Neuroblastoma

Neuroblastoma is a rare and aggressive cancer that develops from immature nerve cells called neuroblasts, which are part of the sympathetic nervous system. It most commonly starts in the adrenal glands, which sit on top of the kidneys, but it can also develop in nerve tissue in the neck, chest, abdomen, or pelvis.

Neuroblastoma is the most common solid cancer in infants and young children outside the brain. It is most frequently diagnosed in children under the age of five, with the peak diagnosis occurring around one to two years of age. It is very rarely diagnosed in adults.

The disease can behave very differently depending on:

• The child’s age at diagnosis
• The location of the tumour
• Genetic characteristics of the tumour
• How far it has spread

In some very young infants, certain forms of neuroblastoma can shrink or disappear on their own without treatment. In others, particularly children with high-risk disease, neuroblastoma is one of the most challenging childhood cancers to treat.

Because neuroblastoma is a cancer of the neuroendocrine system and children with Neuroblastome would be referred to Cancer Hub and Neuroblastoma Australia.

Understanding neuroblastoma

The sympathetic nervous system is a network of nerve cells that helps regulate many automatic body functions, including heart rate, blood pressure, digestion, and the body’s response to stress.

During normal development, immature nerve cells called neuroblasts gradually mature into functioning nerve cells or other specialised tissues. In neuroblastoma, some neuroblasts fail to mature properly. Instead, they multiply uncontrollably and form a tumour.

Because neuroblasts are present throughout the developing sympathetic nervous system, neuroblastoma can arise in many locations in the body. However, the adrenal medulla (the inner part of the adrenal gland), which develops from neural crest cells and contains neuroendocrine cells, is the most common primary site.

Neuroblastoma cells often retain some features of the neuroendocrine system, including the ability to produce certain hormones and chemicals. This has important implications for both diagnosis and treatment.

Where neuroblastoma develops

The most common site for neuroblastoma is the adrenal gland, accounting for approximately 40 per cent of cases. The adrenal glands sit on top of each kidney and produce hormones including adrenaline and noradrenaline.

Neuroblastoma can also arise in the:

• Abdomen, along the nerve chains running alongside the spine
• Chest, particularly in younger infants
• Neck
• Pelvis

In some cases, neuroblastoma is first detected because of spread to lymph nodes, bones, bone marrow, liver, or skin before the primary tumour has been identified.

Causes and risk factors

Neuroblastoma arises from genetic changes that occur in developing nerve cells, either during foetal development or shortly after birth. These changes prevent neuroblasts from maturing normally, causing them to multiply and form tumours.

The vast majority of neuroblastoma cases occur by chance, with no identifiable inherited cause. Only approximately one to two per cent of neuroblastoma cases are linked to an inherited genetic mutation, which means that a family history of neuroblastoma is uncommon.

No specific environmental exposures, maternal health factors, or lifestyle causes have been identified as contributing factors to neuroblastoma.

Familial neuroblastoma

In the rare cases where neuroblastoma does run in families, it is often associated with mutations in the ALK gene or PHOX2B gene. Familial neuroblastoma may present at a younger age and can sometimes involve multiple tumour sites.

Genetic counselling is recommended for families where an inherited cause is suspected.

Symptoms of neuroblastoma

The symptoms of neuroblastoma vary widely depending on the size and location of the tumour and whether it has spread.

General symptoms

• A firm lump or swelling in the abdomen, neck, or chest
• Unexplained weight loss or poor weight gain
• Persistent fever without a clear cause
• Fatigue, pallor, or general irritability
• Loss of appetite

Symptoms related to bone spread

• Bone pain or tenderness
• Limping or refusal to walk or bear weight
• Joint swelling

Eye-related symptoms

• Dark circles around the eyes, sometimes called “raccoon eyes” (periorbital bruising)
• Bulging or protrusion of one or both eyes (proptosis)
• A drooping upper eyelid, a smaller pupil, or reduced sweating on one side of the face (Horner syndrome), which can occur when a tumour in the neck or chest presses on nearby nerve pathways

Neurological symptoms

• Weakness, numbness, or difficulty moving limbs if the tumour presses on the spinal cord
• Back pain in older children
• Bladder or bowel changes if the tumour presses on nearby structures

Hormone-related symptoms

Because neuroblastoma cells can produce hormones and other chemicals, some children develop symptoms caused by these substances, including:

• High blood pressure
• Rapid heart rate
• Persistent diarrhoea
• Sweating or flushing of the skin

These symptoms are more common when the tumour is large or has spread.

Associated syndromes

In some children, neuroblastoma can trigger rare but distinctive medical conditions.

Opsoclonus-Myoclonus-Ataxia Syndrome (OMS)

OMS is sometimes called “Dancing Eyes, Dancing Feet” syndrome. It is a rare autoimmune condition in which the immune system produces antibodies that mistakenly attack normal nerve tissue while fighting the tumour.

