Neuroblastoma

by Jason Wasserman MD PhD FRCPC
March 18, 2025

Neuroblastoma is a type of cancer that develops from nerve cells called neuroblasts, which are usually found in infants and young children. It typically starts in parts of the body that form from special neural crest cells during fetal development. Common locations include the adrenal glands (near the kidneys), the chest, abdomen, pelvis, and along the spine. Neuroblastoma is most commonly diagnosed in children younger than five years of age.

What are the symptoms of neuroblastoma?

The symptoms of neuroblastoma depend on where the tumour is located and whether it has spread. Common symptoms include a lump or swelling in the abdomen, difficulty breathing due to a mass in the chest, bone pain, swollen lymph nodes, and dark circles or bruising around the eyes (often called raccoon eyes). Neuroblastoma can sometimes cause special conditions known as paraneoplastic syndromes, leading to severe diarrhea, muscle weakness, coordination problems, or high blood pressure.

What causes neuroblastoma?

Neuroblastoma occurs when normal neuroblast cells become abnormal and begin to grow uncontrollably. Doctors do not fully understand what causes this transformation, but mutations (genetic changes) affecting certain genes, such as MYCN and ALK, or genes controlling how cells age (telomeres), play important roles. While most tumours are not inherited, a small number can run in families, usually due to mutations in the ALK or PHOX2B genes.

How is this diagnosis made?

Neuroblastoma is diagnosed based on imaging tests (like ultrasound, MRI, or CT scans) followed by a biopsy, where a pathologist examines a small sample of the tumour under a microscope. Special stains and tests, including immunohistochemistry and molecular testing, are used to confirm the diagnosis and to understand the characteristics of the cancer.

Types of neuroblastoma

Neuroblastomas are divided into three types based on how closely the cancer cells resemble normal nerve cells, a process called neuroblastic differentiation:

• Undifferentiated neuroblastoma: This rare type has primitive cells that do not look like nerve cells under the microscope. The cells appear as small, round, blue cells without clearly recognizable nerve features.
• Poorly differentiated neuroblastoma: This is the most common type. These cancer cells show some early signs of nerve cells, including small extensions called neurites and structures known as Homer Wright rosettes, but very few mature nerve-like features.
• Differentiating neuroblastoma: This type has cells clearly beginning to mature into normal nerve cells. These cells are larger, with abundant neurites and nuclei that show features of nerve cell maturation, including more defined cell structures.

Mitosis-karyorrhexis index

The mitosis-karyorrhexis index (MKI) is a measure used by pathologists to assess how quickly tumour cells are dividing or dying. It counts the number of cells undergoing mitosis (division) or karyorrhexis (cell death) per 5000 tumour cells examined under the microscope. The MKI is classified as low, intermediate, or high. Tumours with a high MKI tend to grow faster and have a worse prognosis. MKI helps determine whether the tumour has favourable or unfavourable histology according to the International Neuroblastoma Pathology Classification system.

Immunohistochemistry

Immunohistochemistry (IHC) is a test used by pathologists to detect specific proteins inside cancer cells, helping to confirm the diagnosis of neuroblastoma. Typical neuroblastoma cells show positive staining for proteins associated with nerve cells, including PHOX2B, synaptophysin, chromogranin, CD56, and tyrosine hydroxylase. These results help pathologists differentiate neuroblastoma from other types of tumours.

Molecular tests

Pathologists perform molecular tests on neuroblastoma tissue to better understand the cancer and predict its behaviour. These tests look at specific genes that play important roles in neuroblastoma, including:

• MYCN gene: Amplification (extra copies) indicates a more aggressive cancer.
• ALK gene: Mutations in this gene suggest a potentially aggressive tumour.
• TERT gene: Changes causing increased activity of this gene can make the tumour more aggressive.
• ATRX gene: Mutations linked to abnormal telomere lengthening are associated with poorer prognosis, particularly in older children.

International Neuroblastoma Pathology Classification

Pathologists use the International Neuroblastoma Pathology Classification system to group neuroblastomas into categories based on microscopic features such as the type of neuroblastoma, neuroblastic differentiation, and the mitosis-karyorrhexis index (MKI). This system classifies neuroblastomas into favourable or unfavourable histology. Favourable histology indicates the cancer is less aggressive, while unfavourable histology suggests a higher likelihood of rapid growth and spread.

Prognosis

The prognosis (outcome) for children with neuroblastoma depends on several factors:

• Clinical features: Younger children generally have a better prognosis than older children.
• Histologic features: Tumours with differentiating or favourable histology usually have a better outcome. Those with undifferentiated or poorly differentiated features, especially with a high MKI, tend to have worse outcomes.
• Molecular and genetic factors: MYCN gene amplification, ALK gene mutations, and abnormal telomere lengthening (TERT or ATRX changes) are linked to poorer outcomes.

Overall, the prognosis varies widely depending on these factors. Many children recover fully with appropriate treatment, while others may have more aggressive disease requiring intensive treatment.

Can neuroblastoma happen in adults?

Although very rare, neuroblastoma can occasionally occur in adults, but it behaves differently and tends to be more aggressive.

Can neuroblastoma be inherited?

Most cases of neuroblastoma occur without any family history. However, about 1–2% of cases run in families, usually related to genetic changes in the ALK or PHOX2B genes.

Is neuroblastoma always aggressive?

No, not all neuroblastomas behave aggressively. Some neuroblastomas in infants may even shrink or disappear on their own, while others require treatment. The behaviour of neuroblastoma depends on its location, molecular changes, and histologic classification.