Neuroblastoma

• Applies to children who have a tumour in only one place. Surgeons can remove all of it that they can see.

Stage 2 is divided into 2A and 2B

• 2A applies to children who have a tumour in only one place. Surgeons cannot remove all of it that they can see.
• 2B applies to children who have a tumour in only one place and cancer cells in nearby lymph nodes. Doctors may or may not be able to remove all of the tumour.

Stage 3 applies to children who have any one of these:

• A tumour that doctors cannot remove all the way. The tumour has spread to the other side of the body and maybe to nearby lymph nodes.
• A tumour that doctors cannot remove all the way and that is in the middle of the body. It has spread to both sides of the body (in lymph nodes or other structures).
• A tumour in one place on one side of the body. Cancer also is found in lymph nodes on the other side of the body.

Stage 4 

• Stage 4 applies to children whose tumour has spread to distant lymph nodes or other parts of the body.

Signs and symptoms

The first symptoms of neuroblastoma are often vague making diagnosis difficult. Fatigue, loss of appetite, fever, and joint pain are common. Symptoms depend on primary tumour locations and metastases if present:

• In the abdomen, a tumour may cause a swollen belly and constipation.
• A tumour in the chest may cause breathing problems.
• A tumour pressing on the spinal cord may cause weakness and thus an inability to stand, crawl, or walk.
• Bone lesions in the legs and hips may cause pain and limping.
• A tumour in the bones around the eyes or orbits may cause distinct bruising and swelling.
• Infiltration of the bone marrow may cause pallor from Anemia.

Neuroblastoma often spreads to other parts of the body before any symptoms are apparent and 50 to 60% of all neuroblastoma cases present with metastases.

The most common location for neuroblastoma to originate (i.e., the primary tumour) is in the adrenal glands. This occurs in 40% of localised tumours and in 60% of cases of widespread disease. Neuroblastoma can also develop anywhere along the sympathetic nervous system chain from the neck to the pelvis. Frequencies in different locations include: neck (1%), chest (19%), abdomen (30% non-adrenal), or pelvis (1%). In rare cases, no primary tumour can be discerned.

Rare but characteristic presentations include transverse myelopathy (tumour spinal cord compression, 5% of cases), treatment-resistant diarrhea (tumour vasoactive intestinal peptide secretion, 4% of cases), Horner's syndrome (cervical tumour, 2.4% of cases), opsoclonus myoclonus syndrome and ataxia (suspected paraneoplastic cause, 1.3% of cases), and hypertension (catecholamine secretion or renal artery compression, 1.3% of cases).

Cause

The cause of neuroblastoma is not well understood. The great majority of cases are sporadic and non-familial. About 1–2% of cases run in families and have been linked to specific gene mutations. Familial neuroblastoma in some cases is caused by rare germline mutations in the anaplastic lymphoma kinase (ALK) gene. Germline mutations in the PHOX2A or KIF1B gene have been implicated in familial neuroblastoma as well. Neuroblastoma is also a feature of neurofibromatosis type 1 and the Beckwith-Wiedemann syndrome.

MYCN oncogene amplification within the tumor is a common finding in neuroblastoma. The degree of amplification shows a bimodal distribution: either 3- to 10-fold, or 100- to 300-fold. The presence of this mutation is highly correlated to advanced stages of disease.

Duplicated segments of the LMO1 gene within neuroblastoma tumor cells have been shown to increase the risk of developing an aggressive form of the cancer.

Neuroblastoma has been linked to copy-number variation within the NBPF10 gene, which results in the 1q21.1 deletion syndrome or 1q21.1 duplication syndrome.

Several risk factors have been proposed and are the subject of ongoing research. Due to characteristic early onset many studies have focused on parental factors around conception and during gestation. Factors investigated have included occupation (i.e. exposure to chemicals in specific industries), smoking, alcohol consumption, use of medicinal drugs during pregnancy and birth factors; however, results have been inconclusive.

Other studies have examined possible links with atopy and exposure to infection early in life, use of hormones and fertility drugs, and maternal use of hair dye.

Treatment

When the lesion is localized, it is generally curable. However, long-term survival for children with advanced disease older than 18 months of age is poor despite aggressive multimodal therapy (intensive chemotherapy, surgery, radiation therapy, stem cell transplant, differentiation agent isotretinoin also called 13-cis-retinoic acid, and frequently immunotherapy with anti-GD2 monoclonal antibody therapy).

