Response of subependymal giant cell astrocytoma with spinal cord metastasis to everolimus.

Tuberous sclerosis (TS) is an autosomal dominant disorder with variable penetrance that affects multiple organs ranging from mild skin manifestations to severe neurologic manifestations such as seizures, mental retardation, and autism. Brain lesions include tubers, subependymal nodules (SENs), and subependymal giant cell astrocytomas (SEGAs). These tumors result from abnormal cell migration during embryogenesis. Their location and size are believed to correlate with the severity of neurological manifestations. SEGAs are slow growing tumors of glioneuronal differentiation arising near the foramen of Monro. They are thought to originate from SENs, which, when enlarged, can cause cerebrospinal fluid obstruction, leading to intracranial hypertension and hydrocephalus. SEGAs arise in up to 20% of TS patients. Histologically, the presence of a high mitotic rate or necrosis has not been associated with a poor prognosis.1 However, increasing age has been associated with worse prognosis. Older TS patients are more likely to have large, highly vascular tumors that are not amenable to complete resection. Therefore, SEGAs in these patients are associated with inferior outcomes compared with SEGAs diagnosed in younger patients.2 Complete surgical resection is one of the most important treatments for SEGAs. However, success of resection depends on tumor location and carries important risks and complications. Incomplete resection is associated with a high risk of local recurrence.3 Another treatment modality is gamma knife stereotactic radiosurgery. However, its role remains unclear, especially in patients whose tumor is at risk of malignant degeneration and development of an aggressive glial neoplasm, such as glioblastoma, because of the presence of a mutation in one of the tuberous sclerosis complex (TSC) tumor suppressor genes.4 In addition to mortality, SEGAs have significant implications in the quality of life of patients.5 Therefore, it is important to understand the molecular pathways that promote tumor proliferation in patients with TS. Inactivating mutations of the genes TSC1 or TSC2 are found in over 85% of TS patients.6 TSC1 and TSC2 proteins form a heterodimer complex that inhibits the mammalian target of rapamycin (mTOR) complex 1 (mTORc1). mTORc1 is a serine-threonine kinase that regulates cell growth and proliferation through interaction with several transcription factors. When TSC1 or TSC2 are deficient, mTORc1 is over-activated, leading to abnormal cell proliferation and growth.7 Thus, inhibitors of mTORc1, such as everolimus, may be used as effective treatment modalities for TS-associated tumors. Preclinical studies of mTOR inhibitors in animal models of TS have demonstrated efficacy in prolonging survival, preventing seizures, and improving learning deficits.8,9 Initial reports of efficacy of mTOR inhibitors against SEGAs were published as case series. One of them reported on the response of 3 patients with SEGAs who were treated with single-agent rapamycin. All 3 demonstrated tumor reductions between 50% and 75%, suggesting that singleagent treatment with rapamycin may be a viable alternative to surgical resection.10 In addition, Lam et al11 reported on the results of 3 TS patients with SEGAs who responded to rapamycin treatment with >50% reduction of tumor size by magnetic resonance imaging (MRI), as well as improvements in other important clinical parameters. An initial clinical trial of the mTOR inhibitor everolimus included 28 TS patients with progressive SEGA of the brain who underwent single-agent therapy with everolimus. Seventy-five percent of patients demonstrated a decrease in tumor size of at least 30%. Thirty-two percent demonstrated a tumor reduction of at least 50% within the initial 3 months of therapy. An additional benefit included decreased seizure activity. No patient required surgery or developed new SEGAs while receiving everolimus. The most common adverse effects included upper respiratory infections and stomatitis. Elevation of total cholesterol, LDL, and triglycerides levels were also reported. Severe adverse effects included bronchitis, leukopenia, or vomiting.12 On the basis of these encouraging results, everolimus was recently granted accelerated approval by the FDA for treatment of SEGA in patients with TSC who are not surgical candidates. We present the case of a patient with a SEGA in the right lateral ventricle; leptomeningeal enhancement of the brainstem, medulla, and cranial nerves; and nodular disease along the spinal cord, who demonstrated a significant clinical and radiographic response to treatment with everolimus.