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Neuroblastoma – 2016

UPDATED FEBRUARY 2016

1. General information

1.1 What is the disease and how is it treated?

What is neuroblastoma?
Neuroblastoma is a malignant childhood tumour that develops from immature nerve cells. It may arise in several body areas, including the adrenal glands (atop the kidneys), other areas of the abdomen, near the spine, in the chest, in the neck, or in the pelvis.

What are the causes of the disease?
Neuroblastoma arises when immature nerve cells (called neuroblasts) do not become mature, normal nerve cells, but keep multiplying and form a tumour. This process is caused by genetic mutations, which are being discovered and studied. It is not clear what causes these mutations, but exposure of parents to certain chemicals, drugs, and other agents before the child’s birth seems to increase the risk.

Is it a frequent disease?
Neuroblastoma is a very rare tumour. However, it is the most frequent solid tumour in children aged less than 5 years.

How is it treated?
In infants sometimes neuroblastoma disappears spontaneously, so in some cases your doctor may choose a wait-and-see approach. Treatment may include a combination of surgery, chemotherapy, radiotherapy, biological therapy and blood stem cell transplantation.

2. What is it, how does it occur, how is it diagnosed?

2.1 What is Neuroblastoma?

Neuroblastoma is a malignant tumour arising in the sympathetic nervous system, a part of the autonomic nervous system. The sympathetic nervous system includes nerves and ganglia placed along the spine, and some hormone-producing cells similar to nerve cells located inside the adrenal glands (atop the kidneys). Neuroblastoma arises from immature nerve cells called neuroblasts, which during normal development in the foetus and in early infancy multiply and then become mature nerve cells, unable to multiply. If neuroblasts fail to mature appropriately and begin multiplying uncontrollably, they may form a tumour, and may spread to other parts of the body. Sometimes, especially in young infants with small tumours which cause no major symptoms, these abnormal neuroblasts finally disappear or mature spontaneously into normal nerve cells and stop dividing, so the tumour goes away on its own without treatment.
Neuroblastoma most commonly arises in children up to 5 years of age, but it may occur in older children, too. Sometimes it forms before birth. The term “neuroblastoma” is usually employed – though inaccurately – to encompass a wider family of childhood tumours derived from immature nerve cells, which include the following: proper neuroblastoma, a malignant tumour; ganglioneuroblastoma, a mix of malignant and benign cells, whose diagnosis and treatment are similar to those of neuroblastoma; and ganglioneuroma, a benign tumour which usually requires no treatment beyond surgical removal.

2.1.1 Genetic anomalies

The abnormal behaviour of neuroblastoma cells is due to changes (mutations) in their DNA. Only in very few cases are these changes inherited from a parent and can be transmitted to one’s children; this condition is called familial neuroblastoma. In most cases, the gene changes happen during early development of the child.
Scientists are investigating which mutations cause neuroblastoma, what these genes do normally in the nerve cells, and if the presence or absence of some mutations may help in predicting the likely outcome of neuroblastoma and choosing a specific treatment. The following is an overview of mutations that have already been identified as having a role in neuroblastoma and prospects for the future.

2.1.1.1 MYCN oncogene

At least 20% of neuroblastoma patients have extra copies of the MYCN oncogene, and this percentage is even higher in patients with stage 4 disease (see section 4 below, Stages of neuroblastoma). The presence of extra copies of a gene is called gene amplification. MYCN amplification plays a crucial role in the tumour’s aggressiveness; several studies show that it promotes tumour growth and progression, leading to a poor prognosis both in patients with localized tumours and in high-risk patients with disseminated cancer, who have a faster progression than those without MYCN amplification.

2.1.1.2 Genomic abnormalities

Neuroblastoma cells often show chromosomal abnormalities, such as an extra chromosome, a missing chromosome, or the gain or loss of a part of a chromosome. These chromosomal aberrations alter gene activity and have been found to predict a poor prognosis. Several kinds of abnormalities may be found in a patient, and they may affect prognosis differently according to the number and kinds of abnormalities present and factors such as patient age and localized or metastatic cancer. Studies (such as the Low-Intermediate Neuroblastoma European Study) are being performed to better evaluate how these aberrations affect patient risk. The most frequent abnormalities include chromosome 1p deletion; chromosome 17q gain; and chromosome 11q loss.