Biologic and genetic characteristics have been identified, which, when added to classic clinical staging, has allowed patient assignment to risk groups for planning treatment intensity. These criteria include the age of the patient, extent of disease spread, microscopic appearance, and genetic features including DNA ploidy and N-myc oncogene amplification (N-myc regulates microRNAs), into low, intermediate, and high risk disease. A recent biology study (COG ANBL00B1) analyzed 2687 neuroblastoma patients and the spectrum of risk assignment was determined: 37% of neuroblastoma cases are low risk, 18% are intermediate risk, and 45% are high risk. (There is some evidence that the high- and low-risk types are caused by different mechanisms, and are not merely two different degrees of expression of the same mechanism.)

The therapies for these different risk categories are very different.

• Low-risk disease can frequently be observed without any treatment at all or cured with surgery alone.
• Intermediate-risk disease is treated with surgery and chemotherapy.
• High-risk neuroblastoma is treated with intensive chemotherapy, surgery, radiation therapy, bone marrow / hematopoietic stem cell transplantation, biological-based therapy with 13-cis-retinoic acid (isotretinoin or Accutane) and antibody therapy usually administered with the cytokines GM-CSF and IL-2.

With current treatments, patients with low and intermediate risk disease have an excellent prognosis with cure rates above 90% for low risk and 70–90% for intermediate risk. In contrast, therapy for high-risk neuroblastoma the past two decades resulted in cures only about 30% of the time. The addition of antibody therapy has raised survival rates for high-risk disease significantly. In March 2009 an early analysis of a Children's Oncology Group (COG) study with 226 high-risk patients showed that two years after stem cell transplant 66% of the group randomized to receive ch14.18 antibody with GM-CSF and IL-2 were alive and disease-free compared to only 46% in the group that did not receive the antibody. The randomization was stopped so all patients enrolling on the trial will receive the antibody therapy.

Chemotherapy agents used in combination have been found to be effective against neuroblastoma. Agents commonly used in induction and for stem cell transplant conditioning are platinum compounds (cisplatin, carboplatin), alkylating agents (cyclophosphamide, ifosfamide, melphalan), topoisomerase II inhibitor (etoposide), anthracycline antibiotics (doxorubicin) and vinca alkaloids (vincristine). Some newer regimens include topoisomerase I inhibitors (topotecan and irinotecan) in induction which have been found to be effective against recurrent disease.

Prognosis

Between 20% and 50% of high-risk cases do not respond adequately to induction high-dose chemotherapy and are progressive or refractory. Relapse after completion of frontline therapy is also common. Further treatment is available in phase I and phase II clinical trials that test new agents and combinations of agents against neuroblastoma, but the outcome remains very poor for relapsed high-risk disease.

Most long-term survivors alive today had low or intermediate risk disease and milder courses of treatment compared to high-risk disease. The majority of survivors have long-term effects from the treatment. Survivors of intermediate and high-risk treatment often experience hearing loss. Growth reduction, thyroid function disorders, learning difficulties, and greater risk of secondary cancers affect survivors of high-risk disease. An estimated two of three survivors of childhood cancer will ultimately develop at least one chronic and sometimes life-threatening health problem within 20 to 30 years after the cancer diagnosis.

Epidemiology

Neuroblastoma comprises 6–10% of all childhood cancers, and 15% of cancer deaths in children. The annual mortality rate is 10 per million children in the 0- to 4-year-old age group, and 4 per million in the 4- to 9-year old age group.

The highest incidence is in the first year of life, and some cases are congenital. The age range is broad, including older children and adults, but only 10% of cases occur in people older than 5 years of age. A large European study reported less than 2% of over 4000 neuroblastoma cases were over 18 years old.

Refractory and relapsed neuroblastoma

Microscopic view of a NB cell line (SH-SY5Y) used in preclinical research for testing new agents

Some children (particularly in high-risk cases) do not respond completely to frontline treatment (with a complete response or very good partial response) and are labeled refractory. These children are removed from the frontline therapy (clinical trial) and are eligible for clinical trials using new therapies. Many high-risk children have a good response to frontline therapy and achieve a remission, but later the disease recurs (relapse). These children are also eligible for new therapies being tested in clinical trials.

Chemotherapy with topotecan and cyclophosphamide is frequently used in refractory setting and after relapse. A randomized study (2004) with 119 patients (comparing topotecan alone to topotecan and cyclophosphamide) revealed a 31% complete or partial response rate with two-year progression-free survival at 36% in the topotecan and cyclophosphamide group. Irinotecan (intravenous or oral) and oral temozolomide are also used in refractory and recurrent neuroblastoma.

