Neuroblastoma is the most common cancer among infants Overview of Pediatric Cancer In the US, the overall incidence of cancer in children and adolescents has increased over time. From 1975 to 2022, rates increased by approximately 0.8 per 100,000 each year. However, death... read more and accounts for 7 to 8% of all childhood cancers (1 Reference Neuroblastoma is a cancer arising in the adrenal gland or less often from the extra-adrenal sympathetic chain, including in the retroperitoneum, chest, and neck. Diagnosis is confirmed by biopsy... read more ). Almost 90% of neuroblastomas occur in children < 5 years of age.
Neuroblastomas are immature, undifferentiated, malignant tumors. Ganglioneuroblastomas are intermediate tumors, and ganglioneuromas are fully differentiated, benign variants of neuroblastoma; collectively, these are referred to as neural crest tumors.
Most neuroblastomas produce catecholamines, which can be detected as elevated levels of urinary catecholamine breakdown products. Neuroblastomas do not typically cause severe hypertension because these tumors do not usually secrete epinephrine.
Neuroblastomas may begin in the abdomen (about 65%), thorax (15 to 20%), neck, pelvis, or other sites. Neuroblastoma occurs very rarely as a primary central nervous system cancer Overview of Central Nervous System Tumors in Children Central nervous system tumors are the most common solid cancer in children < 15 years old and are the leading cause of childhood death due to cancer. Diagnosis is typically by imaging (usually... read more .
About 40 to 50% of children have localized or regional disease at diagnosis; 50 to 60% have metastases at diagnosis. Neuroblastoma may metastasize to bone marrow, bone, liver, lymph nodes, or, less commonly, skin or brain. Bone marrow metastases may cause anemia and/or thrombocytopenia. Anemia also occasionally occurs when bleeding into these highly vascular tumors causes a rapid drop in hemoglobin.
Most neuroblastomas occur spontaneously, but 1 to 2% appear to be inherited. Some markers (eg, MYCN oncogene amplification, DNA index, segmental chromosomal aberrations, histopathology) correlate with progression and prognosis. MYCN amplification occurs in about 20% of neuroblastoma cases and is associated with advanced disease and unfavorable biology.
Pearls & Pitfalls
1. Park JR, Hogarty MD, Bagatell R, et al: Neuroblastoma: Epidemiology. In Pizzo and Poplack's Pediatric Oncology, 8th ed., edited by SM Blaney, LJ Helman, PC Adamson. Philadelphia, Wolters Kluwer, 2021, p. 647.
Symptoms and Signs of Neuroblastoma
Symptoms and signs of neuroblastoma depend on the site of the primary cancer and pattern of disease spread. The most common symptoms are abdominal pain, discomfort, irritability, decreased appetite, and a sense of fullness due to an abdominal mass.
Certain symptoms may result from metastases. These include bone pain due to widespread bone metastases, periorbital ecchymosis and proptosis due to retrobulbar metastasis, and abdominal distention and respiratory problems due to liver metastases, especially in infants. Children with anemia may have pallor, and those with thrombocytopenia may have petechiae.
Children occasionally present with focal neurologic deficits or paralysis due to direct extension of the cancer into the spinal canal. Tumors in the neck or upper chest may cause Horner syndrome Horner Syndrome Horner syndrome is ptosis, miosis, and anhidrosis due to dysfunction of cervical sympathetic output. (See also Overview of the Autonomic Nervous System.) Horner syndrome results when the cervical... read more (ptosis, miosis, anhidrosis). They may also present with paraneoplastic syndromes Paraneoplastic Syndromes Paraneoplastic syndromes are symptoms that occur at sites distant from a tumor or its metastasis. Although the pathogenesis remains unclear, these symptoms may be secondary to substances secreted... read more , such as cerebellar ataxia, opsoclonus-myoclonus, watery diarrhea, or hypertension.
Rare diseases that are associated with neural crest tumors (eg, neuroblastoma, ganglioneuroblastoma, ganglioneuroma) include ROHHADNET (rapid-onset obesity with hypothalamic dysfunction, hypoventilation, autonomic dysregulation, and neuroendocrine tumors) and congenital central hypoventilation syndrome.
