Neuroblastoma in Children: Symptoms, Treatment & Survival

What Is Neuroblastoma?

Neuroblastoma is a cancer that develops from immature nerve cells called neuroblasts in the sympathetic nervous system. It most commonly arises in the adrenal glands but can occur anywhere along the sympathetic nerve chain, including the chest, neck, abdomen, and pelvis. It is the most common solid tumor outside the brain in children under 5 years of age.

Neuroblastoma represents one of the most unique cancers in pediatric oncology. Unlike most cancers, which invariably progress and spread if left untreated, neuroblastoma exhibits a remarkable spectrum of clinical behaviors. At one extreme, some tumors in infants undergo spontaneous regression and completely disappear without any treatment. At the other extreme, aggressive high-risk tumors can be resistant to intensive multimodal therapy and have a poor prognosis despite aggressive treatment.

The sympathetic nervous system, where neuroblastoma originates, is part of the autonomic nervous system that controls involuntary functions such as heart rate, blood pressure, digestion, and the "fight or flight" response. This nervous system develops from a structure called the neural crest during fetal development. Neuroblastoma arises when neural crest cells fail to mature properly and instead proliferate uncontrollably.

The adrenal glands, located on top of each kidney, are the most common site for neuroblastoma, accounting for approximately 40% of cases. The adrenal medulla (inner part of the adrenal gland) develops from neural crest cells and produces hormones like adrenaline. Other common locations include the paraspinal sympathetic ganglia in the abdomen (25%), chest (15%), pelvis (5%), and neck (5%).

Who Gets Neuroblastoma?

Neuroblastoma is predominantly a disease of early childhood. Approximately 90% of cases are diagnosed in children under 5 years of age, with the median age at diagnosis being around 18 months. About 37% of cases occur in infants under one year of age. The disease is slightly more common in boys than girls, with a male-to-female ratio of approximately 1.2:1.

Neuroblastoma accounts for approximately 6-10% of all childhood cancers but causes a disproportionate 15% of cancer deaths in children, reflecting the aggressive nature of high-risk disease. In the United States, approximately 700-800 new cases are diagnosed each year. The incidence is similar across different ethnic groups and geographic regions worldwide.

What Causes Neuroblastoma?

The exact cause of neuroblastoma remains unknown in most cases. Unlike many adult cancers, neuroblastoma is not associated with environmental exposures, lifestyle factors, or anything that parents did or did not do. The cancer appears to arise from genetic changes that occur during fetal development, when nerve cells are rapidly dividing and maturing.

Approximately 1-2% of neuroblastoma cases are hereditary, passed down through families. These familial cases are associated with germline mutations in genes such as ALK (anaplastic lymphoma kinase) and PHOX2B. Children with hereditary neuroblastoma tend to be diagnosed at a younger age and may develop tumors at multiple sites. Genetic counseling may be recommended for families with a history of neuroblastoma.

The vast majority of neuroblastoma cases (98-99%) are sporadic, occurring in children with no family history of the disease. In these cases, the genetic changes occur spontaneously during cell division and are not inherited. Researchers have identified several genetic alterations that are common in neuroblastoma cells and influence how the disease behaves and responds to treatment.

What Are the Symptoms of Neuroblastoma?

Common symptoms of neuroblastoma include a painless abdominal lump or swelling, bone pain, fever, weight loss, fatigue, and dark circles under the eyes (raccoon eyes). Symptoms depend on where the tumor is located and whether it has spread. Some children are diagnosed incidentally when a mass is found during examination for other reasons.

The symptoms of neuroblastoma are highly variable and depend primarily on the location of the primary tumor, whether the cancer has spread (metastasized) to other parts of the body, and whether the tumor produces hormones that cause systemic effects. Because many symptoms are nonspecific and can be caused by common childhood illnesses, neuroblastoma can sometimes be difficult to diagnose early.

In many cases, neuroblastoma is discovered incidentally when a child is being examined for something else. A parent or doctor may feel an unusual lump in the abdomen during a routine examination, or a chest X-ray taken for respiratory symptoms may reveal a mass. Sometimes prenatal ultrasounds detect adrenal masses that turn out to be neuroblastoma after birth.

Symptoms Based on Tumor Location

When neuroblastoma develops in the abdomen (the most common location), symptoms may include a visible or palpable mass or swelling in the belly, abdominal pain or discomfort, decreased appetite, constipation, or difficulty urinating if the tumor presses on the bladder. The abdomen may appear distended, and the child may have difficulty eating full meals.