2.1.1.3 The evolution of nanotechnology and sequencing of the neuroblastoma genome

Our ability to detect gene and chromosome anomalies, both in normal and cancer cells, has been improving quickly thanks to new technologies. So, while in the 1990s it was possible to look only for a few specific anomalies (such as MYCN oncogene amplification), in the last decades it has become possible to search for a wider range of abnormalities. Nowadays technologies routinely employed to evaluate patients (e.g., array CGH) allow us to identify several kinds of anomalies, but they cannot discover certain small mutations that can dramatically change the behaviour of the tumour.
In research studies, scientists have already sequenced the full genome of hundreds of neuroblastomas and stored the data in public databases, making it possible to identify the damaging mutation even when only a single base of DNA is changed, and to predict the damage made by the altered protein coded by this mutated DNA. We foresee that in the near future each patient will undergo a new analysis, next-generation sequencing, performed by advanced nanotechnological instruments, which is able to sequence the whole genome of neuroblastoma cells and detect even small mutations. This could make it possible to tailor therapy based on the specific anomalies of each patient’s cancer, getting better results especially in advanced, hard-to-treat cases.

2.1.1.4 Gene expression abnormalities

In addition to mutations (changes in gene sequence), the activity of several genes is altered in neuroblastoma, with some genes being too active and others not active enough, and these anomalies drive the growth of tumour cells. In the last decade, the activity of thousands of genes has been analyzed in a large number of tumours, showing which alterations are typical of neuroblastoma and, specifically, which genes are too active or not active enough in cancers with a better or worse prognosis (what is known as “gene signatures” associated with favourable or unfavourable tumour progression). However, analysis of gene activity is more difficult and less reliable than analysis of gene mutations, so it is presently being used only in research and not in routine patient evaluation and prognostication.
An altered expression in some neuroblastomas has been found for three groups of genes: TRK, CD44, and ALK.
A group of genes involved in neuroblastoma belong to the TRK gene family, which contributes to the regulation of growth, differentiation, and death of neurons. At least three genes in this family – TRKA, TRKB, and TRKC – have some role in neuroblastoma development. Among these, the best known is TRKA. Tumour cells expressing TRKA tend to disappear spontaneously or to become normal, mature neurons and stop dividing, so these tumours tend to have a favourable outcome.
CD44 is a protein involved in a variety of functions in several tissues. It is widely expressed in ganglioneuroblastoma and in some forms of neuroblastomas. In neuroblastoma a higher CD44 expression leads to better survival and, conversely, a lack of this protein often leads to poor survival.
Children with a form of lymphoma (anaplastic large cell lymphoma) have an altered gene called ALK (the anaplastic lymphoma kinase gene), created by the fusion of two different genes because of a chromosome anomaly. The ALK gene acts as an oncogene and has recently been identified as the first gene that predisposes a person to neuroblastoma. It is expressed excessively in advanced neuroblastomas and in some forms with unfavourable outcome. Its activity can be inhibited by some drugs, such as crizotinib, which is employed in the therapy of other cancers and has been tried in neuroblastoma, as well. However, after a while the tumour tends to become resistant to ALK inhibitors, so new therapeutic strategies will be needed to overcome this limit.

2.1.1.5 Near future

Scientists are still revealing new details about the mechanisms that lead to neuroblastoma development and spread, so new molecules are being discovered in tumour cells which in the near future could help us detect neuroblastoma, predict its behaviour and risk, and develop new drugs to stop these molecules. Among them are what are known as miRNAs, a relatively new RNA family discovered in cancer which regulates the expression of several genes. Some of them (with names such as miR-17-5p-92 and miR-34) contribute to the aggressiveness of neuroblastoma, and a recent study discovered a set of 25 miRNAs that predicts high-risk patients’ survival. These results suggest that miRNAs regulate neuroblastoma cell activity and growth, so they could be used to predict patient outcome.
Another RNA group, long non-coding RNA (lncRNA), is emerging in neuroblastoma. It can regulate gene expression, but its role is still being clarified.
These studies should become easier in the near future because scientists discovered that some tumour cells and tumour DNA circulate in the blood stream of patients and can be retrieved. So scientists can get more and more easily accessible tumour samples without the need for a biopsy (biopsies of high-risk neuroblastoma patients often collect too little tissue to conduct a complete analysis).

