Paraneoplastic syndromes in neuroblastoma.

The term “paraneoplastic syndromes” refers to dysfunction of an organ or tissue caused by cancer, but not a direct effect of either the tumor or its metastases. Paraneoplastic syndromes have several causes. Organ infarction (e.g., brain) caused by tumor hypercoagulability is sometimes the presenting sign in a patient not known to have cancer. Lymphomainduced immune deficiency can lead to opportunistic infections that are sometimes fatal. In this issue of the Journal, Chan et al describe a patient whose neuroblastoma caused two paraneoplastic syndromes, each with a different pathogenesis. The first symptom, diarrhea, resulted from secretion by the tumor of a normal substance (vasoactive intestinal peptide) that is toxic in excess. The second symptom was opsoclonus caused by an immune reaction to the tumor that damaged structures in the brain. As is characteristic of paraneoplastic syndromes, both preceded discovery of the tumor. That substances secreted by a tumor can cause symptoms remote from the site of the tumor (in Chan et al’s patient, diarrhea) is well known. In the adult, hypercalcemia caused by secretion of parathyroid hormone-related protein and Cushing’s syndrome from secretion of an ACTH-like protein are both well-recognized syndromes with systemic and neurologic symptoms. Even more common is weight loss and cachexia associated with cancers, probably caused by tumor secretion of catabolic cytokines. The importance of these hormone-induced paraneoplastic syndromes is that they may, as in the patient presented by Chan et al, be the presenting complaint of a tumor. If treatment is delayed, patients may not have such a benign prognosis as in the patient described here. The second reason is the treatment of the tumor may ameliorate the paraneoplastic syndrome. That an immune response generated by a cancer can damage normal tissue is also well known. Antibodies that react both with the tumor and the tissue that is damaged have been identified and characterized in many neurologic paraneoplastic syndromes of adults, such as paraneoplastic cerebellar degeneration, opsoclonus-myoclonus, and Lambert-Eaton myasthenic syndrome. In opsoclonus-myoclonus-ataxia occurring in children with neuroblastoma, the situation is different. A specific antibody has been sought intensively, and although anti-neuronal antibodies are found at increased frequency in neuroblastoma patients with opsoclonus-myoclonus, no antibody that meets the criteria established in the adult disorders has yet been found. This is curious because the disorder certainly appears to be immune-mediated. Not only do patients with neuroblastoma-associated opsoclonusmyoclonus have indolent tumors, but also one usually finds an intense inflammatory response in those tumors associated with the paraneoplastic syndrome, suggesting an immune reaction against the tumor. Furthermore, pleocytosis in the cerebrospinal fluid suggests a nervous system immune reaction; there is also often a dramatic clinical response to immune suppression with corticosteroids or ACTH. Thus, although the exact pathogenesis of ataxia and opsoclonus-myoclonus in children with neuroblastoma is unknown, an immunemediated pathogenesis certainly seems far and away the most likely cause. Whether the tissue destruction is antibody or T-cell mediated, or both, is unclear. Nor is it clear whether early diagnosis of the tumor and its appropriate treatment obviate some of the long-term consequences of this abnormality. Whatever the pathogenesis or its long-term effect, ap-