Diagnosis of Neuroblastoma
Sometimes bone marrow aspirate or marrow core biopsy plus measurement of urinary catecholamine intermediates
Routine prenatal ultrasonography occasionally detects neuroblastoma. Patients presenting with abdominal symptoms or a mass require CT or MRI. Diagnosis of neuroblastoma is then confirmed by biopsy of any identified mass.
Alternatively, diagnosis can be established without biopsy or surgery of the primary tumor by finding characteristic cancer cells in a bone marrow aspirate or core biopsy plus elevated urinary catecholamine intermediates. These methods of diagnosis are not commonly done but can be useful in situations where biopsy and/or surgery is considered high risk because of patient or tumor characteristics.
Urinary vanillylmandelic acid (VMA), homovanillic acid (HVA), or both are elevated in ≥ 90% of patients. A 24-hour urine collection can be used, but a spot urine test is usually sufficient. If the primary site of the neuroblastoma is adrenal, it must be differentiated from Wilms tumor Wilms Tumor Wilms tumor is an embryonal cancer of the kidney composed of blastemal, stromal, and epithelial elements. Genetic abnormalities have been implicated in the pathogenesis, but familial inheritance... read more and other renal masses. It may also need to be differentiated from rhabdomyosarcoma Rhabdomyosarcoma Rhabdomyosarcoma is a cancer arising from embryonal mesenchymal cells that have potential to differentiate into skeletal muscle cells. It can arise from almost any type of muscle tissue in any... read more , hepatoblastoma Hepatoblastoma Primary liver cancer is usually hepatocellular carcinoma. The first manifestations of liver cancer are usually nonspecific, delaying the diagnosis. When diagnosed at advanced stages, prognosis... read more , lymphoma Overview of Lymphoma Lymphomas are a heterogeneous group of tumors arising in the reticuloendothelial and lymphatic systems. The major types are Hodgkin lymphoma Non-Hodgkin lymphoma See table Comparison of Hodgkin... read more , and tumors of genital origin.
Staging of neuroblastoma
The following should be done to evaluate for metastases:
Bone marrow aspirates and marrow core biopsies from multiple sites (typically, both posterior iliac crests)
Bone scan or iodine-131 metaiodobenzylguanidine (MIBG) scan (MIBG uptake occurs in > 90% of neuroblastomas)
Abdominal, pelvic, and chest CT or MRI
Cranial imaging with CT or MRI is indicated if symptoms or signs suggest brain metastases.
Results of these tests determine stage (extent of spread) of disease. The International Neuroblastoma Staging System (INSS) requires the results of surgery to determine stage. The International Neuroblastoma Risk Group Staging System (INRGSS) uses imaging-defined risk factors rather than surgery to stage neuroblastoma.
Neuroblastoma also has a unique stage called stage 4S (per INSS) or MS (per INGRSS) that often regresses spontaneously without treatment. This stage includes children < age 12 months (4S) or 18 months (MS) who have a localized primary tumor that has dissemination limited to skin, liver, and/or bone marrow. Marrow involvement should be minimal and limited to < 10% of the total nucleated cells and cannot involve the cortex of the bone.
At diagnosis, attempts should be made to obtain adequate tumor tissue to analyze for DNA index (the ratio of the amount of DNA in a tumor cell to the amount in a normal cell; the DNA index is thus a quantitative measure of chromosome content) and amplification of the MYCN oncogene.
Risk categorization of neuroblastoma
After staging, the staging information, along with other known prognostic factors, including patient age, histology, MYCN amplification, molecular information from the tumor, and DNA index, is used to categorize patients to guide treatment intensity and determine the prognosis for and likelihood of a recurrence of disease after treatment.
Risk categorization is complex, and two major risk group stratification systems exist, the Children's Oncology Group (COG) risk group and the International Neuroblastoma Risk Group (INRG) classification. In both systems, the staging and prognostic factors are used to stratify patients into low-, intermediate-, and high-risk categories that help determine prognosis and guide treatment. In addition, chromosome 11q aberrations are considered in the INRG classification.