Chest tumors may cause breathing difficulties, wheezing, or a persistent cough. The tumor may compress the airways or lungs, making it hard for the child to breathe comfortably, especially during physical activity. Some children develop Horner syndrome if the tumor affects nerves in the chest or neck, causing drooping eyelid, small pupil, and decreased sweating on one side of the face.

Tumors in the neck may present as a visible lump that parents notice when dressing or bathing the child. These tumors can also cause Horner syndrome or difficulty swallowing if they grow large enough to compress the esophagus.

Symptoms of Metastatic Disease

Approximately half of all neuroblastoma cases have already spread to other parts of the body at the time of diagnosis. Metastatic neuroblastoma most commonly spreads to the bone marrow, bones, lymph nodes, liver, and skin. When the cancer spreads, it causes additional symptoms related to the affected organs.

Bone and bone marrow involvement can cause bone pain, limping, or refusal to walk or bear weight on a limb. Children may become irritable and cry when picked up or moved. The child may appear pale and tired due to anemia caused by bone marrow infiltration. Bruising or bleeding may occur if platelet counts are low.

One of the most characteristic signs of metastatic neuroblastoma is periorbital ecchymosis, commonly called "raccoon eyes" - dark bruising around the eyes caused by tumor spread to the bones of the skull. This distinctive finding should prompt immediate medical evaluation for possible neuroblastoma.

Hormone-Related Symptoms

Some neuroblastomas produce catecholamines (stress hormones like adrenaline and noradrenaline), which can cause systemic symptoms such as sweating, flushing, rapid heartbeat, high blood pressure, and irritability. These symptoms are caused by the excess hormones circulating in the blood, not by the tumor itself.

A small percentage of children with neuroblastoma develop opsoclonus-myoclonus syndrome (OMS), a rare paraneoplastic condition characterized by rapid, chaotic eye movements ("dancing eyes"), jerky muscle movements, unsteady gait, and behavioral changes. OMS is thought to be caused by an immune reaction triggered by the tumor. While children with OMS-associated neuroblastoma often have favorable tumor biology, the neurological symptoms can be challenging to treat and may cause long-term developmental problems.

Another hormone-related symptom is intractable diarrhea caused by vasoactive intestinal peptide (VIP) secretion from certain tumors. This can lead to severe dehydration and electrolyte imbalances if not recognized and managed appropriately.

How Is Neuroblastoma Diagnosed?

Neuroblastoma is diagnosed through a combination of blood and urine tests measuring catecholamine metabolites (VMA, HVA), imaging studies (ultrasound, CT, MRI, MIBG scan), bone marrow biopsy, and tumor tissue biopsy. Genetic testing of the tumor helps determine risk classification and guides treatment decisions.

When neuroblastoma is suspected based on symptoms or physical examination findings, doctors perform a series of tests to confirm the diagnosis, determine the extent of disease (staging), and identify biological characteristics that predict behavior and guide treatment. This comprehensive evaluation typically takes place at a specialized pediatric cancer center.

The diagnostic workup for neuroblastoma is designed to answer several key questions: Is this neuroblastoma? Where is the primary tumor located? Has the cancer spread to other parts of the body? What are the biological characteristics of the tumor that will predict its behavior? The answers to these questions determine which risk group the child falls into and what treatment approach is most appropriate.

Blood and Urine Tests

Blood tests provide important information about the child's overall health and can suggest the presence of neuroblastoma. A complete blood count may show anemia or low platelet counts if bone marrow is involved. Serum lactate dehydrogenase (LDH) and ferritin levels are often elevated in neuroblastoma and have prognostic significance - higher levels are associated with more aggressive disease.

Urine tests for catecholamine metabolites are a key diagnostic tool for neuroblastoma. More than 90% of neuroblastomas produce catecholamines that are broken down into metabolites called vanillylmandelic acid (VMA) and homovanillic acid (HVA). These metabolites are excreted in the urine and can be measured with a simple urine collection. Elevated VMA and HVA levels strongly suggest neuroblastoma and can also be used to monitor response to treatment and detect recurrence.

Imaging Studies

Imaging studies are essential for determining the location and extent of the primary tumor and identifying any spread to other parts of the body. The imaging workup typically includes multiple modalities to provide a complete picture of the disease.

