Neuroblastomas

Neuroblastoma is a solid tumour that arises from the developing sympathetic nervous system.^[1]Neuroblastoma is an embryonal neoplasm that is predominantly a disease of early childhood. It is the most common extracranial, solid neoplasm and is responsible for 7% of malignancies in patients younger than 15 years and around 15% of all paediatric oncology deaths.^[2]

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

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.^[3]
• 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.^[4]
• 90% of those diagnosed are under the age of 5, with a peak age of incidence of 2-3.^[5]
• The aetiology is unknown. Several genes have been shown to be associated with familial neuroblastoma.^[6]
• 60% of cases present in children under the age of 5 and it is even occasionally diagnosed prenatally on ultrasound scan.^[7]

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.^[3]

Presentation

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.

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.^[8]

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

Investigations

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.

Radio-imaging

• Computed tomography (CT) is the preferred method for assessment of tumours in the abdomen, pelvis, or mediastinum. Magnetic resonance imaging (MRI) is better for paraspinal lesions and is essential when assessing the potential for cord compression.^[9]
• Bone scan may be used to assess secondary lesions. Metaiodobenzylguanidine (MIBG) is taken up specifically by catecholaminergic cells and can help to detect metastatic disease in bones as well as in soft tissue. If this is negative but metastases are clinically suspected, technetium bone scan may be helpful.^[2]

Procedures

Biopsy of the lesion or of deposits in bone marrow are necessary in order to make a definitive diagnosis.

For an unequivocal diagnosis, the following must apply:

• Light microscopy of tumour biopsy samples with or without electron microscopy plus increased catecholamine levels or immunohistology.
• Identification of tumour cells from bone marrow aspirate and increased levels of serum or urinary catecholamines.

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.^[10]

Management

Modern management is tailored to the risk stratification of individual patients:

• Low-risk patients are simply observed for spontaneous resolution or are treated with local resection.
• Intermediate-risk patients may be offered multimodal therapy including surgery, chemotherapy and radiation therapy.
• High-risk patients are given multi-agent chemotherapy, surgery and radiotherapy, followed by consolidation with high-dose chemotherapy and peripheral blood stem cell rescue.

General points

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

Surgery

• Most localised neuroblastomas have favourable biological features and most are successfully treated with surgery alone. More commonly, surgery is combined with chemotherapy.
• An initial laparotomy is usually performed to determine an accurate diagnosis, remove all of the primary tumour and provide accurate staging.
• Intraoperative radiotherapy has been found to improve survival rates and causes fewer adverse effects than external beam radiotherapy.^[11]
• A further operation is often performed to remove residual disease.

Medical

• Chemotherapy is used in inoperable cases or as an adjunct to surgery or radiotherapy. Various combinations of agents have been tried, particularly carboplatin, cyclophosphamide, doxorubicin and etoposide. The duration of treatment can vary from 6 to 24 weeks. More severe cases may also be treated with high-dose cisplatin and ifosfamide in addition to this regime.
• MIBG is a noradrenaline (norepinephrine) analogue which can be labelled with radioactive 131 iodine and used as a radiotherapeutic metabolic agent in stage 3 or stage 4 neuroectodermal tumours.^[12]
• Other therapies currently being investigated include biological response modifiers, anti-angiogenesis agents which inhibit blood vessel growth in the more vascular neuroblastomas and targeted immunotherapy.

Complications

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.^[13]The clinical outcome remains poor in patients with high-risk neuroblastoma, in which chemo-resistant relapse is common following high-intensity conventional treatment.^[14]

Prognosis can be assessed by the INRGSS:^[10]

• Children of any age (with localised disease) and children under the age of 1 at presentation (with advanced disease) tend to respond well to treatment. They may have prolonged disease-free periods. A few lesions will spontaneously regress or mature into benign lesions.
• Neuroblastoma in adolescence or adulthood has a more difficult and prolonged course. 50% achieve a minimal disease state with aggressive chemotherapy but the long-term prognosis remains poor. Older children with advanced disease may have a two-year survival rate of 20% despite aggressive chemotherapy.^[2]