2.1.2 Disease stats

Neuroblastoma is a very rare tumour; however it is the most frequent solid tumour in children aged less than 5 years. It is unusual in adolescents and adults. Ninety-five percent of all neuroblastoma occurs in children under 5 years of age. In some cases, neuroblastoma has been found even before birth, during ultrasound examination, and some patients whose cancer is already detected before birth or diagnosed in the first days of life undergo spontaneous regression.
Incidence: according to the RARECAREnet project, a network that follows rare cancers in Europe, in the period 2000-2007 the annual incidence rate in European children (0-14 years) was 6 cases per million. In Europe (EU28), almost 500 new cases of neuroblastoma were diagnosed in 2013. The occurrence was more frequent by about 13% in boys than girls. Incidence was highest in Southern Europe.
Prevalence: about 12,000 persons were estimated to be alive in Europe (EU27) at the beginning of 2008 with a diagnosis of malignant neuroblastoma or ganglioneuroblastoma, of whom 14% had been diagnosed within the previous 2 years and 29% within the previous 5 years (within 2 and 5 years treatment has presumably been completed, but patients are still undergoing active follow-up for recurrence and late consequences). Thirty-eight percent of those patients had been diagnosed more than 15 years earlier and are considered cured of their cancer.
Survival: the 5-year event-free survival for high-risk neuroblastoma is less than 50%, including patients with the worst outlook (those with metastatic neuroblastoma with ages older than 18 months, and those with metastatic or locally spread neuroblastoma and MYCN gene amplification).

2.2 Risk factors

Due to the rarity of neuroblastoma, it is difficult to study if it is more or less frequent in persons exposed to some chemicals or other environmental factors. However, a body of literature has begun to emerge suggesting that exposure to certain environmental agents is more common in neuroblastoma patients, so these agents might contribute to promoting the disease. The early age at diagnosis of neuroblastoma suggests that prenatal exposure might play an important role.
It is well established that foetal exposure to alcohol disrupts normal neuronal development, and several studies showed an increasing risk of disease (an increase between 20% and 1,200%) with use of alcohol during pregnancy.
There is little evidence that maternal tobacco use in pregnancy increases the risk of neuroblastoma.
Several studies investigated potential links between parental occupational exposures before conception or during pregnancy and neuroblastoma risk in their children. A study found an increased risk (between 2 and 6 times) if parents at work were exposed to electromagnetic fields or pesticides. The same researchers identified significant risk increases (between 1.5 and 10 times) for wood dusts, solders, non-volatile and volatile hydrocarbons contained in diesel fuels, lacquer thinner, and turpentine.
Two studies showed that the use of oral contraceptives or other sex hormones in early pregnancy may increase the risk of neuroblastoma in children. A few studies showed that the use of diuretics or other pills to treat water retention in pregnancy increases the risk (between 5.8 and 1.2 times). A risk increase (3.4 times) was also found with medications containing codeine during pregnancy or lactation.
Several studies observed a protective effect of childhood allergies and family history of asthma, which seem to reduce the risk.
A small protective effect was also reported with maternal vitamin intake during pregnancy. A decline in rates of neuroblastoma was observed in Ontario after the 1997 implementation of a folic acid fortification program for cereal grains. This finding is relevant, given that maternal folate intake is important for neuronal cell development in utero. In fact, another anomaly of nervous system development, i.e., neural tube defects, declined in the same period.
Low birth weight is another factor that seems to increase the risk (between 1.2 and 2.1 times).