Many phase I and phase II trials are currently testing new agents against neuroblastoma in children who have relapsed or are resistant to initial therapy. Investigators are currently studying new agents, alone and in new combinations, using small molecule targeted therapy, 131-I MIBG radiation therapy, angiogenesis agents, new monoclonal antibodies, vaccines, oncolytic viruses, as well as new myeloablative regimens.

A group of 16 children's hospitals in the United States known as the New Advances in Neuroblastoma Therapy (NANT) consortium coordinates the I-131 MIBG radiation therapy trials. The NANT consortium also offers trials using an oral powder formulation of fenretinide, intravenous fenretinide, bisphosphonate (Zometa) with other agents, and combining I-131 MIBG with the inhibitor vorinostat.

The SIOPEN group investigated a new delivery method for anti-GD2 antibody ch14.18/CHO given as long term continuous infusion mostly combined with cytokine IL2 (Ref 1) in order to achieve a better tolerated treatment regimen.

Other research study groups such as The Neuroblastoma and Medulloblastoma Translational Research Consortium (NMTRC) also conduct clinical trials to treat relapse neuroblastoma. Institutions in Europe are studying novel therapies to treat relapse, including haploidentical stem cell transplant. Many hospitals conduct their own institutional studies as well.

The protein p53 is believed to play a role in the development of resistance to chemotherapy. A November 2009 study in mice shows that activating the tumor suppressor p53 with a new drug, nutlin-3, may slow tumor growth. In this study, physician Tom Van Maerken of Ghent University Hospital in Belgium and his colleagues used nutlin-3 to neutralize MDM2, a protein that binds to the p53 protein and obstructs p53's ability to trigger programmed cell death. Earlier studies have shown that nutlin-3 can specifically prevent MDM2 from disabling p53.

How neuroblastoma is diagnosed

A variety of tests and investigations may be needed to diagnose neuroblastoma. These include a biopsy, blood and bone marrow tests, x-rays, CT or MRI scans, and special nuclear medicine scans called MIBG scans (see below). The tests are done to find out if your child definitely has neuroblastoma and what the exact position of the original tumour site is within the body. The tests will also find out whether the neuroblastoma has spread. This process is known as staging (see below).
VMA and HVA tests

A specific type of urine test will also be done. Nearly all children with neuroblastoma (9 out of 10) will have the substances vanillylmandelic acid (VMA) or homovanillic acid (HVA) in their urine. Measuring the VMA and HVA in the urine can help to confirm the diagnosis. Your child will also have their VMA and HVA levels checked during and after treatment. The levels of these substances will fall if the treatment is working. As these chemicals are produced by the tumour cells, and can be used to measure tumour activity, they are sometimes known as tumour markers.

MIBG scans

Most children will have an MIBG (metaiodobenzyl guanidine) scan. MIBG is a substance that's taken up by neuroblastoma cells. It's given by injection. Attaching a small amount of radioactive iodine to the MIBG enables the tumours to be seen by a radiation scanner. MIBG can also be used as a treatment.

Biopsy

A small sample of cells is usually taken from the tumour during an operation under a general anaesthetic. This is known as a biopsy. These cells are then examined under a microscope.

Other tests, collectively referred to as tumour biology, are also carried out on these
cells in the laboratory. These tests look at the chromosomes and 'biological markers' in the tumour cells. One of these 'markers' is called MYCN. The presence of a certain amount of MYCN in the cells (known as MYCN amplification) can suggest that the neuroblastoma may be a more aggressive type. In this situation, the treatment needs to be more intensive. 

Staging of neuroblastoma 

The stage of a cancer is a term used to describe its size and whether it has spread beyond its original site. Knowing the particular type and stage of the cancer helps the doctors to decide on the best treatment for your child.

A commonly used staging system for neuroblastoma is described below.

Stage 1

The cancer is contained within one area of the body (localised) and there's no evidence of it having spread. It can be completely removed by surgery, or there may be very small (microscopic) amounts of tumour left after surgery.

Stage 2A

The cancer is localised and has not begun to spread, but it cannot be completely removed by surgery.

Stage 2B

The cancer is localised and has begun to spread into nearby lymph nodes.

Stage 3

The cancer has spread into surrounding organs and structures, but has not spread to distant areas of the body.

Stage 4

The cancer has spread to distant lymph nodes, bone, bone marrow, the liver, the skin or other organs.