Ultrasound is often the first imaging test performed because it is quick, does not involve radiation, and does not require sedation. It can identify abdominal masses and provide information about their size and characteristics. However, ultrasound has limitations in evaluating tumor extent and detecting spread.

CT (computed tomography) and MRI (magnetic resonance imaging) provide detailed cross-sectional images of the tumor and surrounding structures. These scans help determine whether the tumor can be safely removed surgically and identify lymph node involvement. MRI is particularly useful for evaluating spinal cord involvement in tumors near the spine.

MIBG scan (metaiodobenzylguanidine scintigraphy) is a specialized nuclear medicine test highly sensitive for detecting neuroblastoma cells. MIBG is a compound similar to noradrenaline that is taken up specifically by neuroblastoma cells. When tagged with a radioactive isotope (iodine-123 or iodine-131), it can be injected and then detected throughout the body using a gamma camera. MIBG scans are excellent for staging disease and detecting spread to bones, bone marrow, and soft tissues.

Tissue Biopsy and Genetic Testing

A definitive diagnosis of neuroblastoma requires examination of tumor tissue under a microscope by a pathologist. Tissue can be obtained through surgical biopsy, needle biopsy, or bone marrow biopsy. In some cases, extensive bone marrow involvement with tumor cells showing characteristic features may be sufficient for diagnosis without a separate tumor biopsy.

Once tissue is obtained, several tests are performed to characterize the tumor's biology and determine risk stratification:

• MYCN amplification: The MYCN gene is amplified (present in many extra copies) in about 20% of neuroblastomas. MYCN amplification is associated with aggressive disease and poor prognosis, regardless of age or stage.
• DNA ploidy: Tumors with extra chromosomes (hyperdiploidy) tend to have a better prognosis than those with normal chromosome numbers (diploidy).
• Histopathology: Tumor cells are examined for signs of differentiation. More differentiated tumors generally have better outcomes.
• Segmental chromosomal aberrations: Certain chromosomal gains and losses (like 11q deletion, 1p deletion) are associated with higher-risk disease.

How Is Neuroblastoma Treated?

Neuroblastoma treatment depends on risk classification. Low-risk tumors may be observed or treated with surgery alone. Intermediate-risk cases typically receive surgery and moderate chemotherapy. High-risk neuroblastoma requires intensive multimodal therapy including induction chemotherapy, surgery, high-dose chemotherapy with stem cell rescue, radiation therapy, immunotherapy, and retinoid therapy.

The treatment of neuroblastoma has become increasingly sophisticated and personalized over the past several decades. Rather than applying the same treatment to all children, doctors now tailor therapy intensity based on risk classification. This approach avoids unnecessary treatment for children with favorable tumors while providing intensive therapy for those with high-risk disease.

Treatment is always provided by a specialized team at a pediatric cancer center, including pediatric oncologists, surgeons, radiation oncologists, nurses, pharmacists, social workers, child life specialists, and other support staff. Treatment protocols are typically based on international clinical trials that have established evidence-based approaches for each risk group.

Low-Risk Neuroblastoma

Children with low-risk neuroblastoma have an excellent prognosis, with survival rates exceeding 95%. Treatment is minimally intensive and may involve observation alone, surgical removal of the tumor, or a short course of low-intensity chemotherapy.

Some infants with small, localized tumors or even stage MS disease (metastatic to liver, skin, and/or bone marrow but with favorable biology) may be observed without immediate treatment. This approach recognizes that some neuroblastomas, particularly in very young children, can spontaneously regress and disappear completely. Close monitoring with regular examinations and imaging ensures that treatment can be started promptly if the tumor grows or causes symptoms.

For low-risk tumors that require treatment, surgical removal alone may be curative. If the tumor cannot be completely removed or if there are residual symptoms, a brief course of low-intensity chemotherapy may be given to shrink the tumor.

Intermediate-Risk Neuroblastoma

Intermediate-risk neuroblastoma requires more treatment than low-risk disease but less than high-risk. The survival rate is approximately 90-95%. Treatment typically involves a combination of surgery and moderate-dose chemotherapy.

Chemotherapy is usually given first to shrink the tumor and make surgical removal safer and more complete. Several cycles of chemotherapy using drugs such as carboplatin, etoposide, cyclophosphamide, and doxorubicin are administered over several months. The tumor is then surgically removed if possible. Some children may receive additional chemotherapy after surgery based on how well the tumor responded.