2.3 What are the symptoms?

Neuroblastoma may present with a variety of symptoms, depending on its location, size, and behaviour (e.g., if cancer cells spread or secrete hormones). Most symptoms are not specific and they are often due to other reasons than neuroblastoma, so the doctor will have to check for the causes.
In two-thirds of cases neuroblastoma originates in the abdomen and presents as an abdominal mass or swelling with symptoms of compression of the abdominal organs: children may feel full and refuse food, or have pain, or have trouble urinating or passing stools if the tumour presses against their bladder or bowel. Or they may have a swelling in the legs if the tumour compresses the blood and lymph vessels, blocking blood or lymph flow.
In 20% of cases neuroblastoma originates in the chest, sometimes presenting with a mass or severe respiratory problems. Pressure on blood vessels in the chest can cause a swelling in the face, neck, chest, or arms, plus headaches and dizziness. Pressure on the throat can cause problems in breathing or swallowing and cough. Pressure on nerves may cause loss of sensation or movement in the limbs.
In the remaining patients neuroblastoma originates from the neck, where it appears as a mass or as Bernard-Horner syndrome, or from the pelvis.
In 60% of patients metastases are already present in bones and bone marrow at the time of diagnosis, and sometimes the first symptoms noticed by patients and doctors are those caused by these metastases, such as anorexia, fever, pain, or bruising around the eyes. According to their location, metastases may also cause enlarged lymph nodes, limb weakness and numbness, tiredness, or lumps (e.g., under the scalp).
About 7% of patients present with symptoms of spinal cord compression (such as weakness, numb limbs, and pain) due to cancer infiltration inside the spine. In most cases the effects of this compression are reversible with timely diagnosis and treatment.
Important symptoms at diagnosis are opsoclonus, due to autoantibodies that target the cerebellum; patients whose disease presents with these symptoms generally have a favourable outcome. However, approximately one third of these patients have severe psycho-motor consequences despite the use of immunosuppressive agents.
In rare cases the disease presents with watery diarrhoea, caused by a hormone (vasoactive intestinal peptide) produced by cancer cells. Symptoms caused by hormones in organs where the tumour has not spread are called paraneoplastic syndromes.

2.4 Diagnosis

The doctor will check your child’s condition by performing a physical exam and asking about the child’s symptoms and behaviour. Then, to help confirm the diagnosis and decide a specific treatment, the doctor may ask for a number of exams, including the following:

  • blood and urine tests, to search for some substances found in the urine which are produced in excess by neuroblastoma cells (catecholamines), or for abnormal levels of certain substances in the blood (ferritin, serum LDH, neuron-specific enolase or NSE), or to check if the symptoms may be due to other causes instead of neuroblastoma;
  • a biopsy of tumour tissue, both of the primary tumour and/or metastases, to confirm that it is a neuroblastoma and reveal what types of cells are present and their genetic characteristics;
  • a bone marrow biopsy (called a bone marrow aspirate, performed by inserting a needle into the hipbone or lower back to extract the marrow) to evaluate if neuroblastoma has spread to the bone marrow;
  • several kinds of imaging tests, including among others: computerized tomography (CT) or magnetic resonance imaging (MRI) of the site of the primary tumour to evaluate its extension; a test called meta-iodo-benzyl-guanidine (MIBG) scintigraphy, to evaluate the site of the primary tumour and detect metastases, and also to evaluate the response to treatment in metastatic sites; and CT of the bones which MIBG scan has shown to be positive, in children less than 1 year old.

3. How is neuroblastoma treated?

3.1 General information

The behaviour of neuroblastoma ranges from spontaneous healing with maturation into normal, non-cancerous nerve cells, to inexorable progression despite intensive therapy with several different interventions. This variability in behaviour depends on genetic differences in the tumour.
Treatment may be complex and involve several kinds of doctors and other professionals, such as nurses, psychologists, rehabilitation professionals, and more. Treatment approaches may include wait-and-see, surgery, chemotherapy, radiotherapy, biological therapy, and blood stem cell transplantation (see below, 3.5.3).