Symptoms include:

• Rapid, irregular, and involuntary eye movements (opsoclonus)
• Sudden jerky muscle movements (myoclonus)
• Unsteadiness and poor coordination (ataxia)
• Irritability and behavioural changes

OMS can persist or recur even after the neuroblastoma is treated. It requires specialist neurological management alongside oncology care.

Paraneoplastic syndromes

Because neuroblastoma cells originate from neuroendocrine tissue, some tumours secrete hormones and proteins that cause systemic effects, including:

• Persistent watery diarrhoea
• Flushing of the skin
• Sweating
• High blood pressure

These effects are known as paraneoplastic syndromes and may improve with treatment of the tumour.

Diagnosis of neuroblastoma

Diagnosing neuroblastoma and assessing its extent involves a combination of blood tests, urine tests, imaging, tissue sampling, and specialised nuclear medicine scans.

1. Urine and blood tests

Neuroblastoma cells produce catecholamines; hormones including adrenaline and noradrenaline. These break down into compounds called homovanillic acid (HVA) and vanillylmandelic acid (VMA), which are measured in urine.

Elevated HVA and VMA levels are found in the majority of children with neuroblastoma and are a key part of the diagnostic workup.

2. Imaging

Imaging is used to locate the primary tumour and identify any spread.

Tests may include:

• Ultrasound: often the first investigation when an abdominal mass is suspected
• CT scan: provides detailed imaging of the tumour, lymph nodes, and abdomen
• MRI: particularly useful for assessing spinal cord involvement or soft tissue detail
• Chest X-ray or CT: if chest involvement is suspected

3. MIBG scan

A meta-iodobenzylguanidine (MIBG) scan is a specialised nuclear medicine test. It uses a small amount of radioactive tracer that is specifically absorbed by neuroblastoma cells, allowing the disease to be mapped throughout the entire body.

MIBG scanning is a cornerstone of neuroblastoma staging and is also used to monitor treatment response. A positive MIBG scan in the appropriate clinical setting strongly supports the diagnosis of neuroblastoma.

4. Tissue biopsy

A biopsy is taken from the primary tumour to confirm the diagnosis and test for important biological features. These include:

• MYCN gene amplification: when the MYCN gene is amplified, it drives more aggressive tumour behaviour and is associated with high-risk disease
• Tumour histology (how the cells look under the microscope)
• Other chromosomal and molecular features that influence risk classification

5. Bone marrow biopsy

A bone marrow biopsy checks whether neuroblastoma cells have spread to the bone marrow. This is an important part of staging, particularly for children with suspected metastatic disease.

Staging of neuroblastoma

Neuroblastoma is staged using the International Neuroblastoma Risk Group Staging System (INRGSS), which classifies tumours based on imaging characteristics rather than surgical findings alone.

Stages are broadly described as:

• L1: Localised tumour without image-defined risk factors (features that make surgery more complex or risky)
• L2: Localised tumour with one or more image-defined risk factors
• M: Metastatic disease (spread to distant lymph nodes, bones, bone marrow, liver, lungs, or other sites)
• MS: Metastatic special – a unique category for infants under 18 months with spread confined to the liver, skin, or bone marrow. Some MS tumours regress spontaneously.

Risk stratification

Neuroblastoma is classified into risk groups, low, intermediate, and high, based on the child’s age, tumour stage, tumour biology (including MYCN status), and histology. The risk group determines the treatment approach.

Low-risk neuroblastoma

Low-risk neuroblastoma includes small, localised tumours without aggressive biological features. In some infants, particularly those with MS stage disease, the tumour may shrink and disappear on its own without active treatment – a phenomenon called spontaneous regression.

Treatment may involve:

• Active observation with close monitoring
• Surgical removal of the tumour when appropriate

Intermediate-risk neuroblastoma

Intermediate-risk disease involves larger localised tumours or tumours that have spread to regional lymph nodes but without high-risk biological markers.

Treatment usually involves:

• Surgery
• Moderate-intensity chemotherapy

High-risk neuroblastoma

High-risk neuroblastoma includes advanced metastatic disease or tumours with MYCN amplification. It accounts for approximately 40 to 50 per cent of neuroblastoma cases and is the most challenging to treat.

Treatment is intensive and typically involves multiple phases:

• Induction chemotherapy: to shrink the primary tumour and disease at other sites
• Surgery: to remove as much of the primary tumour as possible
• High-dose chemotherapy with autologous stem cell rescue: intensive chemotherapy followed by return of the child’s own stem cells to restore bone marrow function
• Radiation therapy: to the primary tumour site and sometimes other areas
• Immunotherapy: anti-GD2 antibodies such as dinutuximab target a protein (GD2) found on the surface of neuroblastoma cells, helping the immune system destroy remaining cancer cells
• Differentiation therapy: isotretinoin (13-cis-retinoic acid) is given after consolidation to encourage remaining neuroblastoma cells to mature and stop dividing
• Maintenance therapy: emerging agents such as eflornithine (DFMO) are used in some settings to reduce the risk of relapse

Treatment for high-risk neuroblastoma is typically delivered over many months and coordinated by specialist paediatric oncology teams.

