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.
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.
- Fewer 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.
- The aetiology is unknown, but it is thought that some may have a genetic predisposition, with chromosome 1 or chromosome 16 being the most likely source.
- 60% of cases present in children under the age of five, and it is even occasionally diagnosed prenatally on ultrasound scan.
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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. It is found in approximately 25% of cases and is more common in patients with advanced-stage disease. Patients whose tumours have MYCN over-expression tend to have a poor prognosis, even when other low-risk factors are present.
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.
- Loss of appetite.
- Occasionally watery diarrhoea due to vaso-active intestinal polypeptide (VIP) secretion.
- Weight loss.
- 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.
- 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.
Tumours of early childhood such as:
Other conditions that may need to be considered include:
- Rheumatoid arthritis
- Disseminated bone disease
- Primary neurological disease
- Inflammatory bowel disease
- 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 96% of patients with metastases, indicating a poor prognosis.
- Computed tomography (CT) is the preferred method for assessment of tumours in the abdomen, pelvis, or mediastinum. Magnetic resonance imaging is better for paraspinal lesions, and is essential when assessing the potential for cord compression.
- 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.
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.
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 an overall survival probability of 85% to 92%.
The International Risk Group Staging System (INRGSS) has been developed to define homogeneous, pretreatment 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.
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. The addition of 13-cis-retinoic acid (isotretinoin) is sometimes beneficial in these patients.
Families with an affected child will need long-term support and may benefit from referral to specialist nurses, eg Macmillan nurses.
- 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.
- Intra-operative radiotherapy has been found to improve survival rates and causes fewer adverse effects than external beam radiotherapy.
- A further operation is often performed to remove residual disease.
- Plasmapheresis and intravenous gammaglobulin may be useful, especially in some cases with eye involvement (opsoclonus/myoclonus syndrome).
- Chemotherapy is used in inoperable cases or as an adjunct to surgery or radiotherapy. Various combinations of agents have been tried, of which the most common 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.
- Metaiodobenzylguanidine (MIBG) is a noradrenaline analogue which can be labelled with radioactive 131 iodine and used as a radiotherapeutic metabolic agent in stage 3 or stage 4 neuroectodermal tumours.
- Adrenocortical hormone (ACTH) is sometimes useful in controlling symptoms and has even been implicated in some cases of 'spontaneous' remission.
- 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.
- 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.
- Injury to major vessels or nerves.
This can be assessed by the International Risk Group Staging System (INRGSS):
- 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 2-year survival rate of 20% despite aggressive chemotherapy.
Further reading & references
- Maris JM, Hogarty MD, Bagatell R, et al; Neuroblastoma. Lancet. 2007 Jun 23;369(9579):2106-20.
- Neuroblastoma in children, Macmillan Cancer Support
- Maris JM, Weiss MJ, Mosse Y, et al; Evidence for a hereditary neuroblastoma predisposition locus at chromosome 16p12-13. Cancer Res. 2002 Nov 15;62(22):6651-8.
- Neuroblastoma, Penn State Children's Hospital
- Lacayo N et al, Pediatric Neuroblastoma, Medscape, Oct 2010
- Joyner BD et al, Neuroblastoma, Medscape, Dec 2010
- Kushner BH; Neuroblastoma: a disease requiring a multitude of imaging studies. J Nucl Med. 2004 Jul;45(7):1172-88.
- Cohn SL, Pearson AD, London WB, et al; The International Neuroblastoma Risk Group (INRG) classification system: an INRG J Clin Oncol. 2009 Jan 10;27(2):289-97. Epub 2008 Dec 1.
- Matthay KK, Villablanca JG, Seeger RC, et al; Treatment of high-risk neuroblastoma with intensive chemotherapy, radiotherapy, autologous bone marrow transplantation, and 13-cis-retinoic acid. Children's Cancer Group. N Engl J Med. 1999 Oct 14;341(16):1165-73.
- Gillis AM, Sutton E, Dewitt KD, et al; Long-term outcome and toxicities of intraoperative radiotherapy for high-risk neuroblastoma. Int J Radiat Oncol Biol Phys. 2007 Nov 1;69(3):858-64. Epub 2007 May 22.
- Mitchell WG, Davalos-Gonzalez Y, Brumm VL, et al; Opsoclonus-ataxia caused by childhood neuroblastoma: developmental and neurologic sequelae. Pediatrics. 2002 Jan;109(1):86-98.
- Russo C, Cohn SL, Petruzzi MJ, et al; Long-term neurologic outcome in children with opsoclonus-myoclonus associated with neuroblastoma: a report from the Pediatric Oncology Group. Med Pediatr Oncol. 1997 Apr;28(4):284-8.
- Procedure guidelines for 131I-meta-iodobenzylguanidine (131I-mIBG) therapy, European Association of Nuclear Medicine (2008)
- Tucker GR; Adrenocorticotropic hormone in the aetiology and regression of neuroblastoma. Med Hypotheses. 2002 Aug;59(2):117-28.
- Ikeda AK et al, Pediatric Tumor Lysis Syndrome, Medscape, Jul 2010
|Original Author: Dr Laurence Knott||Current Version: Dr Hayley Willacy|
|Last Checked: 20/04/2011||Document ID: 1711 Version: 22||© EMIS|
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