High-Risk Neuroblastoma

High-risk neuroblastoma is the most challenging form of the disease, requiring intensive multimodal treatment over 12-18 months. Despite aggressive therapy, the survival rate remains approximately 40-50%, though this has improved significantly with newer treatments including immunotherapy.

Treatment for high-risk neuroblastoma is typically divided into three phases:

Induction phase: Multiple cycles of high-dose chemotherapy are given to shrink the primary tumor and eliminate metastatic disease. This phase lasts several months and uses combinations of powerful drugs including cisplatin, cyclophosphamide, etoposide, doxorubicin, and vincristine. During this phase, stem cells are collected from the child's blood for later use in transplantation.

Consolidation phase: After induction, children receive high-dose chemotherapy with stem cell rescue (also called autologous stem cell transplant). This intensive treatment aims to eliminate any remaining cancer cells. The previously collected stem cells are infused back to restore the bone marrow. Following transplant, radiation therapy is given to the primary tumor site and sometimes to sites of metastatic disease.

Maintenance phase: After consolidation, children receive treatment to eliminate minimal residual disease and prevent recurrence. This includes immunotherapy with anti-GD2 antibodies (dinutuximab) combined with cytokines (GM-CSF, IL-2), and oral isotretinoin (13-cis-retinoic acid) for six months. The anti-GD2 antibody targets a molecule found on neuroblastoma cells, while isotretinoin promotes differentiation of any remaining cancer cells.

Newer and Emerging Treatments

Research continues to improve outcomes for children with neuroblastoma, particularly high-risk disease. Several newer treatments are being studied or have recently become available:

• MIBG therapy: Radioactive iodine-131 attached to MIBG can deliver targeted radiation directly to neuroblastoma cells. This treatment is being studied for relapsed and refractory disease.
• ALK inhibitors: Drugs targeting abnormal ALK protein (present in some neuroblastomas) are showing promise, especially for tumors with ALK mutations.
• CAR-T cell therapy: Engineered immune cells targeting neuroblastoma are being developed and tested in clinical trials.
• Vaccine therapies: Immunotherapy approaches using vaccines to stimulate immune response against neuroblastoma are under investigation.

What Is the Prognosis for Neuroblastoma?

Neuroblastoma prognosis varies dramatically based on risk group, age at diagnosis, tumor biology, and stage. Low-risk neuroblastoma has greater than 95% survival, while high-risk disease has approximately 40-50% survival despite intensive treatment. Children under 18 months generally have better outcomes, and some infant tumors can regress spontaneously.

The outcome for children with neuroblastoma depends on multiple factors that are carefully assessed at diagnosis and used to classify each child into a risk group. Understanding these prognostic factors helps families and medical teams make informed decisions about treatment and provides realistic expectations about likely outcomes.

The single most important prognostic factor is the risk classification at diagnosis. Children with low-risk neuroblastoma have excellent outcomes with minimal treatment, while high-risk disease remains challenging despite intensive multimodal therapy. However, even within risk groups, individual outcomes can vary.

Factors That Affect Prognosis

Age at diagnosis is a powerful prognostic factor. Children diagnosed before 18 months of age have significantly better outcomes than older children, even with similar tumor characteristics. This age effect is so important that it is incorporated into risk classification systems. The reasons for better outcomes in younger children are not fully understood but may relate to differences in tumor biology and the developing immune system.

MYCN amplification is perhaps the most important tumor biological factor. Tumors with MYCN amplification (about 20% of cases) are aggressive and have poor outcomes regardless of other factors. Even infants and children with localized MYCN-amplified tumors are classified as high-risk and require intensive treatment.

Tumor stage indicates whether the disease is localized or has spread to distant sites. Metastatic disease (stage M) generally has worse outcomes than localized disease, though the special MS stage in infants has favorable outcomes despite spread to liver, skin, or limited bone marrow involvement.

Histopathology refers to how the tumor cells appear under the microscope. Tumors showing signs of differentiation (maturing toward normal nerve cells) have better outcomes than undifferentiated tumors. This is assessed using the International Neuroblastoma Pathology Classification.