Targeted and emerging therapies

Research has produced several targeted treatments now used in neuroblastoma care.

Anti-GD2 immunotherapy

GD2 is a protein expressed on the surface of neuroblastoma cells. Monoclonal antibodies targeting GD2 (including dinutuximab and naxitamab) help the immune system identify and attack neuroblastoma cells. Anti-GD2 therapy has become a standard part of high-risk neuroblastoma treatment.

ALK inhibitors

Mutations in the ALK gene are present in approximately 10 to 15 per cent of neuroblastoma cases. Targeted therapies called ALK inhibitors, including lorlatinib, are being studied and used in selected children whose tumours carry ALK mutations.

DFMO (eflornithine)

Eflornithine (DFMO) is a maintenance therapy that blocks polyamine synthesis: a process neuroblastoma cells rely on for growth. It has been approved for post-consolidation maintenance in high-risk neuroblastoma in some countries and is being evaluated in clinical trials.

CAR T-cell therapy

Clinical trials are investigating the use of chimeric antigen receptor (CAR) T-cell therapies in neuroblastoma. These approaches involve genetically modifying a child’s own immune cells to recognise and attack neuroblastoma cells.

Eligibility for specific therapies and clinical trials should be discussed with the treating paediatric oncology team.

Spontaneous regression

One of the most remarkable features of neuroblastoma is that some tumours (particularly in very young infants) can spontaneously shrink and disappear without any treatment. This is most commonly seen in infants with MS stage disease and in some localised low-risk tumours.

The biological mechanisms underlying spontaneous regression in neuroblastoma are an active area of research. Not all low-risk tumours will regress, so careful monitoring is required to determine whether active treatment is needed.

Late effects of treatment

Children who are treated for high-risk neuroblastoma may face significant long-term health effects from intensive treatment. These are known as late effects and can affect multiple body systems.

Understanding the risk of late effects helps guide long-term follow-up and health monitoring.

Hearing loss

Hearing loss is one of the most common late effects, affecting a significant proportion of high-risk neuroblastoma survivors. It is primarily caused by platinum-based chemotherapy drugs such as cisplatin, which can damage the hearing structures of the inner ear. Regular hearing assessments are an important part of long-term follow-up.

Growth and endocrine effects

High-dose chemotherapy and radiation can affect the hormonal systems that regulate growth and development. Late effects may include:

• Growth failure or short stature
• Hypothyroidism (underactive thyroid)
• Delayed or disrupted puberty
• Reduced bone density

Long-term monitoring by an endocrinologist may be needed.

Organ function

Some children experience long-term effects on:

• Heart function: certain chemotherapy agents can affect the heart muscle over time
• Lung function: radiation to the chest can reduce lung capacity
• Kidney function: platinum-based chemotherapy and some other agents can affect kidney filtration

Secondary cancers

A small proportion of long-term survivors of high-risk neuroblastoma may develop a different type of cancer later in life, related to the intensive treatments received. This includes a risk of blood cancers such as acute myeloid leukaemia. Regular long-term follow-up is important for early detection.

Neurodevelopmental effects

Children treated for neuroblastoma, particularly those who received intensive or cranial-directed therapies, may be at higher risk of:

• Learning difficulties
• Attention and concentration problems
• Anxiety and emotional difficulties
• Challenges with peer relationships and social development

Educational support, psychological assessment, and school liaison are important components of comprehensive survivorship care.

Living with neuroblastoma: for families and carers

A neuroblastoma diagnosis is one of the most confronting experiences a family can face. The rarity and complexity of the disease, the intensive nature of treatment, and the uncertainty about outcomes can create enormous emotional and practical strain.

Families may need support with:

• Understanding the diagnosis, risk group, and treatment plan
• Managing treatment side effects and hospital admissions
• Supporting siblings and other family members
• Navigating schooling, employment, and financial impacts
• Connecting with other families who have experience with neuroblastoma
• Preparing for and managing the transition to long-term follow-up

Many families find that connecting with specialised support services makes a significant difference during and after treatment.

Follow-up and surveillance

Follow-up after neuroblastoma treatment depends on the risk group, treatment received, and response to therapy.

