Neuroblastoma

Though considered rare overall, neuroblastoma is the most common non-brain tumor in infants and accounts for 15% of all pediatric cancer-related deaths.[5] It occurs in as many as 800 children in the US annually, with a prevalence of approximately 1 case in 7,000 live births.[6] The overall incidence is 8.3 cases per 1 milllion children under the age of 15 years. Ninety percent of all cases are diagnosed before the age of 5 years, and the median age at diagnosis is 17 months.[3]

Based on US cancer statistics, non-Hispanic white children have the highest risk of developing neuroblastoma. Black patients have a 25% lower risk and Hispanic patients have roughly half the risk of white children.[6]

Though it is likely caused by genetic variants, the pathogenic mutations accounting for the majority of cases have not been identified. Screening for neuroblastoma in the general population is not currently recommended.

In 75% of familial cases of neuroblastoma, an ALK gene variant has been identified[7] (though familial cases account for only perhaps 2% of patients with neuroblastoma).[2] Other gene variants that may play a role include PHOX2B, germline deletions at the 1p36 or 11q14-23 locus, BARD1, ERCC2, CHEK2, MSH3, and MYCN overexpression, among others.[1,2] The most malignant tumors demonstrate MYCN gene amplification, which is associated with a poorer prognosis.[1]

This neoplasia forms from neuroblasts or neural crest progenitor cells. Though it is often first diagnosed within the first 18 months of life, changes to the neuroblasts may appear even prior to birth. Tumors often first appear in the adrenal glands, but they can be found virtually anywhere in the sympathetic nervous system, including the spine and paraspinal nerve tissue, from the neck to the pelvis.[2]

Its presentation is highly variable and may range from a relatively benign palpable tumor to a high-risk, aggressively metastatic disease. An individual patient’s risk score is defined by either the traditional Children’s Oncology Group definition (i.e., low, intermediate, or high risk) or the more current International Neuroblastoma Response Criteria (INRC) (i.e., very low, low, intermediate, and high risk). The INRC classification utilizes the child’s age, cancer staging, tumor histology, MYCN gene amplification status, chromosome 1p or 11q changes in tumor cells, and DNA ploidy in the tumor cells.[3]

The most common initial presentation is an abdominal mass. In cases of metastatic disease, a range of signs and symptoms may appear, including abdominal distension, bone pain, pancytopenia, paralysis (which may be related to spinal cord compression), subcutaneous skin nodules, and proptosis or periorbital ecchymosis.[3]

Furthermore, patients may have chronic diarrhea due to the secretion of vasoactive intestinal peptide. If the neuroblastoma has spread to the bone, significant pain may be apparent or even fractures, and a limp may be noticeable. In addition, thoracic lesions may present (concurrent with Horner syndrome).[3]

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As mentioned earlier, the presentation and progression of neuroblastoma is highly variable. The diagnosis of neuroblastoma is generally based on medical history and exam, a neurologic examination, imaging tests (which may include ultrasound, x-rays, CT or MRI scanning), as well as laboratory testing (e.g., blood and urine testing for catecholamine levels).

Tumor and/or bone marrow biopsy will confirm the diagnosis. An imaging scan of meta-iodobenzylguanidine (MIBG), which uses radioactive iodine as a marker, can help identify whether the neuroblastoma has metastasized (and identify the location of the new tumor[s]).[2]

Treatment for an individual patient is dependent on their risk classification and whether the patient is experiencing a relapse or initial presentation.[1] For example, if the neuroblastoma is small and localized, and the patient’s tumor is considered to be low risk, surgical removal alone may be possible. For larger tumors that are classified as intermediate or high risk, chemotherapy may be used before or after surgery to shrink it in preparation for surgical removal or to ensure that any remaining cancer cells are eliminated.[2] Chemotherapy may include a combination of several well-known pharmaceuticals, including cisplatin, cyclophosphamide, vincristine, doxorubicin, etoposide, and potentially others.

Patients with high-risk disease are more likely to be given high-dose chemotherapy followed by stem-cell transplant. After completing this therapy, patients may be prescribed isotretinoin, which has been shown to reduce the risk of a neuroblastoma relapse.[2]

Radiation therapy may be given in one of two ways: external beam radiation or MIBG radiotherapy. With MIBG radiotherapy, a radioactive form of MIBG is injected, which targets neuroblastoma cells only.[2]

Anti-GD2 monoclonal antibodies are given to children with high-risk or relapsed neuroblastoma after high-dose chemotherapy and stem-cell transplant. This form of immunotherapy targets the GD2 antigen on the surface of most neuroblastoma tumor cells.[3] Two GD2-targeted agents are FDA approved for use in neuroblastoma. Naxitamab, which was approved by the FDA in 2020, is administered with granulocyte-macrophage colony-stimulating factor. Dinutuximab was approved in 2015 and is typically used after high-dose chemotherapy and stem-cell transplant, along with GM-CSF, interleukin-2, and isotretinoin, to target residual cancer cells and destroy them.[3]