Stage 4S (also called special neuroblastoma)

This is found in children under one year old. The cancer is localised (as in stage 1, 2A or 2B) but has begun to spread to the liver, skin or bone marrow.

A newer staging system has been developed by the International Neuroblastoma Risk Group (INRG). This system (described below) is beginning to be used more widely. It looks at whether or not certain 'image-defined risk factors' are present in a neuroblastoma tumour before treatment. These risk factors can be detected by scans and help doctors understand the extent of the disease. Your doctor can explain more about this.

Stage L1

The tumour is localised and has not spread into important areas (vital structures) nearby. It can be removed by surgery.

Stage L2

The tumour is localised but has 'image-defined risk factors' and can't be safely removed by surgery.

Stage M

The tumour has spread to other parts of the body.

Stage MS

The tumour has spread to the skin, liver and/or the bone marrow in children younger than 18 months old.

If the cancer has spread to distant parts of the body, this is known as secondary or metastatic cancer.

If the cancer comes back after initial treatment, this is known as recurrent or relapsed cancer.

Treatment for Neuroblastoma 

The treatment of neuroblastoma depends on the age of the child, the size and position of the tumour, the tumour biology (including the MYCN status) and whether the neuroblastoma has spread.

Surgery

For tumours that have not spread (localised tumours), the treatment is usually surgery. If the tumour is at an early stage and there's no evidence that it has spread to the lymph nodes or any other parts of the body, an operation to remove the tumour, or as much of it as possible, will be done.

A cure is usually possible for children with localised tumours. However, if the tumour is classed as high-risk due to the tumour biology results, further treatment with chemotherapy and possibly radiotherapy will be needed. If the tumour is, at first, too large or in too difficult a position to remove safely, chemotherapy will be given to shrink it before surgery.

Chemotherapy

If the tumour has already spread by the time of diagnosis, or is indicated as being high-risk by the tumour biology result, intensive chemotherapy is needed. Chemotherapy is the use of anti-cancer (cytotoxic) drugs to destroy cancer cells. It's usually given as a drip  or injection into a vein. Your child's specialist will discuss with you the type and amount of chemotherapy needed.

High-dose chemotherapy with stem cell support

If the neuroblastoma has spread to several parts of the body, or is high-risk with MYCN amplification, high-dose chemotherapy with stem cell support is used after the initial courses of chemotherapy.

High doses of chemotherapy wipe out any remaining neuroblastoma cells, but they also wipe out the body's bone marrow, where blood cells are made. To prevent the problems this causes, stem cells (blood cells at their earliest stages of development) are collected from your child through a drip before the chemotherapy is given. These stem cells are then frozen and stored.

After the chemotherapy, the stem cells are given back to your child through a drip. They make their way into the bone marrow, where they grow and develop into mature blood cells over a period of 14-21 days.

Monoclonal antibody treatment

Monocolonal antibodies can destroy some types of cancer cells while causing little harm to normal cells. A new monoclonal antibody treatment called anti-GD2 is currently being tested in people with high-risk neuroblastoma. Children in the UK with high-risk neuroblastoma are being given anti-GD2 as part of a clinical trial. There is good evidence from a clinical trial carried out in America in 2009 that this may be a promising therapy when given alongside other standard treatment for neuroblastoma.

It is not yet a standard treatment for people with neuroblastoma because it has very unpleasant side effects. The benefits still need to be fully proven and the best way to administer it needs to be confirmed. Patients with high-risk neuroblastoma may be able to receive anti-GD2 in the UK if they are being treated within the European high-risk clinical trial. 

Your child's specialist will be able to tell you more about this treatment.

Radiotherapy

External radiotherapy may be given if the neuroblastoma is high-risk, or has spread to several parts of the body. This uses high-energy rays to destroy the cancer cells, while doing as little harm as possible to normal cells. External radiotherapy is given from a machine outside the body.

Internal radiotherapy may sometimes be given using radioactive MIBG (metaiodobenzyl guanidine). Radioactive MIBG is similar to the MIBG used in an investigation to diagnose a neuroblastoma (see above), but uses higher doses of radioactivity to kill the cancer cells.

Younger children

Children under 18 months old with neuroblastoma often have low-risk tumours, and as long as there is no MYCN amplification, their outlook is good. Most children in this age group are cured.

Children with stage 4S disease almost always get better with very little treatment or none at all. These tumours either regress spontaneously or after chemotherapy, which is only given if the tumour is causing symptoms. They disappear completely or develop into a non-cancerous (benign) tumour, called a ganglioneuroma. Many of these children, after their initial diagnostic tests and staging investigations, will just need careful monitoring for some years.

