Neuroblastoma is a rare form of childhood cancer that develops in immature nerve tissue, most commonly affecting babies and young children before the age of five. This complex disease begins in nerve cells called neuroblasts and often occurs in the adrenal glands, though it can appear anywhere along the sympathetic nervous system from the neck to the pelvis.

Understanding the Scope: Epidemiology of Neuroblastoma

Neuroblastoma stands as one of the most puzzling cancers in pediatric medicine. While it is rare in the general population, it represents the most common cancer found in babies and the third most common type of childhood cancer overall, following leukemia and brain tumors. In the United States, approximately 650 to 800 new cases are diagnosed each year, which translates to about one case for every 7,000 live births^[1][2][3].

The disease shows a strong preference for very young children. About 37 percent of patients are diagnosed as infants, and approximately 90 percent are younger than five years at diagnosis. The median age when neuroblastoma is first detected is just 17 months^[3][7]. What makes this particularly striking is that the highest rate of diagnosis occurs in the first month of life, highlighting how neuroblastoma is truly a disease of infancy and early childhood^[7].

Interestingly, neuroblastoma appears to affect different racial and ethnic groups at varying rates. Non-Hispanic White children have the highest risk of developing this cancer compared to all other race and ethnicity groups. Hispanic children, non-Hispanic Asian or Pacific Islander children, non-Hispanic American Indian and Alaska Native children, and non-Hispanic Black children all show lower relative risks^[7]. There is also a slight gender difference, with boys being affected slightly more often than girls at a ratio of about 1.2 to 1^[9].

What Causes Neuroblastoma?

The exact cause of neuroblastoma remains largely unknown to medical science. Unlike many adult cancers that can be linked to lifestyle factors or environmental exposures, neuroblastoma develops from changes in cells that occur before or shortly after birth. The disease arises when developing nerve cells, called neuroblasts (immature nerve cells that have not yet fully developed), begin to grow and multiply uncontrollably^[1][2].

These neuroblasts are present in a developing baby and normally mature into functioning nerve cells or into cells that make up the adrenal glands. However, in neuroblastoma, something goes wrong during this development process. Changes to genes or chromosomes may cause these developing nerve cells to multiply uncontrollably, leading to the formation of tumors. These tumors often form before birth during the fetal stage, though symptoms may not appear until later in infancy or early childhood^[2][3].

Scientists have identified several genetic changes associated with neuroblastoma. The disease involves various cytogenetic aberrations (abnormalities in chromosomes), including loss of parts of chromosome 1p and 11q, changes in the number of copies of 1q21, and gain of chromosome 17q^[3]. Particularly important is the amplification of the MYCN oncogene (a gene that when altered can contribute to cancer development), which is found in approximately 25 percent of patients and is associated with the poorest outcomes^[3].

Studies of environmental factors have not clearly linked any specific exposures during pregnancy or conception to the development of neuroblastoma. While researchers continue to investigate possible environmental influences, no definitive connections have been established^[3][7].

Risk Factors: Who Is More Likely to Develop Neuroblastoma?

Most cases of neuroblastoma occur sporadically, meaning they happen by chance without any clear reason. However, certain factors have been identified that may increase the risk of developing this cancer. Understanding these risk factors helps families and doctors stay vigilant, though it’s important to note that having a risk factor does not guarantee a child will develop the disease^[11].

Family history plays a small but significant role in neuroblastoma. About one to two percent of children with neuroblastoma have a family history of the disease, known as familial or inherited neuroblastoma^[2][3]. In these families, genetic mutations in specific genes have been identified. The most commonly affected genes are ALK and PHOX2B, and mutations in these genes are associated with inherited forms of neuroblastoma^[2][3].

Children with familial neuroblastoma often have some distinguishing features. They are frequently diagnosed at an earlier age than children with sporadic disease, with a median age of nine months. They are also more likely to have multiple primary tumors, meaning cancer can appear in more than one location in the body^[9].

Certain genetic conditions and cancer predisposition syndromes also increase the risk of neuroblastoma. Children with Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, Noonan syndrome, Costello syndrome, neurofibromatosis type 1, or pheochromocytoma/paraganglioma syndromes have an elevated risk compared to the general population^[2][11]. Some children with these conditions may benefit from regular screening for neuroblastoma until they reach ten years of age^[4].

Neuroblastoma has also been diagnosed in conjunction with other congenital conditions such as Hirschsprung’s disease and congenital hypoventilation disorder^[3]. While these associations exist, most children with neuroblastoma have no identifiable risk factors or family history.

Recognizing the Signs: Symptoms of Neuroblastoma

The symptoms of neuroblastoma can vary greatly from child to child, depending primarily on where the tumor is located in the body and whether the cancer has spread to other areas. Because neuroblastoma can occur anywhere along the sympathetic nervous system, the signs can be quite different from one patient to another. This variability sometimes makes the disease challenging to recognize in its early stages^[1][3].

The most common symptom is a lump or swollen area that can be felt or seen. Since neuroblastoma most often starts in the adrenal glands or in nerve tissue in the abdomen, many children present with a mass in the belly area. Parents might notice their child’s stomach appears swollen or protruding. If the tumor is in the chest, it might cause difficulty breathing or a lump that can be felt in the chest area. When neuroblastoma occurs in the neck, a visible or palpable lump may appear there^[2][4].

Bone pain is another significant symptom, particularly when neuroblastoma has spread to the bones. Children may complain of pain in their bones or may start limping without any apparent injury^[2][4]. This can be especially noticeable if the child was previously walking normally and suddenly develops an unexplained limp.

