Neuroblastomas

• Neuroblastoma is an embryonal neoplasm and is predominantly a disease of early childhood.¹
• Other than brain tumours it is the most common solid tumour of childhood and is currently responsible for the highest number of disease related deaths in pre-school age children.²
• The neuroblastoma originates from sympathetic nervous tissue most commonly in the adrenal or paraspinal sites.
• Metastases are present in approximately 60% at the time of diagnosis.

• Less than 100 children are diagnosed with neuroblastoma each year in the UK.
• 90% of those diagnosed are under the age of 5 with a peak age of incidence of 2-3.³
• The aetiology is unknown, but is thought that some may have a genetic predisposition with chromosome 1 or chromosome 16 being the most likely source.⁴
• 60% of cases present in children under the age of five and it is even occasionally diagnosed pre-natally on ultrasound scan.⁵

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)
• Cerebellar ataxia and myoclonus - rare
• 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, results in a characteristic appearance

The differential diagnosis includes other tumours of early childhood such as :

• Rhabdomyosarcoma
• Lymphoma
• Neuroectodermal tumour
• Wilms' Tumour

Depending on presentation, other conditions that may need to be considered include:

• Osteomyelitis
• Rheumatoid arthritis
• Disseminated bone disease
• Primary neurologic disease
• Inflammatory bowel disease

Laboratory tests

• Full blood count - this may detect anaemia.
• ESR may be raised.
• Coagulation tests -
  • Prothrombin time and partial thromboplastin time may be abnormal once liver involvement occurs.
  • Thrombocytopaenia may occur when once 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 96% of patients with metastases, indicating a poor prognosis.

Radio-imaging

• Plain abdominal X-ray may be a useful initial screening test for any child with an abdominal mass.
• Ultrasound will help to further assess the site and size of any intra-abdominal tumour and any abnormalities of the urogenital tract. Small flecks of calcification may be seen in the abdomen or posterior mediastinum.
• MRI⁸ and CT scanning may add further information regarding is the site of primary or secondary tumours.
• Bone scan may be used to assess secondary lesions. A compound called metaiodobenzylguanidine (MIBG) is taken up specifically by catecholaminergic cells and can help to detect metastatic disease in bones as well as soft tissue. If this is negative but metastases are clinically suspected, technetium bone scan may be helpful.

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.

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 4.⁶

More recently, an attempt has been made to introduce some international uniformity. This is important both to compare treatment strategies and because modern treatment is very much tailored to the risk classification of individual patients. The result has been the development of the International Risk Group Staging System (INRGSS). Clinical and biological factors were combined to define low, intermediate, high (4 groups) or ultra-high-risk.⁹

Non-drug

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

Drug⁷

• Plasmapheresis and intravenous gammaglobulin may be useful, especially in some cases with eye involvement (opisclonus/myoclonus syndrome).^10,11
• Chemotherapy is used in inoperable cases or as an adjunct to surgery or radiotherapy. Various combinations of agents have been tried, of which the commonest are carboplatin, cyclophosphamide, doxorubicin and etoposide. The duration of treatment can vary from 6 to 24 weeks. More severe cases (25-30% survival) may also be treated with high dose cisplatin and ifosfamide in addition to this regime.
• Adrenocortical hormone (ACTH) is sometimes useful in controlling symptoms and has even been implicated in some cases of 'spontaneous' remission.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.

Surgery⁷

• Surgical removal of the tumour alone may be used in some low risk tumours (90% survival), but more commonly surgery is combined with chemotherapy.
• An initial laparotomy is usually performed, to determine an accurate diagnosis, remove all of the primary tumor and provide accurate staging.
• Intra-operative radiotherapy has been found to improve survival rates and causes less adverse effects than external beam radiotherapy.¹³
• A further operation is often performed to remove residual disease.

Modern management is tailored to the risk stratification of individual patients. In basic terms:

• 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 multiagent chemotherapy, surgery and radiotherapy, followed by consolidation with high-dose chemotherapy and peripheral blood stem cell rescue. The addition of 13-cis-retinoic acid (isotretinoin) is sometimes beneficial in these patients.¹⁴

Complications at presentation

• Cord compression from paraspinal tumour
• Severe hypertension
• Renal insufficiency

Complications during or after chemotherapy

• Myelosuppression and immunosuppression
• Impaired renal function
• Hearing loss
• Tumour lysis syndrome - hyperkalemia, hyperuricaemia, hyperphosphataemia and other metabolic abnormalities¹⁵

Surgical complications

• Haemorrhage
• Intussusception
• Injury to major vessels or nerves

• The prognosis varies with the age of the patient, the site of the primary, the stage of the disease, lymph node involvement and the tumour histology.
• 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 and may have prolonged disease free periods. Older children with advanced disease may have a 2 year survival rate of 20% despite aggressive chemotherapy.
• Neuroblastoma in adolescence or adulthood has a more prolonged course, 50 % achieving a minimal disease state with aggressive chemotherapy, but the long term prognosis remains poor. A few lesions will spontaneously regress or mature into benign lesions.
• It is hoped that further work on the histopathological types of neuroblastoma, the genetic factors and governing tumour growth and the biological markers produced by such genetic aberration will help to refine the determination of prognosis in individual patients.^16,17