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 by the tumor, or may have protein-losing enteropathy with intestinal lymphangiectasia. Vasoactive intestinal peptide secretion may also occur upon chemotherapeutic treatment, and tumor resection reduces vasoactive intestinal peptide 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.[16,17,18]
The opsoclonus/myoclonus syndrome appears to be caused by an immunologic mechanism that is not yet fully defined.[16,19] Unlike most other neuroblastomas, the primary tumor is typically diffusely infiltrated with lymphocytes. 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.
Some patients may clinically respond to removal of the neuroblastoma, but improvement may be slow and partial; symptomatic treatment is often necessary. Adrenocorticotropic hormone treatment is thought to be effective, but some patients do not respond to adrenocorticotropic hormone.[17,19] Various drugs, plasmapheresis, intravenous gamma globulin, and rituximab have been reported to be effective in selected cases.[17,21,22,23] The long-term neurologic outcome may be superior in patients treated with chemotherapy, possibly because of its immunosuppressive effects.[15,21] The use of immunosuppressive therapy with and without intravenous gamma globulin in the treatment of patients with neuroblastoma and opsoclonus/myoclonus syndrome is under study by the Children's Oncology Group (COG) (COG-ANBL00P3).