients with neuroblastoma. These include:
    

    • Homovanillic acid (HVA) and vanillylmandelic acid (VMA). A low VMA-to-HVA ratio is consistent with a poorly differentiated tumour and indicative of a poor prognosis.

    • Neuron-specific enolase (NSE) - elevated levels can be demonstrated in most patients with metastases, indicating a poor prognosis.

The ultimate diagnosis of neuroblastoma can be confirmed either by tumour tissue biopsy with histopathological diagnosis or by the combination of either elevated urine or serum catecholamine levels or a positive MIBG scan plus a bone marrow aspirate or biopsy with detectable tumour cells.

The evaluation to determine the disease stage in children with neuroblastoma commonly includes imaging of the primary tumour site with CT or MRI to determine primary tumour size and regional invasion and spread as well as additional imaging of the chest, abdomen, and pelvis to identify spread to another distant site.

Meta-iodobenzylguanidine (MIBG) scans can be used to detect primary tumours and metastatic sites, with approximately 90% of patients having MIBG-avid tumours. For those patients who do not have MIBG-avid disease, [18 F]-fluorodeoxyglucose positron emission tomography (FDG-PET) scans are recommended for detecting metastatic disease.

Either head CT or brain MRI imaging should also be performed when intracranial metastases are suspected or when otherwise clinically indicated.

In addition to imaging studies, bone marrow aspirates and biopsies from at least two independent sites are generally obtained to determine tumour involvement.

Staging

The International Neuroblastoma Staging System (INSS) was developed as a prognostic and research tool. Localised tumours were divided into stages 1, 2 and 3, according to regional lymph node involvement and whether the tumour infiltrates across the midline or is resectable. All patients over the age of 1 with distant involvement were categorised as stage 4.

Almost half of all patients presenting with neuroblastoma are stage 3 or stage 4 at diagnosis but, if those patients have a favourable tumour genome and histology, they may still fall into the low-risk category with a very good overall survival.

The International Risk Group Staging System (INRGSS) has been developed to define homogeneous, pre-treatment patient cohorts to facilitate accurate comparison in risk-based clinical trials. Clinical and biological factors were combined to define low, intermediate, high (4 groups) or ultra-high risk.⁹

Management of neuroblastomas

Treatment varies from observation alone for certain low risk patients to intense multimodal therapy for high risk patients.⁸

Modern protocols, including induction chemotherapy, surgical resection, high-dose chemotherapy with autologous stem cell rescue (ASCR), external beam radiotherapy (EBRT), and immunotherapy or differentiating agents, have improved outcomes, with 3-year survival rates now exceeding 60%.¹

Families with an affected child will need long-term support and may benefit from referral to specialist nurses - eg, Macmillan nurses.

Complications of neuroblastomas

At presentation

• Cord compression from paraspinal tumour.

• Severe hypertension.

• Renal insufficiency.

During or after chemotherapy

• Myelosuppression and immunosuppression.

• Impaired renal function.

• Hearing loss.

• Tumour lysis syndrome - hyperkalaemia, hyperuricaemia, hyperphosphataemia.

Surgical complications

• Haemorrhage.

• Intussusception.

• Injury to major vessels or nerves.

Prognosis

Neuroblastoma may cause a broad spectrum of clinical features ranging from spontaneous regression to fatal outcome despite aggressive treatment.¹⁰

Modern treatments have improved outcomes, with 3-year survival rates now exceeding 60%.¹ However, children with neuroblastoma have widely divergent outcomes, ranging from cure in more than 90% of patients with low risk disease to below 50% for those with high risk disease.⁷

The clinical outcome remains poor in patients with high-risk neuroblastoma, in which chemo-resistant relapse is common following high-intensity conventional treatment.¹¹

Prognosis can be assessed using the International Neuroblastoma Risk Group Staging System (INRGSS) and incorporating segmental chromosome aberrations as an additional genomic biomarker.¹²