3.2 Surgery

Surgery plays a key role both for diagnosis and treatment. The objectives of surgery are to define the diagnosis, acquire tumour tissue for biological studies, and cut away the tumour with minimal damage to healthy tissues.
When the anatomical characteristics of the tumour (site, dimensions, relationship with the surrounding organs, presence of a pseudo-capsule) indicate that a surgical resection is feasible, surgery is the treatment of choice for patients presenting with localized disease.
When imaging tests (such as CT or MRI) show that tumour removal could cause serious damage because of its size, position, or other risk factors, pre-surgical chemotherapy is performed in order to shrink the tumour and make surgery safer.
Since neuroblastoma often tends to infiltrate lymphatic vessels and lymph nodes, these structures are also explored during surgery to look for tumour spread, especially in abdominal and pelvic tumours. If the tumour is near the spine, infiltrates it, and compresses the spinal cord, causing neurological symptoms, a decompression surgery, also called laminectomy, may be performed in selected cases. But in many patients it is not necessary because chemotherapy can rapidly shrink the tumour, relieving the spinal cord compression.
By contrast, it is less clear if surgery is useful in metastatic disease. However, as local relapses are frequent, in most cases the primary tumour is removed after chemotherapy-induced remission of the metastases.

3.3 Chemotherapy

Chemotherapy has an important role in treating neuroblastoma, since the majority of patients already have metastases or locally advanced disease when the neuroblastoma is diagnosed, and therefore require systemic treatment. Several drugs have a well-known efficacy in neuroblastoma and are used as standard options: cyclophosphamide, ifosfamide, busulfan, and melphalan (belonging to a group of drugs called alkylating agents), cis-platinum and carboplatin (platinum analogues), vincristine, VP16, and VM26 (epipodophyllotoxins), and doxorubicin (an anthracycline).
In the last few years other drugs, such as topotecan, irinotecan, or temozolomide, have proved to be effective, and further combinations including those drugs are being investigated in trials and might be used routinely in the near future.

3.4 Radiotherapy

Neuroblastoma is a tumour sensitive to radiation, so radiotherapy can be employed, in doses and ways of administration depending on site, volume, and age of the patient.
The role of irradiation with an external beam is under continuous refinement, as doctors are trying to understand better and better when it is useful and when it is best avoided in low-risk patients. Unfortunately, randomized clinical trials addressing the contribution of radiotherapy to the outcome are lacking, and this hampers proper evaluation of the impact of this treatment.
However, the more recent trend is towards the use of radiotherapy, either in combination with surgery or not, for treatment at the site of the primary tumour in patients with MYCN-amplified tumours (see above, 2.1), or in stage 4 disease, or in stage 3 disease with unfavourable biological or histological prognostic factors (see 5, Prognosis). Furthermore, external beam radiotherapy is largely and successfully used as palliative care, to reduce pain where present in patients with end-stage neuroblastoma.
Another approach to radiotherapy is the use of radiometabolic therapy: the patient receives a radioactive drug (I-131 benzylguanidine) which is incorporated by neuroblastoma cells and destroys them. However this approach has several limitations (e.g., it is difficult to assess the correct doses, the drug is toxic, and its uptake by the tumour cells is non-homogeneous), so it is used only in selected centres. Radiometabolic therapy is also being investigated in the treatment to prepare patients who are undergoing stem cell transplantation or as consolidation treatment.

3.5 Treatment strategy

Treatment is currently determined by 3 parameters: disease stage, patient age, and biological characteristics of the tumour, such as gene mutations.
The status of the MYCN oncogene (see 2.1) in the tumour is a criterion for defining treatment risk: when MYCN is amplified, intensive experimental treatments are used, regardless of the stage and age of the patient.
Patients with high-risk clinical prognostic factors (age older than 18 months and advanced stage disease) also often have unfavourable biologic risk factors, including unfavourable histopathology, MYCN oncogene amplification, and chromosome abnormalities.
Patients less than 18 months old at diagnosis have a significantly better outcome than older children, and some infants undergo a spontaneous remission of the disease (especially those whose tumour is already present at birth in the adrenal glands, and those with stage 4S disease; see section 4, Stages of neuroblastoma). For these reasons, in selected newborns or infants it may be appropriate to adopt a wait-and-see approach, and to perform surgery only if the tumour does not regress spontaneously after several months. When systemic treatment is necessary, excellent results can be achieved with less intensive treatments than those used in older children.
For other patients, the following strategies are employed.

