Neuroblastoma

What Is Neuroblastoma and What Are the Symptoms of Neuroblastoma in a Child?

Neuroblastomas are childhood tumors of the peripheral nervous system (outside the brain or spinal cord), that grow out of the sympathetic nervous system, or the “fight or flight” response system. They form in the adrenal glands (above the kidneys) or in the paraspinal sympathetic chain (alongside the spine), with different effects on the body based on where they grow.

They can develop in different ways in different patients, sometimes becoming benign (grow as a noncancerous tumor that cannot spread to other parts of the body), low-risk cancers (cells that have the potential to spread to other parts of the body but can be usually cured with surgery alone), or intermediate- or high-risk cancers (more aggressive cancers needing medical and surgical treatment). Patients with these tumors have unique challenges specific to their disease.

Children with neuroblastoma may show a variety of symptoms. Some children actually never show any symptoms; these children tend to have low-risk tumors, which are discussed below. Some children may show one or more of the following:

• A lump or mass in the belly (abdomen) or on their back, next to the spine
• Larger swelling in the abdomen
• Weight loss or an inability to gain weight
• Prolonged fevers (lasting more than a week) and no reason is found for the fevers
• Sudden new pale appearance (pallor) or particularly unusual bruising (e.g, bruises on the chest or back without any explanation) 
• Swelling of the arms or legs, or a new inability or refusal to walk
• Drooping eyelids, or new bruises around the eyes (“raccoon eyes”)
• New bone pain or a broken bone with little or no trauma

Some patients may also have a specific set of neurologic symptoms, including:

• Rapid, uncontrollable movements of the eyes back and forth (“dancing eyes” or opsoclonus”)
• New inability to walk normally or stand, particularly after they had been able to
• Random movements or twitching of the arms or legs (myoclonus)
• Particularly extreme inability to be consoled or even rage
• Particularly poor sleep because of the movements 

These are symptoms of a rare complication of neuroblastoma, called opsoclonus-myoclonus-ataxia syndrome, discussed below.

How Can Doctors Determine If My Child Has Neuroblastoma?

When there is enough concern that a child may have cancer, including neuroblastoma, they are referred to doctors trained in the diagnosis and treatment of cancer and blood diseases in children (pediatric hematologists and oncologists). In addition to taking a thorough interview of the child and family (patient history) and examining the child, the doctors will likely obtain additional tests. These may include:

• Lab tests on blood and urine
• Ultrasound of the abdomen
• CT Scans of parts or all of the body
• MRI (Magnet Resonance Imaging)
• MIBG scan (a special type of imaging that identifies neuroblastoma in the body)
• Bone Marrow Aspiration and Biopsies 

If a tumor is identified on these tests, the oncologists will request that a sample of the tumor be obtained. This may be done by one of the following:

• Sampling of the tumor (biopsy) with needles, using scans to guide specialized doctors called interventional radiologists;
• Sampling of the tumor through a brief surgery (laparoscopic or open biopsy), by a pediatric surgeon;
• Removal of the tumor all at once (tumor resection), by a pediatric surgeon.

This sampling allows the oncologists to test the tumor to confirm if it neuroblastoma and how aggressive it may be. Each of these methods have their risks and benefits; your child’s oncologist would explain which one would be best for their case. 

When a diagnosis of neuroblastoma is made, additional tests may also be obtained, to see how the patient’s health is otherwise and how well they will tolerate treatment. Your doctors will discuss this in more detail as appropriate. 

What Are the Different Types of Neuroblastoma and How Are They Treated?

There are a number of different types of neuroblastoma that are diagnosed in children or adults. These types are defined by different factors, including the age of the patient, if the tumor is in one part of the body or if it has spread to other parts of the body, how the tumor looks under the microscope, and some genetic factors of the tumor itself. Each type has its own treatment approach and expected outcomes.

