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Neuroblastoma

By

Renee Gresh

, Nemours A.I. duPont Hospital for Children

Last full review/revision Jul 2019| Content last modified Jul 2019
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Topic Resources

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. Treatment may include surgical resection, chemotherapy, radiation therapy, high-dose chemotherapy with stem cell transplantation, cis-retinoic acid, and immunotherapy.

Neuroblastoma is the most common cancer among infants. Almost 90% of neuroblastomas occur in children < 5 years of age. Most neuroblastomas occur spontaneously, but 1 to 2% appear to be inherited. Some markers (eg, MYCN oncogene amplification, hyperdiploidy, 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

  • Neuroblastoma is the most common cancer among infants.

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.

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 are immature, undifferentiated, malignant tumors. Ganglioneuroblastomas are intermediate tumors, and ganglioneuromas are fully differentiated, benign variants of neuroblastoma.

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.

Symptoms and Signs

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, 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 (ptosis, miosis, anhidrosis). They may also present with paraneoplastic syndromes, such as cerebellar ataxia, opsoclonus-myoclonus, watery diarrhea, or hypertension.

ROHHADNET (rapid-onset obesity with hypothalamic dysfunction, hypoventilation, autonomic dysregulation, and neuroendocrine tumors) is a very rare disease that can be associated with ganglioneuroblastomas and ganglioneuromas in the abdomen and lungs.

Diagnosis

  • CT/MRI

  • Biopsy

  • 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 and other renal masses. It may also need to be differentiated from rhabdomyosarcoma, hepatoblastoma, lymphoma, 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)

  • Skeletal survey

  • Bone scan or iodine-131 metaiodobenzylguanidine (MIBG) scan

  • Abdominal, pelvis, 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 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, and DNA index, is used to categorize patients to guide treatment intensity and determine the prognosis and likelihood of a recurrence of disease after treatment. Risk categorization is complex, and two major risk group stratification systems exist, one developed by the Children's Oncology Group (COG) and the other by the International Neuroblastoma Risk Group Staging System.. 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, the International Neuroblastoma Risk Group considers chromosome 11q aberrations in the evaluation.

Prognosis

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%. 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

  • 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.

Treatment

  • Surgical resection

  • Usually chemotherapy

  • Sometimes high-dose chemotherapy followed by stem cell transplantation

  • Sometimes radiation therapy

  • Cis-retinoic acid for maintenance therapy in high-risk disease

  • Immunotherapy

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 disease. High-dose chemotherapy with stem cell transplantation and cis-retinoic acid are frequently used for children with high-risk disease.

Radiation therapy is sometimes needed for children with intermediate-risk or high-risk disease or for inoperable tumors.

Immunotherapy using monoclonal antibodies against neuroblastoma antigens combined with cytokines is the latest approach to treating high-risk disease.

More Information

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