3.5.1 Treatment for non-metastatic, resectable disease

In all cases where risk factors, as defined by the criteria in section 4 (Stages of neuroblastoma) are absent, surgical resection can be effective. If MYCN amplification is absent, surgical resection has a high chance of cure; 5-year event-free survival is more than 95% for completely resected tumours and more than 85% for incompletely resected tumours (since complete resection could cause serious damage because of tumour size, position, or other risk factors). Rarely, patients with localized stage 2 disease have MYCN amplification, in which case they need chemotherapy and radiotherapy, as well.

3.5.2 Treatment for locally advanced, unresectable disease

Since complete resection of the tumour is the principal objective, when this is not possible because surgery could cause serious damage (because of tumour size, position, or other risk factors), presurgical chemotherapy should be performed first, in order to shrink the tumour and carry out a complete resection with minimal risks of morbidity. Presurgical chemotherapy is given for around 4 months and may be based on a variety of combinations of cyclophosphamide, doxorubicin, vincristine, platinum derivatives, and etoposide.
If, nonetheless, complete resection is not possible, radiotherapy is administered to some patients, depending on their age and site of residual disease. However, it is not yet clear if such radiotherapy is useful.

3.5.3 Treatment for advanced disease or MYCN amplified disease

Unfortunately children with metastatic disease still have a poor outcome, with a 5-year overall survival of around 30%, with the exception of young infants without MYCN amplification.
To try to improve this outcome, international studies have employed highly intensive treatments, including the following: intense multidrug chemotherapy; local treatment of the primary tumour with surgery and/or radiotherapy; a procedure called myeloablative treatment with autologous blood stem cell transplantation (also called autologous bone marrow transplantation; cells in the bone marrow, including cancer cells that have spread, are killed with high-dose chemotherapy and then replaced by blood stem cells previously collected from the patient’s own bone marrow); and maintenance therapy with the drug isotretinoin or immunotherapy. These combinations often obtain good short-term results leading to tumour remission, with more than 70% of patients responding to treatment. However, in the long term therapy often fails, since more than half of these patients develop a recurrence at the primary tumour site or elsewhere, and the percentage of survivors remains low. Failures mostly occur because the tumour becomes resistant to chemotherapy.

4. Stages of neuroblastoma

Staging of a disease is the determination of distinct phases in its course, to help decide what exams and treatment the patient should undergo. The stage of neuroblastoma, together with MYCN status and age, is largely used to define prognosis and decide the treatment plan.
To assign a stage, the doctor may request imaging exams such as those described for diagnosis (see 2.4, Diagnosis), to evaluate how much the tumour has grown locally, if it has spread to distant organs forming metastases, and, when there are no metastases, if the tumour can be removed surgically (Table 2).
Two different staging systems are used for neuroblastoma. You can ask your child’s doctor to explain the system used for your child and its meaning.
The system used in the past two decades, called International Neuroblastoma Staging System (INSS), was based on the possibility to remove the tumour, judged by the surgeon at the time of diagnosis (Table 1).

Table 1. International Neuroblastoma Staging System (INSS).
Stage Characteristics
I The tumour is localized (limited to the area where it arose) and all visible tumour tissue may be completely removed with surgery
(though some microscopically visible cancer cells may remain). Lymph nodes connected to the tumour that are removed with it
during surgery may contain cancer cells, but other nearby lymph nodes do not have cancer cells
IIA  The tumour is localized but may not be completely removed with surgery.
Nearby lymph nodes not connected to the tumour do not contain cancer cells
IIB The tumour is localized and may or may not be completely removed with surgery, but nearby lymph nodes on the same body side contain cancer cells.
Cancer cells have not spread to lymph nodes on the opposite body side or to other distant areas.
III The tumour has grown to the other body side, beyond the spine, and cannot be completely removed with surgery;
or nearby lymph nodes on the opposite body side contain cancer cells;
or the tumour is in the midline of the body (where the spine is) and is growing on both sides, infiltrating nearby tissues or spreading to lymph nodes.
IV The tumour spread (metastasized) to other parts of the body such as distant lymph nodes, bone, bone marrow, liver, or other organs
(except as defined for Stage IVS).
IVS This stage is a special form of neuroblastoma that only occurs in infants younger than 1 year old and behaves differently from other forms.
The primary tumour is localized, and metastases have spread only to the liver, skin, or in very small amounts to the bone marrow.
Despite the tumour spread, children often recover, and sometimes neuroblastoma disappears spontaneously without any treatment.