• Ganglioneuromas are benign tumors that can be found at any age. These benign tumors are not cancers, so they cannot spread to other parts of the body. However, they can grow in size and physically press on parts of the body, causing problems including on growth and development. These tumors usually require surgery to avoid complications, but they do not have a risk of spreading to other parts of the body (metastasis) or coming back (recurrence).
• Ganglioneuroblastomas and other low-risk neuroblastomas generally are found in children under 18 months of age. While these are cancers, they are usually small when they are first diagnosed and have not spread to other parts of the body (no metastasis). These can be surgically removed (resected), but some of these tumors may go away with time (involute) as the child grows and develops and may not require surgery; this is more likely to happen in infants under one year of age. In either case, patients require monitoring for a few years (visits to clinic, labwork, and scans) but usually the cancer does not come back (recurrence). We consider the patient to be cured if the cancer does not come back within 5 years.
• There is a special type of neuroblastoma in infants, called Stage MS (formerly called 4S), where the cancer cells can spread (metastasize) to the liver, skin, or bone marrow, but these children also generally have low-risk disease and can be monitored without necessarily needing treatment. If they do need treatment, it is usually chemotherapy only (medicine that fights the cancer), and most of these children can be cured with few or no effects on their growth, development, and overall health.
• Intermediate-risk neuroblastomas are slightly more aggressive cancers, usually found in infants where the cancer has already spread to other parts of the body (metastasized), or in children ages 2-5 where the cancer has not yet metastasized. Patients with these tumors generally require some chemotherapy and surgery to remove the main tumor. This treatment lasts about 4-8 months, and the patient spends much of that time at home with some visits to our outpatient clinic. They do not need radiation therapy or other aggressive treatment. Patients need to be monitored for five years after therapy, but the majority of these patients are cured after this treatment as well. There are usually few long-term effects but these patients can benefit from long-term follow-up to help with any side effects, in our survivorship clinic.
• Some patients, usually with low or intermediate-risk neuroblastoma, may suffer from a specific neurologic complication at diagnosis, called opsoclonus-myoclonus-ataxia syndrome (OMAS). In these patients, their immune system actually fights the cancer but also starts to attack the patient’s neurologic system. If this happens, it can cause abnormal movements of the eyes (opsoclonus), problems with speech, unstable walking, difficulty using their hands and feet, and behavioral problems including rage attacks and disrupted sleep. This immune reaction can continue even if the tumor is fully removed. In these patients, the primary treatment is controlling the immune system, using a combination of medications. Prompt treatment is important in these cases; with good control, the patients can have very good quality of life, but uncontrolled OMAS can harm their long-term development.
• High-risk neuroblastomas are cancers that are very aggressive, and approximately half of all children diagnosed with neuroblastoma have high-risk disease. They can grow in a single spot in the body (localized), but more commonly they have already spread (metastasized) by the time the child is diagnosed. Children with these tumors may have no symptoms or can be quite sick. Treatment for high-risk neuroblastoma is also aggressive; all hospitals in the US start treatment with chemotherapy and surgery. As part of this process, we collect a sample of the patient’s bone marrow cells, or blood stem cells, early in treatment. After the initial chemotherapy and surgery, we give the patient a larger dose of chemotherapy followed by transfusing those blood stem cells so that the child can heal (autologous bone marrow transplant). This is followed by radiation therapy, then a treatment where we make the body’s immune system fight the cancer (antibody-based immunotherapy) and biological therapy (Accutane). This treatment can take over 1 ½ years, and it will cure approximately 60-70% of these patients. These patients can have long-term side effects, but these can be managed by our neuroblastoma team and by the doctors and nurses in our survivorship clinic.

Unfortunately, neuroblastoma can be resistant to treatment (refractory disease) or grow back in some patients (relapse). In the past, these children had few treatment options, but now we have many new ways to treat these patients. These include:

• advanced genetic testing of tumors (genomics) that identify personalized treatment plans
• infused radiation treatments (I-131 MIBG therapy) that can target multiple sites of disease
• new combinations of chemotherapy, antibody therapy and specialized cell therapies
• other experimental drug studies

These treatments, all available at Nationwide Children’s Hospital, have improved outcomes for patients whose neuroblastoma has come back or hasn’t responded to standard treatment.

Children with neuroblastoma at Nationwide Children's Hospital are treated by members of the Comprehensive Neuroblastoma Program. This is a multidisciplinary, full-service program focused on improving outcomes for children afflicted with neuroblastomas of any type, including those with relapsed or refractory disease.

Patients with any of these types of neuroblastoma can suffer from long-term effects of their tumors or the treatment used to cure them, particularly those with high-risk disease. This can include:

• effects on growth and development
• lung and heart function
• hormone levels
• bone health
• education
• fertility

Patients with OMAS have additional challenges neurologically and developmentally. In our survivorship clinic, we have approaches to control symptoms and help patients with any of these conditions, allowing them to lead full and long lives.

