Paraneoplastic neurologic findings, including cerebellar ataxia or opsoclonus/myoclonus, are rare in children with neuroblastoma. Opsoclonus/myoclonus syndrome is frequently associated with pervasive and permanent neurologic and cognitive deficits, including psychomotor retardation. Neurologic dysfunction is most often a presenting symptom but may arise long after removal of the tumor.[34,35,36]
Patients who present with opsoclonus/myoclonus syndrome often have neuroblastomas with favorable biological features and are likely to survive, though tumor-related deaths have been reported.
The opsoclonus/myoclonus syndrome appears to be caused by an immunologic mechanism that is not yet fully defined.[34,37] The primary tumor is typically diffusely infiltrated with lymphocytes.
Some patients may clinically respond to removal of the neuroblastoma, but improvement may be slow and partial; symptomatic treatment is often necessary. Adrenocorticotropic hormone or corticosteroid treatment is thought to be effective, but some patients do not respond to corticosteroids.[35,37] Various drugs, plasmapheresis, intravenous gamma globulin, and rituximab have been reported to be effective in selected cases.[35,39,40,41] The long-term neurologic outcome may be superior in patients treated with chemotherapy, possibly because of its immunosuppressive effects.[33,39]
Diagnostic evaluation of neuroblastoma includes the following:
- Metaiodobenzylguanidine (mIBG) scan.[42,43]
- Imaging of the primary tumor mass: This is generally accomplished by computed tomography or magnetic resonance imaging (MRI) with contrast. Paraspinal tumors that might threaten spinal cord compression are imaged using MRI.
- Urine catecholamine metabolites: Urinary excretion of the catecholamine metabolites vanillylmandelic acid (VMA) and homovanillic acid (HVA) per mg of excreted creatinine is measured before therapy. Collection of urine for 24 hours is not needed. If elevated, these markers can be used to determine the persistence of disease.
Serum catecholamines are not routinely used in the diagnosis of neuroblastoma except in unusual circumstances.
- Biopsy: Tumor tissue is often needed to obtain all the biological data required for risk-group assignment and subsequent treatment stratification in current Children's Oncology Group (COG) clinical trials. There is an absolute requirement for tissue biopsy to determine the International Neuroblastoma Pathology Classification (INPC). In the risk/treatment group assignment schema for COG studies, INPC has been used to determine treatment for patients with stage 3 disease, stage 4S disease, and patients aged 18 months or younger with stage 4 disease. Additionally, a significant number of tumor cells are needed to determine MYCN copy number, DNA index, and 11q and 1p loss of heterozygosity. For patients older than 18 months with stage 4 disease, bone marrow with extensive tumor involvement combined with elevated catecholamine metabolites may be adequate for diagnosis and assigning risk/treatment group; however, INPC cannot be determined from tumor metastatic to bone marrow. Testing for MYCN amplification and 1p/11q loss of heterozygosity may be successfully performed on involved bone marrow if there is at least 30% to 40% tumor involvement.
In rare cases, neuroblastoma can be discovered prenatally by fetal ultrasonography. Management recommendations are evolving with regard to the need for immediate diagnostic biopsy in infants aged 6 months and younger with suspected neuroblastoma tumors that are likely to spontaneously regress. Biopsy was not required for infants entered into a COG study of expectant observation of small adrenal masses in neonates, and 81% avoided undergoing any surgery at all. In a German clinical trial, 25 infants aged 3 months and younger with presumed neuroblastoma were observed without biopsy for periods of 1 to 18 months before biopsy or resection. There were no apparent ill effects of the delay.