In 2009, a new classification system was developed, the International Neuroblastoma Risk Group, which classifies patients into risk groups to predict surgical complications, according to how the tumour is related to adjacent organs, as evaluated in imaging exams before surgery (see Table 3 in the Professional Area). These criteria are the basis for the new International Neuroblastoma Risk Group Staging System (INRGSS) (Table 2).

Table 2. International Neuroblastoma Risk Group Staging System (INRGSS).
Stage Characteristics
L1 Imaging exams show no risk factors: the tumour is localized to the area where it arose, has not grown into vital structures,
and is confined to one body compartment, such as the abdomen or the chest.
L2 The tumour is localized or has spread only near the region in which it arose, and images show one or more surgical risk factors.
M The tumour has spread to distant areas (except stage MS).
MS In children younger than 18 months there are metastases only to the skin, liver, or in very small amounts to the bone marrow.

5. Prognosis

5.1 General information

Prognosis indicates the likelihood that treatment will be successful. It is a statistical measure obtained from different studies that observe the progress of the disease in a high number of patients. It is important to remember that these statistics merely provide an indication: no doctor is able to predict exactly what the outcome of treatment in an individual patient will be, nor how long the patient will live, as prognosis depends on several factors, in relation with the individual patient.

5.2 Prognosis of neuroblastoma

Prognosis is very good for infants, while it is not satisfactory in older children.
Five-year survival in children diagnosed between 2000-2007 was 91% in infants, 59% in children aged 1-4 years, 52% in children 5-9 years, and 56% in patients aged 10-14 years. Survival dropped steeply after the first year from diagnosis, so there was a large gap between 1-year survival (87% for the whole population of patients) and 3-year survival (70%), and the decrease was more marked in children.
Overall, survival in Europe has not improved recently; between 1999 and 2007, 5-year survival rose only in European regions that had low survival before. Five-year survival remained low in Eastern Europe (62%) and reached the highest value in Northern Europe (80%), and this large outcome disparity still persists.
As neuroblastoma and ganglioneuroblastoma are very rare in adolescents and adults, the figures for this age group are based on very few cases (59 cases). Unfortunately the outcome in this group was worse than in children, with a 5-year survival of only 48% in 15-24 year old patients and 40% in 25-64 year old patients. The clinical course of neuroblastoma in adults seems modestly influenced by therapy and the outcome is poorer at all stages.

5.3 Prognostic factors

Several international groups have developed a scheme to classify patients into different risk groups, in order to understand the possible outcomes and deliver treatments adapted to their risk level. For example, see Table 5 in the Professional Area for the International Neuroblastoma Risk Group Consensus Pretreatment Classification Scheme, developed by the International Neuroblastoma Risk Group Task Force, which defines patients as being at low, intermediate, and high risk according to several parameters. Or see Table 1 in the Professional Area for The International Neuroblastoma Pathological Classification, which defines patients with favourable or unfavourable histology according to their age and histopathology.
Different factors are considered to evaluate risk, including clinical characteristics (such as patient age and disease stage) and biological features (such as gene mutations); nowadays the most important prognostic factors are age, stage, and MYCN amplification. These parameters define at least 2 different patterns of disease.
The first one is neuroblastoma which arises in the first months of life and has no amplified MYCN gene; this group has the best prognosis, and some patients show a spontaneous regression of the disease or have excellent survival with minimal treatment.
By contrast, an unfavourable outcome is expected for children who have MYCN amplification or are older than 18 months at diagnosis and have metastatic tumours.
Between these two groups there is a less defined group of patients with intermediate characteristics. In this subgroup additional tumour features (such as histopathological classification, tumour ploidy, chromosomal anomalies) could help to better define the prognosis and choose tailored treatments, and are being studied to better understand their relevance.
In adolescents and adults neuroblastoma is very rare and has a different outcome. At diagnosis there are usually no metastases, and often there is no MYCN amplification. However, multiple local relapses or metastasis may occur and the prognosis is unfavourable.

