Metastatic Disease to the Central Nervous System

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Central nervous system (CNS) neuroblastoma, involving brain parenchyma or leptomeninges at the time of diagnosis in all published series is rare. This must be distinguished from dural or bone based metastases without invasion into the parenchyma. In a review of 251 patients with metastatic neuroblas-toma treated at Memorial Sloan-Kettering Cancer, no patient had brain parenchymal or leptomeningeal disease at the time of diagnosis (Kramer et al. 2001). Although CNS neuroblastoma may result from direct extension of spread of neuroblasts from bone or bone marrow, the cerebrospinal fluid (CSF) appears an equally efficient route of neuraxis dissemination (Banerjee et al. 1995). Autopsy findings suggest that the tumor may penetrate the spinal meninges and disseminate through the CSF. In patients with no obvious breakdown of the blood-brain barrier, lep-tomeningeal neuroblastoma is presumed to occur by hematogenous spread. As treatment for high-risk neuroblastoma has become more intensive, the pattern of disease relapse has changed and the neuraxis appears to be an important sanctuary site (Kramer et al. 2001). The incidence of CNS relapse in large series ranges from 1 to 16% (Kramer et al. 2001; Blatt et al. 1997; Shaw 1992; Kellie et al. 1991; Rohrlich et al. 1989), with the median time to CNS relapse from initial diagnosis ranging from 13 to 20 months.

The CNS is increasingly recognized as an isolated site of relapse in patients with no evidence of recurrent systemic disease. No consistent prognostic marker predicts which patients are at risk for development of CNS disease (Table 13.2). In two large series, diagnostic lumbar punctures in patients with known bone marrow disease was associated with relapsed disease in the CNS (Kramer et al. 2001; Matthay et al. 2003), raising the possibility that this procedure may enhance the ability of circulating or epidural microscopic tumor cells to seed the craniospinal axis.

Patients with CNS disease may present with altered mental status, headache, seizures, paresthesias, dysarthria, visual disturbance, vomiting, or ataxia; thus, any new cerebral neurologic symptom should provoke a search for brain metastases (Lassman and DeAngelis 2003). The brain should also be evaluated for disease in the presence of an unexplained rise in urine catecholamines (Kramer et al. 2001). The diagnosis is made by radiographic imaging studies, most commonly CT or MRI. Cerebrospinal fluid cytology is positive in approximately one-third of the patients with disease detected by CT or MRI (Kramer et al. 2001).

By the time neuraxis metastases are clinically evident, limited palliative options exist. The median survival from the time of CNS disease detection in most series is 4-14 months (Kramer et al. 2001; Shaw 1992; Kellie et al. 1991; Rohrlich et al. 1989). Corticosteroids often provide a dramatic, albeit temporary, benefit from brain metastases associated with vasogenic edema (Lassman and DeAngelis 2003). Surgery for solitary metastases and radiotherapy are used for palliation. Stereotactic radiosurgery for small, single

Table 13.2. Statistically significant prognostic factors predicting the development of central nervous system (CNS) metastases in patients with neuroblastoma


No. of CNS events/patients

Prognostic factor(s) identified

Kramer et al.(2001)

11 of 251 patients with metastatic disease (4.4%)

Lumbar punctures performed at diagnosis Elevated serum LDH (>1500 U/ml)

Matthay et al.(2003)

23 of 434 patients with metastatic disease (5.2%)

Lumbar punctures performed at diagnosis MYCN amplification

DuBois SG et al.(1999)

17 of 549 patients with metastatic disease (3.1 %)

MYCN amplification

metastases (<4cm diameter) appears to have a better control rate than whole-brain radiotherapy (Flickinger 2001). New techniques including preoper-ative functional imaging, image-guided neuro-surgery, intraoperative ultrasound, and cortical mapping have improved the success of aggressive surgical resection, and lowered the associated surgical morbidity and mortality (Weinberg et al. 2001). Although systemic chemotherapeutic agents currently used for relapsed neuroblastoma are generally unable to adequately cross the blood-brain barrier, aggressive multi-modality treatments may result in a longer median survival for some patients. Unlike the beneficial effect of prophylactic CNS treatment in survival for patients with leukemia and small cell lung cancer (Vines et al. 2003), the rarity of CNS neuroblastoma makes prophylactic treatment difficult to justify; however, molecular detection of tumor-associated gene products by reverse transcriptase-polymerase chain reaction (RT-PCR) may identify patients at risk for leptomeningeal disease. Ongoing studies are investigating whether the CSF measurements of GD2 synthase, a key enzyme involved in the regulatory expression of complex gangliosides at the cell surface of neuroectodermal-derived tumor cells, including neuroblastoma, has clinical utility as it appears to have in the blood and bone marrow of neuroblas-toma patients (LoPiccolo et al. 2001; Cheung and Cheung 2001). In addition, novel tumor-selective ra-dioimmunotherapeutic strategies may have potential in inhibiting leptomeningeal tumor growth (Bergman et al. 1999; Kramer et al. 2000; Bigner et al. 1998). Intraventricular administration of 131-I-3F8 target ing disialoganglioside GD2 achieves a favorable cerebrospinal to blood ratio and may have clinical utility in the treatment of patients with GD2-positive lep-tomeningeal cancers (Kramer et al. 2000).

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