Treatment of Neuroblastoma
Sometimes high-dose chemotherapy followed by stem cell transplantation
Sometimes radiation therapy
Cis-retinoic acid for maintenance therapy in high-risk disease
Treatment of neuroblastoma is based on the risk category (see also the National Cancer Institute's Neuroblastoma Treatment—Health Professional Version).
Surgical resection is important for low-risk and intermediate-risk disease. It is often delayed until adjuvant chemotherapy is given to improve the chance of adequate surgical resection.
Chemotherapy (typical drugs include vincristine, cyclophosphamide, doxorubicin, cisplatin, carboplatin, ifosfamide, and etoposide) is usually necessary for children with intermediate-risk or high-risk disease. In addition, high-dose chemotherapy with stem cell transplantation and cis-retinoic acid are also frequently used for children with high-risk disease.
Radiation therapy is sometimes needed for children with intermediate-risk disease or for children with inoperable tumors and is a standard part of treatment for local control of high-risk disease.
Immunotherapy using monoclonal antibodies against neuroblastoma antigens (GD2) combined with cytokines is used as maintenance therapy in high-risk disease. In a recent study of relapsed/refractory neuroblastoma, a combination of immunotherapy with chemotherapy led to impressive clinical responses (1 Treatment reference Neuroblastoma is a cancer arising in the adrenal gland or less often from the extra-adrenal sympathetic chain, including in the retroperitoneum, chest, and neck. Diagnosis is confirmed by biopsy... read more ).
1. Mody R, Naranjo A, Van Ryn C, et al: Irinotecan-temozolomide with temsirolimus or dinutuximab in children with refractory or relapsed neuroblastoma (COG ANBL1221): An open-label, randomised, phase 2 trial. Lancet Oncol 18(7):946–957, 2017. doi: 10.1016/S1470-2045(17)30355-8
Prognosis for Neuroblastoma
Prognosis for neuroblastoma depends on age at diagnosis, stage, and biologic factors (eg, histopathology, tumor cell ploidy in younger patients, MYCN amplification). Younger children with localized disease have the best outcome.
Survival rates for low-risk and intermediate-risk disease are about 90 to 95%. Historically, the survival rate for high-risk disease was about 15%. This rate has improved to > 50% with use of more intensified therapy. And a recent randomized study showed intensive therapy combined with immunotherapy resulted in a 2-year event-free survival rate of 66% (1 Prognosis reference Neuroblastoma is a cancer arising in the adrenal gland or less often from the extra-adrenal sympathetic chain, including in the retroperitoneum, chest, and neck. Diagnosis is confirmed by biopsy... read more ).
1. Park JR, Kreissman SG, London WB, et al: A phase III randomized clinical trial (RCT) of tandem myeloablative autologous stem cell transplant (ASCT) using peripheral blood stem cell (PBSC) as consolidation therapy for high-risk neuroblastoma (HR-NB): A Children's Oncology Group (COG) study. J Clin Oncol 34(Suppl 18):LBA3-LBA, 2016. doi: 10.1200/JCO.2016.34.15_suppl.LBA3
The following English-language resources may be useful. Please note that THE MANUAL is not responsible for the content of these resources.
International Neuroblastoma Staging System (INSS): A surgical staging system that requires the results of surgery to determine stage
International Neuroblastoma Risk Group Staging System (INRGSS): A preoperative staging system that uses imaging-defined risk factors rather than surgery to stage neuroblastoma
Children's Oncology Group (COG) and the International Neuroblastoma Risk Group (INRG) classification: COG and INRG risk group stratification systems use staging and prognostic factors to stratify patients into low-, intermediate-, and high-risk categories that help determine prognosis and guide treatment
National Cancer Institute: Neuroblastoma Treatment—Health Professional Version
Drugs Mentioned In This Article
|Drug Name||Select Trade|
|Adrenaclick, Adrenalin, Auvi-Q, Epifrin, EpiPen, Epipen Jr , Primatene Mist, SYMJEPI, Twinject|
|Oncovin, Vincasar PFS|
|Cyclophosphamide, Cytoxan, Neosar|
|Adriamycin, Adriamycin PFS, Adriamycin RDF, Rubex|
|Etopophos, Toposar, VePesid|