6. What to do after treatment

6.1 Late sequelae

Both neuroblastoma and its treatments can cause long-term consequences. The risk of late effects depends on a number of factors, such as the treatments received, their doses, and age when getting the treatment. In particular, the very intensive treatment employed for patients with metastatic disease is toxic and can damage patient fertility, hormonal activity (especially thyroid function), and function of other organs, especially kidney and heart, so these patients should undergo long-term clinical follow-up. Other late consequences may include lung problems, osteoporosis, reduced growth, intellectual and learning problems, and problems in sexual development.
Furthermore, neuroblastoma can relapse, or new tumours (called secondary tumours) can arise because of the treatments. Relapse generally occurs within 2 years after surgery in patients with localized disease, or after the end of treatment in patients with metastatic disease. However, late relapses after 5 years are rare but not exceptional. For this reason, even symptoms arising after several years have to be carefully evaluated to check if they are caused by a relapse.
Secondary tumours can occur, and long-term survivors may have a high risk of secondary tumours, especially if they received total-body irradiation, radiometabolic therapy (see 3.5), or myeloablative therapy with alkylating agents or high-dose epipodophyllotoxins (see 3.5.3 and 3.3).

6.2 Follow-up

After the end of the treatment, patients should undergo regular check-ups for several years to check for late consequences or cancer recurrences. To look for signs of a new local or metastatic cancer, the patient should undergo physical examination, blood and urine tests, and radiological evaluation of the site of the primary tumour (ultrasound or X-ray, depending on the site of occurrence). Assessments should be carried out every 3 months for the first year, every 4 months in the second year, and thereafter every 6 months up to the fifth year post treatment.
In patients with stage 4 disease, relapse usually involves metastatic sites, therefore an MIBG scan and bone marrow biopsy should be performed every six months in the first 2 years of follow-up.

7. What to ask doctors

Here is a list of questions that you might wish to ask your doctor or any specialists you may consult. To avoid unnecessary concern, it is useful to ask about any doubts you might have, no matter how small they may appear.

General questions

• May I phone you? What is the best time? If you are not available, may I ask for other specialists? Whom specifically?
• What leaflets, books, or websites could I read to learn more about neuroblastoma?
• Is there a patient association or online support group I could contact?
• How will the disease and treatments interfere with school and playing? Or with holidays?
• Should my child pay special attention to activities such as playing or sports?
• Is there any contraindication to having a pet?
• Do you have special advice regarding nutrition?
• Is there any contraindication regarding vaccinations?
• Does neuroblastoma run in families? Are my other children at risk of getting neuroblastoma?
• How can I help my child to remain serene?
• Can you refer me for counselling?

Diagnosis and exams

• What type of tumour is it?
• What tests are you going to do?
• What are you looking for?
• How long will the exam take?
• Is biopsy painful? Is it performed under general or local anaesthesia?
• Are CT, MRI, or scintigraphy dangerous because of radiation exposure?
• Will the child be asleep?
• How long will it take to confirm diagnosis?

Treatment

• What should we do to be ready for treatment?
• Do I need a highly specialized centre for my child?
• What other doctors will we see?
• What is the stage of cancer, and what does it mean?
• What is the risk group of my child, and what does it mean?
• What type of treatment is needed?
• Is there any choice of treatment?
• What is the outlook for cure?
• Should my child participate in a clinical trial? If so, in what trial?
• What are the risks and benefits of treatments?
• How long will treatment last? Where will it be done?
• Will treatment reduce symptoms and discomfort?
• What are the possible side effects of therapy? Will my child lose his/her hair, or have nausea and vomiting?
• How can I help to reduce the side effects?
• During treatment should I take special precautions or change any habits?
• Which supportive therapy is suggested during treatment?
• How will treatment affect my child?
• How long will it take to recover?
• What follow-up will be needed after treatment?
• What late effects could treatment have?
• Will treatment increase the risk of other cancer in the future?
• Will treatment affect my child’s growth, school achievements, future sex life, or ability to have children?
• Could neuroblastoma recur?
• Will I pay for treatment? What is it likely to cost?