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Neuroblastoma is a cancer arising in the adrenal gland or less often from the extra-adrenal sympathetic chain, including 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 yr. 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. Although MYCN amplification is associated with advanced disease and unfavorable biology, it is also predictive of survival even in the absence of high-risk features. MYCN amplification occurs in about 20% of cases.
Neuroblastomas may begin in the abdomen (about 65%), thorax (15 to 20%), neck, pelvis, or other sites. Neuroblastoma occurs very rarely as a primary CNS 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. Ganglioneuroma is a fully differentiated, benign variant 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 Hb.
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. 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.
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-h 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.
The following should be done to evaluate for metastases:
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 mo (4S) or 18 mo (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. These factors help determine prognosis and guide intensity of therapy.
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 INRGSS. These systems are based on patient age, stage, histology, MYCN amplification, and DNA index. In addition, the INRG considers chromosome 11q aberrations in the evaluation. In both systems, these factors are used to stratify patients into low-, intermediate-, and high-risk categories that help determine prognosis and guide the intensity of treatment.
Prognosis of 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-yr event-free survival rate of 66%.
Treatment of neuroblastoma is based on the risk category (see also National Cancer Institute's Overview of Neuroblastoma Treatment).
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.
Overview of Neuroblastoma Treatment (National Cancer Institute)
Drug NameSelect Trade
carboplatinNo US brand name
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