Treatment of Childhood Cancers at Nationwide Children’s Hospital

Nationwide Children's Hospital has the largest and most advanced pediatric cancer program in Ohio – and one of the largest in the nation. In 2019, more than 1400 children were treated at Nationwide Children's for oncology or bone marrow transplantation –the highest number of pediatric oncology inpatient visits in the state. More than 85% of children who receive a diagnosis of cancer in 2020 will be cancer-free five years later, though this varies based on each child’s specific diagnosis. Still, much work remains to be done, including:

• improving treatment to give every child a chance to be cured of their cancer
• reducing the toxic side effects of treatment
• managing the short-term and long-term effects of the cancer and treatment

Nationwide Children's Hospital and The Abigail Wexner Research Institute continue to work toward these goals, in our clinics, in the hospital, and in the research labs. Our clinical care is comprehensive; we provide innovative approaches that offer the best chances of disease control and cure, while also provided a number of supportive care services to address other patient needs. These include medical issues, such as management of side effects of treatment, nutritional support, physical therapy services, and innovative pain control approaches including nonopioid approaches, as well as social work support, psychology services for patients and families, genetic counseling, pastoral care, art therapies and educational services.

In addition to these services provided to every patient with cancer, Nationwide Children’s Hospital and The Research Institute continue to perform cutting-edge research for the benefit of these patients. The Abigail Wexner Research Institute ranks in the top 10 of free-standing pediatric research centers based on National Institutes of Health funding, identifying the causes of childhood cancer and finding new ways to attack these cancers while reducing the side effects on the patients. Our clinical services also run a number of clinical trials, both for treatment of the cancers and supportive care, through ideas generated here at NCH as well through regional, national, and international collaborations. These efforts allow us to offer pioneering treatment to our patients, giving many of them chances at survival that they would not otherwise have. See below for more information about clinical trials.

Through all these approaches, the doctors, nurses, scientists and staff at Nationwide Children's Hospital make every effort to bring the best and most comprehensive care available for every child suffering from a childhood cancer or blood disorder.

What Is a Clinical Trial and What Does It Mean for My Child?

A clinical trial is a research study in which physicians find ways to improve cancer treatment. The goals of these studies are to answer scientific questions about preventing, diagnosing and treating cancer and to improve how doctors are able to treat children with cancer. Clinical trials are not “experimentation” on children; they are based on evidence from earlier research with the promise of potential benefit. These trials are carefully planned and closely supervised, and they must undergo review by an ethics board, the Institutional Review Board, before they can be used with patients. 

You or your child may be asked to participate in a clinical trial. Your participation in this research study is voluntary. If you do not want to have your child treated on a clinical trial, the doctors at Nationwide Children's Hospital will use what is considered “standard of care,” or what has been shown to be the acceptable treatment approach for children with that disease. We will still use all our efforts to provide the best possible care for your child.

A clinical trial for cancer treatment occurs in three phases.

• Phase I – This is a first study done on a drug to test how safe it is, to determine the right dose for patients, and to determine when and how to give the drug. These studies are justified by research done in the lab and/or in adult patients. These studies usually are limited to a small number of patients, generally fewer than fifty total.
• Phase II – This type of study comes after a Phase I study, using a dosing regimen that was shown to be safe for patients. A Phase II study evaluates if the treatment is useful against specific types of cancers, and it also confirms the safety of the regimen in those patients. A Phase II study is usually used for patients when there is no good treatment for their cancer, or when the standard treatment for a cancer has failed (“relapse” if the cancer came back, or “refractory” if the first treatment never worked). These studies include more patients than a Phase 1 study but still usually fewer than 100. 
• Phase III –  This type of study involves taking one or medications that showed benefit in a Phase II study and adding it to or replacing the current standard treatment. Usually, some patients are also treated with the standard treatment only, to let us compare if adding the new drugs is better. These studies involve hundreds of patients being treated at many different hospitals. 

Cancer treatment has improved greatly over the past several decades due to the use of clinical trials. It has only been through these types of trials that childhood cancer cure rates have gone from less than 25% in the 1960’s to over 85% today. 

Nationwide Children’s Hospital offers Phase I, Phase II and Phase III clinical trials to its patients, including for neuroblastoma, in addition to standard of care treatments. If you are asked to participate in a clinical trial, the physician will review the study and consent form with you and answer your questions. You will receive a pamphlet with more detailed information about clinical trials to help you make a decision.