Long-Term Follow-Up

Children who survive neuroblastoma require long-term follow-up, potentially for many years into adulthood. This monitoring serves several purposes: detecting any recurrence of the cancer as early as possible, monitoring for late effects of treatment, and supporting optimal development and quality of life.

The risk of neuroblastoma recurring depends on the original risk group. Most relapses occur within the first two years after completing treatment. Children with low-risk disease who complete treatment have a very low risk of relapse. High-risk neuroblastoma has a significant relapse rate, and recurrent disease is very difficult to treat successfully.

Late effects of treatment are an important concern, particularly for children who received intensive therapy for high-risk disease. Potential long-term effects include hearing loss (from certain chemotherapy drugs), fertility issues, heart problems, kidney damage, growth abnormalities, thyroid dysfunction, and risk of secondary cancers. Regular monitoring allows early detection and management of these issues.

How Can Families Cope and Get Support?

Families coping with childhood cancer need comprehensive support including medical care coordination, psychological support, financial assistance, practical help, and connection with other families. Pediatric cancer centers provide multidisciplinary teams including social workers, child life specialists, and psychologists to support families throughout treatment and beyond.

A diagnosis of neuroblastoma in a child is devastating for families. The sudden shift from normal family life to intensive medical treatment, hospital stays, and uncertainty about the future creates enormous stress. However, families are not alone in this journey, and many resources exist to help them cope.

Pediatric cancer centers recognize that treating the cancer is only part of caring for the child and family. Comprehensive support services are built into treatment programs and include professionals trained to help families navigate medical, emotional, financial, and practical challenges.

Medical Team Support

The pediatric oncology team becomes an extended family for many children and parents during treatment. This team includes not only oncologists and surgeons but also nurses, nurse practitioners, pharmacists, nutritionists, and other specialists who work together to provide comprehensive care.

Social workers at pediatric cancer centers help families navigate the healthcare system, connect with resources, address financial concerns, and cope with the emotional impact of the diagnosis. They can help with practical matters like insurance issues, transportation, and housing during treatment, as well as providing counseling and emotional support.

Child life specialists are professionals trained to help children and siblings understand and cope with medical experiences. They use play, preparation, and education to reduce anxiety and help children maintain normalcy during treatment. They also support siblings who may feel scared, confused, or neglected when a brother or sister is ill.

Psychological Support

The psychological impact of childhood cancer affects the entire family. Parents often experience anxiety, depression, grief, guilt, and fear. Children with cancer may have difficulty understanding their illness and may experience fear, anger, or regression. Siblings may feel scared, jealous, or overlooked.

Psychologists and counselors at pediatric cancer centers provide individual and family therapy to help with these challenges. Support groups connecting families with others going through similar experiences can be invaluable. Many families find comfort and practical advice from other parents who truly understand what they are going through.

What Research Is Being Done on Neuroblastoma?

Neuroblastoma research focuses on understanding the biology of the disease, developing more effective and less toxic treatments, and improving outcomes for high-risk patients. Areas of active research include immunotherapy approaches, targeted therapies based on tumor genetics, improved risk stratification, and strategies to overcome treatment resistance.

Research has dramatically improved outcomes for children with neuroblastoma over the past several decades. The development of risk-stratified treatment approaches, improved supportive care, and introduction of immunotherapy for high-risk disease have all resulted from dedicated research efforts. However, much work remains, particularly for children with high-risk and relapsed disease.

Most children with neuroblastoma are treated according to clinical trial protocols, which means they receive the most current evidence-based treatment while also contributing to research that will help future patients. Participation in clinical trials has been central to the progress made against this disease.

Current Research Priorities

Research efforts are focused on several key areas. Understanding the biological differences between tumors that regress spontaneously and those that are aggressive and resistant to treatment could lead to more precise treatment selection. Studies are investigating the genetic and epigenetic changes that drive neuroblastoma behavior.

Developing new treatments for high-risk disease remains a priority. Immunotherapy has already improved survival, and research continues to develop more effective immunotherapeutic approaches including CAR-T cells, vaccines, and combination strategies. Targeted therapies aimed at specific molecular abnormalities in tumors (like ALK inhibitors) are showing promise.

Reducing treatment toxicity while maintaining effectiveness is another important goal. Research aims to identify patients who can safely receive less intensive treatment without compromising outcomes, sparing them from unnecessary side effects. For patients requiring intensive treatment, studies are investigating ways to reduce late effects.