Surveillance typically includes:

• Regular physical and neurological review
• Urine and blood tests for HVA and VMA
• Neck and abdominal imaging
• MIBG or PET scanning when indicated
• Hearing assessments
• Growth and endocrine monitoring
• Cardiac and kidney function assessments
• Neurodevelopmental review
• Psychological and educational support assessment

Children who have completed treatment for high-risk neuroblastoma require long-term follow-up through survivorship programmes at specialist paediatric oncology centres.

Research and future directions

Research into neuroblastoma is advancing rapidly, with a growing focus on targeted and immunological therapies that can improve outcomes while reducing the toxicity of treatment.

Important areas of ongoing research include:

• Refining risk stratification using molecular and genetic tumour profiling
• Better understanding of the biology of spontaneous regression
• Developing more effective and less toxic induction chemotherapy regimens
• Expanding the use of targeted immunotherapy including anti-GD2 agents
• ALK inhibitor trials in ALK-mutant neuroblastoma
• CAR T-cell therapy for relapsed or refractory disease
• Novel maintenance strategies to reduce relapse risk
• Improved management of late effects and long-term survivorship
• Understanding and treating OMS and other associated syndromes

Australia participates in international clinical trials through collaborative paediatric oncology groups. Families should speak with their treating team about whether any clinical trials may be relevant.

Support available through NeuroEndocrine Cancer Australia

A diagnosis of neuroblastoma brings enormous challenges for children and their families. NeuroEndocrine Cancer Australia provides support for families affected by neuroblastoma, including:

• Referral to Neuroblastoma Australia and Cancer Hub
• Access to the NET Nurse service
• Support from NET specialist counsellor
• Patient and carer information and resources
• Education about neuroendocrine cancer
• Support for navigating rare cancer care
• Guidance on questions to ask the treating team
• Connection to specialist information and support pathways

For support, information, and guidance after a neuroblastoma diagnosis, contact NeuroEndocrine Cancer Australia.

References

1. Brodeur GM, Bagatell R. Mechanisms of neuroblastoma regression. Nat Rev Clin Oncol. 2014 https://pubmed.ncbi.nlm.nih.gov/25331179/
2. Maris JM. Recent advances in neuroblastoma. N Engl J Med. 2010 https://pubmed.ncbi.nlm.nih.gov/20558371/
3. Cohn SL, Pearson AD, London WB, et al. The International Neuroblastoma Risk Group (INRG) classification system: an INRG Task Force report. J Clin Oncol. 2009. https://pubmed.ncbi.nlm.nih.gov/19047291/
4. Yu AL, Gilman AL, Ozkaynak MF, et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med. 2010. https://pubmed.ncbi.nlm.nih.gov/20879881/
5. Matthay KK, Maris JM, Schleiermacher G, et al. Neuroblastoma. Nat Rev Dis Primers. 2016 https://pubmed.ncbi.nlm.nih.gov/27830764/
6. Pinto NR, Applebaum MA, Volchenboum SL, et al. Advances in risk classification and treatment strategies for neuroblastoma. J Clin Oncol. 2015 https://pubmed.ncbi.nlm.nih.gov/26304901/
7. Mosse YP, Lim MS, Voss SD, et al. Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children’s Oncology Group phase 1 consortium study. Lancet Oncol. 2013 https://pubmed.ncbi.nlm.nih.gov/23598171/
8. 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. N Engl J Med. 1999 https://pubmed.ncbi.nlm.nih.gov/10519894/
9. London WB, Castel V, Monclair T, et al. Clinical and biologic features predictive of survival after relapse of neuroblastoma: a report from the International Neuroblastoma Risk Group project. J Clin Oncol. 2011 https://pubmed.ncbi.nlm.nih.gov/21768459/
10. Pearson AD, Pinkerton CR, Lewis IJ, et al. High-dose rapid and standard induction chemotherapy for patients aged over 1 year with stage 4 neuroblastoma: a randomised trial. Lancet Oncol. 2008 https://pubmed.ncbi.nlm.nih.gov/18308250/
11. Bagatell R, Cohn SL. Genetic discoveries and treatment advances in neuroblastoma. Curr Opin Pediatr. 2016. https://pubmed.ncbi.nlm.nih.gov/26626486/
12. Cheung NK, Dyer MA. Neuroblastoma: developmental biology, cancer genomics and immunotherapy. Nat Rev Cancer. 2013 https://pubmed.ncbi.nlm.nih.gov/23702928/
13. Laverdière C, Liu Q, Yasui Y, et al. Long-term outcomes in survivors of neuroblastoma: a report from the Childhood Cancer Survivor Study. J Natl Cancer Inst. 2009 https://pubmed.ncbi.nlm.nih.gov/19648511/
14. Ambros PF, Ambros IM, Brodeur GM, et al. International consensus for neuroblastoma molecular diagnostics: report from the International Neuroblastoma Risk Group (INRG) Biology Committee. Br J Cancer. 2009 https://pubmed.ncbi.nlm.nih.gov/19401703/