Ganglioneuromas are usually harmless and will not cause any problems or need any treatment.

Side effects of treatment for neuroblastoma Treatment often causes side effects, and your child’s doctor will discuss this with you before the treatment starts. Any possible side effects will depend on the actual treatment being given and the part of the body that is being treated. Side effects can include:

• feeling sick (nausea) and being sick (vomiting)
• diarrhoea
• hair loss
• increased risk of infection
• bruising and bleeding
• tiredness.

Late side effects 

A small number of children may develop late side effects, sometimes many years after treatment. These include a change in the way the heart and kidneys work, hearing problems, fertility problems, a possible reduction in bone growth if radiotherapy has been given, and a slightly increased risk of developing another cancer in later life.

Your child’s doctor or nurse will talk to you about any possible late side effects. There's more detailed information about these late side effects in the section on children’s cancers.

Clinical trials 

Many children have their treatment as part of a clinical research trial. Trials aim to improve our understanding of the best way to treat an illness, usually by comparing the standard treatment with a new or modified version. Specialist doctors organise many trials for children's cancers.

Children in the UK with neuroblastoma can take part in national and European studies. The European research group is called SIOPEN.

If appropriate, your child's medical team will talk to you about taking part in a clinical trial, and will answer any questions you have. Written information is provided to help explain things.

Taking part in a research trial is completely voluntary, and you'll be given plenty of time to decide if it's right for your child.

Follow-up 

Follow-up after treatment usually involves regular visits to the hospital outpatients department, with scans and urine tests as necessary. For children who have had chemotherapy and/or radiotherapy, more specialised tests may be carried out. For example, hearing tests, kidney and heart function tests, and checking hormone levels. These will be repeated until your child has grown up.

If you have specific concerns about your child’s condition and treatment, it's best to discuss them with your child’s doctor, who knows their situation in detail.

Your feelings 

Your teams of doctors and nurses are there to help support your child and family as well as carry out treatments. It is important to discuss any difficulties you may be having with your treatment team.

The section on children’s cancers talks about the emotional impact of caring for an unwell child and suggests sources of help and support. It also discusses the range of powerful emotions your child may experience throughout their illness, including how you can support your child.

Our booklet Katie’s Garden is a storybook for primary school-age children about a girl's experience of cancer.

Useful organisations 

Children's Cancer and Leukaemia Group (CCLG)

CCLG coordinates research and care for children and their parents. There are 21 CCLG specialist centres for the treatment of childhood cancer and leukaemia, covering all areas of the UK and Ireland (there's a map of the centres on the website). The website also has information about the CCLG, childhood cancer and leukaemia.

CLIC Sargent

CLIC Sargent offers practical support to children and young people with cancer or leukaemia, and to their families.

Neuroblastoma Society

The Neuroblastoma Society offers an opportunity for parents to give each other mutual help, support and comfort. It has an information booklet, which can be downloaded from its website.

Neuroblastoma Children's Cancer Alliance UK (The NCCA UK)

The Neuroblastoma Children’s Cancer Alliance UK (NCCA UK) helps families affected by the childhood cancer neuroblastoma. The NCCA UK’s supports access to the best treatment available internationally for children with neuroblastoma, as well as research, education and awareness initiatives.

References and thanks 

This information has been compiled using a number of reliable sources, including:

• Voute PA, et al. Cancer in Children: Clinical Management. 5th edition. Oxford University Press. 2005.
• Pinkerton R, et al. Evidence-based paediatric oncology. 2nd edition. Blackwell Publishing. 2007
• Gilman, et al. A Phase 3 randomised trial of the chimeric anti-GD2 antibody ch14.18 with GM-CSF and IL2 as immunotherapy following dose-intensive chemotherapy for high-risk neuroblastoma: A Children's Oncology Group (COG) study ANBL0032. Journal Clinical Oncology. 2009. 27.15.
• Matthey, et al. Long-Term Results for Children With High-Risk Neuroblastoma Treated on a Randomized Trial of Myeloablative Therapy Followed by 13-cis-Retinoic Acid: A Children's Oncology Group Study. Journal of Clinical Oncology. 2009. 27.7 1007-10013

With thanks to Dr Kate Wheeler, Consultant Paediatric Oncologist, and the people affected by cancer who reviewed this edition.

Reviewing information is just one way of the ways you could help when you join our Cancer Voices network.