Survival rates are highly dependent on a patient’s early diagnosis and neuroblastoma risk classification.[8] In cases of low-risk neuroblastoma, cure is often achieved. Five-year survival in patients with low-risk disease is greater than 95%. Even in those with intermediate risk, 5-year survival exceeds 90%.[2]

Children with aggressive, high-risk disease who experience relapse with 18 months of initial diagnosis have a poor prognosis (5-year survival < 20%).[9] However, therapeutic advances for the larger population with high-risk disease have improved patients’ prognoses, raising 5-year overall survival to 50%.[1,4]

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A scoring system to rate the amount of MIBG uptake within neuroblastoma tumor sites, Curie scoring has been found to be a useful prognostic indicator for high-risk neuroblastoma. Specifically, a Curie score greater than 2 at the completion of induction chemotherapy portended poor outcomes in two major studies.[10,11]

However, the validity of the Curie scoring as a prognostic indicator had not been tested if the child was administered an anti-GD2 monoclonal antibody after induction chemotherapy, which is becoming a standard of care.[12,13] In 2023, researchers found that for patients receiving high-dose chemotherapy and an anti-GD2 monoclonal antibody, a Curie Score of no more than 12 at diagnosis was associated with a significantly higher 3-year event-free survival and overall survival compared with patients with higher scores. They also found that patients with a Curie Score of 0 at the end of induction also had significantly higher 3-year event-free and overall survivals compared with those who had higher scores at that timepoint.

A check of ClinicalTrials.gov in January 2025 revealed 100 studies actively recruiting patients with neuroblastoma.

American Childhood Cancer Organization

National Organization for Rare Disorders (NORD)

Children’s Neuroblastoma Cancer Foundation

The Neuroblastoma Children’s Cancer Society

1. Matthay KK, Maris JM, Schleiermacher G, et al. Neuroblastoma. Nat Rev Dis Primers. 2016;2:16078.
2. American Cancer Society. Neuroblastoma survival rates by risk group. April 28, 2021. https://www.cancer.org/cancer/types/neuroblastoma/detection-diagnosis-staging/survival-rates.html.
3. National Cancer Institute. Neuroblastoma treatment (PDQ). November 22, 2024. https://www.cancer.gov/types/neuroblastoma/hp/neuroblastoma-treatment-pdq#_534_toc.
4. Shohet JM, Lowas SR, Nuchtern JG. Treatment and prognosis of neuroblastoma. UpToDate 2021. https://www.uptodate.com/contents/treatment-and-prognosis-of-neuroblastoma.
5. Mahapatra S, Challagundla KB: Neuroblastoma. Treasure Island, FL: StatPearls Publishing LLC, 2022. https://www.ncbi.nlm.nih.gov/books/NBK448111/#:~:text=Neuroblastoma%20(NB)%20is%20the%20most,from%20neural%20crest%20progenitor%20cells.
6. American Cancer Society. Cancer Facts & Figures 2020. https://www.cancer.org/research/cancer-facts-statistics/all-cancer-facts-figures/cancer-facts-figures-2020.html
7. Mossé YP, Laudenslager M, Longo L, et al.: Identification of ALK as a major familial neuroblastoma predisposition gene. Nature. 2008;455:930-935.
8. 8.Pinto NR, Applebaum MA, Volchenboum SL, et al. Advances in risk classification and treatment strategies for neuroblastoma. J Clin Oncol. 2015;30:3008-3017.
9. London WB, Castel V, Monclair T, et al. Clinical and biologic features predictive of survival after relapse of neuroblastoma: A report from the International Neuroblastoma Risk Group project. J Clin Oncol. 2011;29:3286-3292.
10. Yanik GA, Parisi MT, Shulkin BL, et al. Semiquantitative mIBG scoring as a prognostic indicator in patients with stage 4 neuroblastoma: A report from the Children’s Oncology Group. J Nucl Med. 2013;54:541-548.
11. Yanik GA, Parisi MT, Naranjo A, et al. Validation of postinduction Curie scores in high-risk neuroblastoma: A Children’s Oncology Group and SIOPEN group report on SIOPEN/HR-NBL1. J Nucl Med. 2018;59:502-508.
12. Streby KA, Parisi MT, Shulkin BL, et al. Impact of diagnostic and end-of-induction Curie scores with tandem high-dose chemotherapy and autologous transplants for metastatic high-risk neuroblastoma: A report from the Children’s Oncology Group. Pediatr Blood Cancer. 2023;70(8):e30418.
13. Ladenstein R, Pötschger U, Valteau-Couanet D, et al. Investigation of the role of dinutuximab beta-based immunotherapy in the SIOPEN High-Risk Neuroblastoma 1 Trial (HR-NBL1). Cancers (Basel). 2020;12(2):309.