Eye-related symptoms are distinctive features of neuroblastoma. Some children develop bulging eyes, dark circles or bruising around the eyes that look like black eyes, or drooping upper eyelids. These symptoms can occur when cancer spreads to the area behind the eyes or when it affects nerves that control eye movement. Some children may also experience uncontrollable eye movements^[2][4].

General symptoms that affect the whole body can also appear. These include unexplained fever, feeling very tired, loss of appetite leading to weight loss, and easy bruising or bleeding. Some children may develop anemia (a condition where the body doesn’t have enough healthy red blood cells)^[2][4].

In some cases, neuroblastoma can cause more unusual symptoms. High blood pressure might develop if the tumor compresses the kidney or if the tumor itself produces substances that raise blood pressure. Some children experience increased heart rate and flushing due to substances produced by the tumor. In rare instances, children might have diarrhea caused by tumor-produced substances. Weakness or even paralysis can occur if the tumor grows near or presses on the spinal cord^[2][8].

A rare but notable condition called opsoclonus/myoclonus syndrome (a neurological condition causing rapid, irregular eye movements and jerky muscle movements) can occur with neuroblastoma. Children with this syndrome experience uncontrollable eye movements and “jerky” body movements^[2][7].

Prevention: Can Neuroblastoma Be Prevented?

Currently, there are no known ways to prevent neuroblastoma from developing. Since the disease originates from changes that occur during fetal development or shortly after birth, and because no specific environmental exposures have been definitively linked to its occurrence, traditional prevention strategies do not apply to this cancer^[3][7].

For families with a known genetic predisposition to neuroblastoma, such as those with mutations in the ALK or PHOX2B genes, or those with certain hereditary syndromes, genetic counseling can be valuable. Genetic counselors and specially trained health professionals can discuss the family’s medical history and help determine whether genetic testing might be beneficial. This information can help families understand their risks and make informed decisions about monitoring^[11].

In families with a history of neuroblastoma or in children with specific genetic mutations or hereditary syndromes, regular screening may be recommended until the child reaches ten years of age. This screening typically involves several tests performed at regular intervals, including abdominal ultrasound to look for tumors, urine tests to check for elevated levels of substances called catecholamines that neuroblastoma cells produce, and chest x-rays. These monitoring approaches aim for early detection rather than prevention, allowing treatment to begin as soon as possible if neuroblastoma develops^[4].

It’s important to understand that large-scale screening programs for neuroblastoma in the general population of infants have been studied but are not recommended. Population-based studies showed that while screening could detect neuroblastomas, it often identified tumors that would have regressed on their own and did not improve overall survival rates^[7].

What Happens in the Body: Pathophysiology of Neuroblastoma

Neuroblastoma originates in the cells that form the sympathetic nervous system. This part of the nervous system controls automatic body functions like heart rate, blood pressure, and digestion. During normal development, special cells called neural crest progenitor cells migrate to various parts of the body and mature into different types of cells, including nerve cells and the cells of the adrenal glands^[3][7].

The adrenal glands sit on top of each kidney in the back of the upper abdomen. These small but important glands make hormones that help the body respond to stress, regulate metabolism, control the immune system, and maintain blood pressure. Neuroblastoma most commonly arises in these adrenal glands, but it can also develop anywhere along the chain of nerve tissue that runs from the neck down through the chest and into the abdomen and pelvis^[1][4].

In neuroblastoma, the normal process of nerve cell development goes wrong. Instead of maturing into fully functional nerve cells, the neuroblasts remain immature and begin to multiply uncontrollably. This uncontrolled growth leads to the formation of a solid tumor mass. The genetic changes that drive this abnormal growth can involve many different genes and chromosomes^[2][3].

One of the most significant genetic changes is the amplification of the MYCN oncogene. When multiple copies of this gene are present, the neuroblastoma tends to be much more aggressive and harder to treat. This genetic change is found in about 25 percent of neuroblastoma cases and strongly influences how doctors classify the disease and plan treatment^[3].

Neuroblastoma has the ability to spread beyond its original location. When this happens, the cancer cells most commonly travel to lymph nodes, bone marrow, bones, liver, and skin in infants and children. In adolescents, the disease may also spread to the lungs and brain. By the time many children are diagnosed, the cancer has already spread to other parts of the body, which is referred to as metastatic disease (cancer that has spread from where it started to other parts of the body). In fact, 70 to 80 percent of children have metastatic disease at the time of diagnosis^[2][11].

The biological behavior of neuroblastoma is highly variable and quite unique among cancers. Some neuroblastomas, particularly in very young infants, can spontaneously mature into benign tumors or simply disappear without any treatment. Other neuroblastomas are extremely aggressive and difficult to treat despite intensive therapy. Scientists are working to understand what makes some neuroblastomas behave so differently from others, and this understanding helps doctors categorize patients into risk groups and tailor treatment accordingly^[2][9].

The tumor can produce various substances that cause symptoms. For example, neuroblastoma cells can make catecholamines, which are chemicals that normally help the body respond to stress. When these are produced in excess by the tumor, they break down into substances called vanillylmandelic acid (VMA) and homovanillic acid (HVA), which can be detected in urine tests. Finding elevated levels of these substances is one way doctors diagnose neuroblastoma^[4].

The location and extent of the tumor affect how it impacts the body. A tumor in the chest might press on airways and make breathing difficult. A tumor in the abdomen can press on organs and cause pain or swelling. If the tumor grows near the spine, it can compress the spinal cord, potentially causing weakness or paralysis. Understanding these physical effects helps doctors anticipate complications and plan appropriate treatment strategies^[2][8].