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The opsoclonus/myoclonus syndrome appears to be caused by an immunologic mechanism that is not yet fully defined.[15,18] Unlike most other neuroblastomas, the primary tumor is typically diffusely infiltrated with lymphocytes.[19] 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.[15]

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.[16,18] Various drugs, plasmapheresis, intravenous gamma-globulin (IVIG), and rituximab have been reported to be effective in selected cases.[16,20,21,22] The long-term neurologic outcome may be superior in patients treated with chemotherapy, possibly because of its immunosuppressive effects.[14,20] The use of immunosuppressive therapy with and without IVIG in the treatment of patients with neuroblastoma and opsoclonus/myoclonus syndrome is under study by the Children's Oncology Group (COG) (COG-ANBL00P3).

Diagnosis

The diagnosis of neuroblastoma requires the involvement of pathologists who are familiar with childhood tumors. Some neuroblastomas cannot be differentiated, via conventional light microscopy, from other small round blue cell tumors of childhood, such as lymphomas, primitive neuroectodermal tumors, and rhabdomyosarcomas. Evidence for sympathetic neuronal differentiation may be demonstrated by immunohistochemistry, electron microscopy, or by finding elevated levels of serum catecholamines (e.g., dopamine and norepinephrine) or urine catecholamine metabolites, such as vanillylmandelic acid (VMA) or homovanillic acid (HVA). The minimum criterion for a diagnosis of neuroblastoma, as has been established by international agreement, is that it must be based on one of the following:

1. An unequivocal pathologic diagnosis made from tumor tissue by light microscopy (with or without immunohistology, electron microscopy, or increased levels of serum catecholamines or urinary catecholamine metabolites).[23]
2. The combination of bone marrow aspirate or trephine biopsy containing unequivocal tumor cells (e.g., syncytia or immunocytologically-positive clumps of cells) and increased levels of serum catecholamines or urinary catecholamine metabolites, as described above.[23]

However, primary tumor tissue is often needed to obtain all the biological data that may be used to determine treatment in current COG clinical trials. There is an absolute requirement for tissue biopsy to determine the International Neuroblastoma Pathology Classification (INPC) (see Cellular Classification section for more information). The INPC was used to determine treatment in the COG risk assignment schema for prior COG studies in patients with stage 2, 3, and 4S tumors. In the risk/treatment group assignment schema for the current COG studies, INPC is used to determine treatment for stage 3 and 4S patients as well as for stage 4 patients aged 18 months or younger. Additionally, a significant number of tumor cells are needed to determine MYCN copy number DNA index and 11q and 1p loss of heterozygosity (LOH). For older stage 4 patients, bone marrow with extensive tumor involvement combined with elevated catecholamine metabolites is adequate for study entry.