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Neuroblastoma

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Original Author(s): Dr Kathleen Duffy and Maximilian Williamson
Last updated: 16th August 2021
Revisions: 9

Original Author(s): Dr Kathleen Duffy and Maximilian Williamson
Last updated: 16th August 2021
Revisions: 9

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Introduction

Neuroblastoma is a paediatric cancer derived from neural crest cells, typically arising in the adrenal glands or abdominal sympathetic chain. It is the most common cancer in children under one year old and is much less common in those older than five.

Epidemiology

Neuroblastoma affects around 90 children per year in the UK and is the most common solid tumour in children under one year of age1. 36% of neuroblastomas arise from the medulla of the adrenal glands, with another 18% arising from the sympathetic chain. 10% are bilateral, and 10% arise from an unknown source and are first diagnosed as secondary metastases2.

Pathophysiology

Like most cancers of infancy, neuroblastoma arises from poorly differentiating embryonic cells (blasts), in this case from the neural crest. Neural crest cells are derived from developing ectoderm, and normally migrate throughout the body to form a range of structures including the sympathetic nervous system and adrenal medulla. When this migration is stalled, neural crest cells have the potential to acquire mutations that eventually lead to a neuroblastoma.

Whilst familial cases of neuroblastoma are rare, neuroblastoma tumours are associated with a specific profile of acquired genetic mutations, in particular of the MYCN and ALK oncogenes, as well as loss-of-function of the tumour suppressor PHOX2B3.

Risk Factors

The vast majority of neuroblastoma cases have no identified cause. But, as a disorder of the neural crest, neuroblastoma is classified as a neurocristopathy. It’s incidence is therefore more likely if the child has other neurocristopathies, such as Hirschsprung’s Disease or Congenital Central Hypoventilation Syndrome4,5,6 .

Clinical Features:

History

Neuroblastoma is renowned for having a diverse range of presenting symptoms. Most often, symptoms will be non-specific and include:

  • Abdominal distension
  • Fatigue
  • Appetite loss

Weight loss is a key feature to note. Other signs may pertain to increased catecholamine secretion (sweating, agitation) or metastasis (bone pain that prevents sleep, recurrent infections). Compression of the sympathetic nervous system can occasionally lead to urinary incontinence. Occasionally, neuroblastomas can arise from the thoracic portion of the sympathetic chain, causes shortness of breath and chest pain.

Examination

The classic feature of neuroblastoma is a dense abdominal swelling, which may cross the midline. These children may also be hypertensive and tachycardic due to excess catecholamine synthesis. More rarely, symptoms of metastasis can be seen, such as periorbital bruising for children with metastases to the skull base7. Similarly, neuroblastoma cells have a habit of seeding metastases in the dermis, leading to scattered purpura across the skin that give a ‘blueberry muffin’ rash, although this is non-specific8. Along with bone pain, significant bone metastases can lead to signs of bone marrow infiltration, such as evidence of recurrent infections and thrombocytopenic purpura.

Differentials

The key differentials for neuroblastoma include the differential for an abdominal mass: cysts (hepatic, polycystic kidney disease), hyperplasia (pyloric stenosis, hepatomegaly, splenomegaly) or neoplasia (Wilms’ tumour, lymphoma, rhabdomyosarcoma, hepatoblastoma). Should the child only present with a blueberry muffin rash, consider TORCH infections or acute myeloid leukaemia.

Investigations

Lab Tests

The key test to do for neuroblastoma is to look for the products of catecholamine breakdown- homovanillic acid (HVA) and vanillylmandelic acid (VMA) in urine. 90% of neuroblastoma patients will have raised HMA and VMA. Additionally, bone marrow and skin biopsies may need to be taken should there be any evidence of metastasis to these sites.

Imaging

Ultrasound is often a key point-of-care test for paediatric abdominal lumps. For further investigation, MRI would be the next choice due to the radiation hazard of CT. For thoracic neuroblastomas, the symptoms would lead you to a Chest X-ray. The definitive test for neuroblastoma is the MIBG scan. Here, a radioactive isotope of iodine is injected, and two scans are take 24 hours apart. The iodine stays in the tumour, becoming an intensely dark region on the scan. 90-95% of children with neuroblastoma will have positive features on the MIBG-scan.

Staging

Multiple different staging systems are using for neuroblastoma. The two most commonly used systems in the UK is the International Neuroblastoma Risk Group (INRG) staging system9, which uses imaging to guide the stage:

Stage

Definition

1 Fully resectable at surgery
2A Tumour is unilateral but Is not fully resectable, with no spread to local lymph nodes
2B Tumour is unilateral but is not resectable, with spread to ipsilateral lymph nodes
3 The tumour has crossed the midline, or spread to contralateral lymph nodes
4 Distant metastasis outside of local lymph nodes
4S Metastases confined to liver, skin or bone marrow in patients younger than 18 months old.

 

Alternatively, the older International Neuroblastoma Staging System10 is still used, which is guided by surgical observations:

Stage

Definition

L1 A localized tumour that does not involve vital structures (surgically resectable)
L2 A localized tumour that does involve vital structures (non-resectable)
M Distant Metastases (excludes local lymph node metastases)
MS Metastases confined to liver, skin or bone marrow in patients younger than 18 months old.

Management

In infants (<18 months old, stage MS), there is a good chance that the tumour may regress to nothing or a benign ganglioma. As such, where there is no evidence of metastasis, these infants can be monitored closely before any medical intervention is completed.

For older children, or those with aggressive disease, surgery is preferred. If staged L1, surgery may be curative. For children with stage L2 disease (affecting vital structures), adjuvant chemotherapy or radiotherapy is used.

