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Types of Cancer > Pediatric Cancers > Neuroblastoma > NCI Resources
NCI/PDQ® Health professionals: Neuroblastoma Treatment (PDQ®)
Affiliation:
National Cancer Institute
Last Modified: December 10, 2009
TABLE OF CONTENTS
- Recurrent Neuroblastoma
Purpose of This PDQ® Summary
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This PDQ® cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of neuroblastoma. This summary is reviewed regularly and updated as necessary by the PDQ® Pediatric Treatment Editorial Board.
Information about the following is included in this summary:
- Unique aspects of neuroblastoma.
- Cellular classification.
- Stage information.
- Treatment options.
This summary is intended as a resource to inform and assist clinicians and other health professionals who care for pediatric cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ® Pediatric and Adult Treatment Editorial Boards use a formal evidence ranking system in developing their level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either standard or under clinical evaluation. These classifications should not be used as a basis for reimbursement determinations.
This summary is also available in a patient version, which is written in less technical language, and in Spanish.
Note: Some citations in the text of this section are followed by a level of evidence. The PDQ® Editorial Boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ® summary on Levels of Evidence for more information.)
The National Cancer Institute (NCI) provides the PDQ® pediatric cancer treatment information summaries as a public service to increase the availability of evidence-based cancer information to health professionals, patients, and the public.
Cancer in children and adolescents is rare. Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, pediatric surgical subspecialists, radiation oncologists, pediatric medical oncologists/hematologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will enable them to achieve optimal survival and quality of life. (Refer to the PDQ® summaries on Supportive and Palliative Care for specific information about supportive care for children and adolescents with cancer).
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. 1 At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients and families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.
In recent decades, dramatic improvements in survival have been achieved for children and adolescents with cancer. Childhood and adolescent cancer survivors require close follow-up since cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ® summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors).
Neuroblastoma is predominantly a tumor of early childhood, with two-thirds of the cases presenting in children aged 5 years or younger. Neuroblastoma originates in the adrenal medulla or the paraspinal sites where sympathetic nervous system tissue is present. These tumors can be divided into low-, intermediate-, and high-risk groups as illustrated in the Stage Information section of this summary. Low- and intermediate-risk patients usually have localized disease or are infants aged 18 months or younger. In rare cases, neuroblastoma can be discovered prenatally by fetal ultrasonography. 2
Predisposition to Neuroblastoma
Little is known about the events that predispose to the development of neuroblastoma. Parental exposures have not been definitively linked. In a genome-wide association study of 1,032 patients with neuroblastoma, a significant association was observed between a common genetic variation (polymorphism) at chromosome 6p22 and neuroblastoma. Tumors that arose in patients with this polymorphism tended to be clinically aggressive. 3 Germline deletion at the 1p36 or 11q14-23 locus are associated with the development of neuroblastoma and the same deletions are found somatically in sporadic neuroblastomas. 4 5
About 1% to 2% of patients with neuroblastoma have a family history of neuroblastoma, and these children are on average younger (9 months); about 20% have multifocal primary neuroblastomas. The primary cause of familial neuroblastoma is germline mutation in the ALK gene. 6 Similar somatic mutations and amplification of the ALK gene are found in 8% to12% of sporadic neuroblastomas. The mutations result in constitutive phosphorylation of ALK, which is critical for cell growth of the ALK-mutant neuroblasts. Thus, inhibition of ALK kinase is a potential target for treatment of neuroblastoma, especially in children whose tumors harbor an ALK mutation or ALK gene amplification. 7 Familial neuroblastoma is rarely associated with Ondine's curse (congenital central hypoventilation syndrome) with germline mutation of the PHOX2B gene. 8
The most common presentation of neuroblastoma is an abdominal mass. The most common symptoms in high-risk patients are due to a tumor mass or to bone pain from metastases. Proptosis and periorbital ecchymosis are common in these high-risk patients and arise from retrobulbar metastasis. Extensive bone marrow metastasis may result in pancytopenia. Abdominal distention with respiratory compromise due to massive liver metastases may occur in infants. Because they originate in paraspinal ganglia, neuroblastomas may invade through neural foramina and compress the spinal cord extradurally, causing paralysis. Horner syndrome may be caused by neuroblastoma in the stellate ganglion, and children with Horner syndrome without apparent cause should be examined for neuroblastoma and other tumors. 9 Fever, anemia, and hypertension are occasionally found. Multifocal (multiple primaries) neuroblastoma occurs rarely, usually in infants, and generally has a good prognosis. 10 On rare occasions, children may have severe, watery diarrhea due to the secretion of vasoactive intestinal peptide (VIP) by the tumor, or may have protein-losing enteropathy with intestinal lymphangiectasia. 11 VIP secretion may also occur upon chemotherapeutic treatment, and tumor resection reduces VIP secretion. 12
Children with neuroblastoma rarely present with paraneoplastic neurologic findings, including cerebellar ataxia or opsoclonus/myoclonus. 13 Neurologic dysfunction is most often a presenting symptom but may arise long after removal of the tumor. Opsoclonus/myoclonus syndrome is frequently associated with pervasive and permanent neurologic and cognitive deficits, including psychomotor retardation. 14 15 16
The opsoclonus/myoclonus syndrome appears to be caused by an immunologic mechanism that is not yet fully defined. 14 17 Unlike most other neuroblastomas, the primary tumor is typically diffusely infiltrated with lymphocytes. 18 Patients who present with this syndrome often have neuroblastomas with favorable biological features and are likely to survive, though tumor-related deaths have been reported. 14
Some patients may clinically respond to removal of the neuroblastoma, but improvement may be slow and partial; symptomatic treatment is often necessary. Adrenocorticotropic hormone (ACTH) treatment is thought to be effective, but some patients do not respond to ACTH. 15 17 Various drugs, plasmapheresis, intravenous gamma-globulin (IVIG), and rituximab have been reported to be effective in selected cases. 15 19 20 21 The long-term neurologic outcome may be superior in patients treated with chemotherapy, possibly because of its immunosuppressive effects. 13 19 The use of immunosuppressive therapy with and without IVIG in the treatment of patients with neuroblastoma and opsoclonus/myoclonus syndrome is currently under study by the Children's Oncology Group (COG) (COG-ANBL00P3).