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. 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.[5,6]
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. 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. Familial neuroblastoma is rarely associated with Ondine's curse (congenital central hypoventilation syndrome) with germline mutation of the PHOX2B gene.
Presentation of Neuroblastoma
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. Fever, anemia, and hypertension are occasionally found. Multifocal (multiple primaries) neuroblastoma occurs rarely, usually in infants, and generally has a good prognosis. 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. VIP secretion may also occur upon chemotherapeutic treatment, and tumor resection reduces VIP secretion.
Children with neuroblastoma rarely present with paraneoplastic neurologic findings, including cerebellar ataxia or opsoclonus/myoclonus. 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.[15,16,17]