More recently, newer treatments are becoming a recognised part of neuroblastoma management, particularly in high-risk disease. In particular, novel immunotherapies like those directed to the neuroblast cell-surface protein GD2 are becoming increasingly important11. In addition, clinical trials are just beginning in a new, indirect N-Myc proto-oncogene inhibitor, fadraciclib, in patients whose tumours show oncogenic mutations in the MYCN gene12.

Supportive care is an essential part of treatment for any child with cancer. In particular, always consider how the nausea caused by chemotherapy or radiotherapy can be better managed through anti-emetics, and how any pain can be managed with analgesia. Allied health professionals, in particular play therapists, have a key role here in providing this supportive care, and in helping the child and their family whilst they are in hospital.

Prognosis and Complications

The overall 5-year survival rate for neuroblastoma is 67%, but the prognosis itself can be highly variable depending on multiple risk factors. In particular, four key factors give an improved prognosis:

  • Younger age at diagnosis
  • Assigned female at birth
  • Lesser tumour stage at diagnosis
  • MYCN mutation absent

By age, children diagnosed before one year of age have a 5-year overall survival of 82%, compared to 43% for children diagnosed between 1-5 years old1.

The primary complication of neuroblastoma is relapse. Sadly, 40-50% of children with high-risk neuroblastoma relapse after 5 years. Relapsed neuroblastoma is often resistant to chemotherapy and radiotherapy.

An additional potential complication of neuroblastoma is opsoclonus-myoclonus ataxic syndrome (OMA syndrome). Occurring in about 2-4% of children with neuroblastoma, this is an autoimmune disorder arising from antibody self-reactivity to proteins from dying neuroblast cells, which then lead to an immune reaction to the central nervous system, in particular the cerebellum. This leads to opsoclonus (uncontrolled, irregular eye movements), myoclonus (muscle spasm) and ataxia (lack of voluntary movement control), as well as confusion and irritability13.

Summary Figure

A summary diagram of neuroblastoma. Produced using BioRender.com

Thoughts from A Parent

Nick Bird; Parent of Adam, who had neuroblastoma.

Adam died in 2013, aged 9.

“Like many parents we visited our GP and paediatric services multiple times over many months before our son was eventually diagnosed with neuroblastoma. Too often it is only once the disease is growing rapidly, causing pain or other serious issues that proper investigations are undertaken. It’s a source of many what-ifs.”

 References

No. Reference
1 Children with Cancer UK: Neuroblastoma [Internet]. [cited 2021 Mar 11]. Available from: https://www.childrenwithcancer.org.uk/childhood-cancer-info/cancer-types/neuroblastoma/
2 David R, Lamki N, Fan S, Singleton EB, Eftekhari F, Shirkhoda A, et al. The many faces of neuroblastoma. Radiographics. 1989;9(5):859–82.
3 Tolbert VP, Coggins GE, Maris JM, Maris JM. Genetic susceptibility to neuroblastoma. Curr Opin Genet Dev [Internet]. 2017;42:81–90. Available from: http://dx.doi.org/10.1016/j.gde.2017.03.008
4 Roshkow JE, Haller JO, Berdon WE, Sane SM. Hirschsprung’s Disease, Ondine’s curse, and neuroblastoma — manifestations of neurocristopathy. Paediatr Radiol. 1988;19(1):45–9.
5 Stovroff M, Dykes F, Teague WG. The complete spectrum of neurocristopathy in an infant with congenital hypoventilation, Hirschsprung’s disease, and neuroblastoma. J Pediatr Surg. 1995;30(8):1218–21.
6 Bluhm E, McNeil DE, Cnattingius S, Gridley G, Ghormli L, Fraumeni JF. Prenatal and Perinatal Risk Factors for Neuroblastoma. Int J Cancer. 2008;123(12):2885–90.
7 Timmerman R. Raccoon Eyes and Neuroblastoma. N Engl J Med. 2003;349(4):e4.
8 Mehta V, Balachandran C, Lonikar V. Blueberry Muffin Baby: A pictoral differential diagnosis. Dermatol Online J. 2008;14(2).
9 Monclair T, Brodeur GM, Ambros PF, Brisse J, Cecchetto G, Holmes K. The International Neuroblastoma Risk Group ( INRG ) Staging System : An INRG Task Force Report. J Clin Oncol. 2009;27(2):298–303.
10 Brodeur BGM, Pritchard J, Berthold F, Carlsen NLT, Castel V, Castleberry RP, et al. Revisions of the international criteria for neuroblastoma diagnosis , staging and response to treatment Revisions of the International Criteria for Neuroblastoma Diagnosis , Staging , and Response to Treatment. J Clin Oncol. 1993;11(8):1466–77.
11 Voeller J, Sondel PM. Advances in Anti-GD2 Immunotherapy for Treatment of High-Risk Neuroblastoma. J Paediatr Haematol Oncol. 2019;41(3):16-3–169.
12 New Drug Targeting High-Risk Children’s Cancer is Ready for Trials [Internet]. Institute for Cacner Research. 2020 [cited 2021 Mar 14]. Available from: https://www.icr.ac.uk/news-archive/new-drug-targeting-high-risk-children-s-cancer-is-ready-for-trials
13 Meena JP, Seth R, Chakrabarty B, Gulati S, Agrawala S, Naranje P. Neuroblastoma presenting as opsoclonus-myoclonus: A series of six cases and review of literature. J Pediatr Neurosci [Internet]. 2016;11(4):373–7. Available from: https://pubmed.ncbi.nlm.nih.gov/28217170

 

 

 

 

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