Inactivation of the tumor suppressor genes hamartin (TSC1
) or tuberin (TSC2
) are associated with tuberous sclerosis complex (TSC), a relatively common autosomal dominant genetic disorder affecting up to one out of 6,000 people [1
]. The TSC1 and TSC2 proteins act as a heterodimer to suppress mammalian target of rapamycin (mTOR), a serine/threonine protein kinase that regulates cell growth and division. Multiple organs are at risk for developing tumors, including the heart, lungs, skin, and kidneys. The most common findings in the brain of TSC patients include tubers in the cortical parenchyma, which are relatively static. Cortical tubers are thought to contribute to the high rate of epilepsy in TSC but do not have a high rate of oncologic growth potential. On MRI imaging, most patients with TSC are found to have subependymal nodules that line the ventricles, with a subset of nodules being completely or partially calcified; some show contrast enhancement [2
]. To date, no radiographic features have been identified that will accurately predict which subependymal nodules will grow and require treatment. Reportedly, 5% to 20% of TSC patients develop low-grade CNS lesions known as subependymal giant cell astrocytomas (SEGAs), which arise from the subependymal nodules [3
]. Serial neuroimaging demonstrates a continuum from subependymal nodules to SEGAs.
Histopathologically, SEGAs are indistinguishable from subependymal nodules, with loosely cohesive clusters of large cells with round to oval nuclei and no (or minimal) atypia; fine, evenly distributed chromatin; and abundant eosinophilic cytoplasm embedded in abundant thin, hairlike processes [5
]. Formed by three types of cells—fibrillated spindle cells, swollen gemistocytic-like cells, and giant pyramidal cells with a ganglioid appearance—SEGAs show both glial and neuronal features. Some authors have demonstrated that all subependymal nodules are clonal and have the capacity to proliferate [6
SEGAs typically arise from subependymal nodules in the area of the foramen of Monro, and can be unilateral or bilateral. SEGAs are slow-growing tumors and typically have no symptoms until obstructive hydrocephalus develops [2
]. They are distinguished from subependymal nodules by increasing size on serial neuroimaging, or by signs and symptoms of obstructive hydrocephalus. Without intervention, SEGAs typically continue to grow slowly over weeks to months, with only sparse evidence of regression or growth stabilization. Rarely, SEGAs can exhibit more aggressive behavior, associated with parenchymal invasion or extensive peritu-moral edema, or they can occur in an atypical location such as the pineal or hypothalamic regions. They typically project into the ventricle and can produce acute or chronic hydrocephalus.
Typically, serial neuroimaging every 1 to 3 years is recommended for pediatric patients with TSC, even in the absence of symptoms [8
]. If a subependymal nodule has grown over the interval of routine imaging, more frequent follow-up imaging is appropriate. Symptoms can be subtle in the early presentation of a SEGA. Complaints in patients with TSC that warrant urgent imaging include positional headache (worse in a dependent position), sudden worsening of seizures, or progression to include nausea, vomiting, diplopia, and lethargy.
Clinical series suggest a male predominance, with a mean age at surgery of 11 years [3
]. In a series of 14 surgical patients, SEGA was identified at a mean of 90 months of age, and surgical intervention occurred at a mean of 38 months after identification. Surgery was performed for evidence of hydrocephalus in nine of 12 patients, and for evidence of tumor growth in five of 12 [9
]. In one series, ten of 21 patients with SEGA died, six as a direct result of tumor growth (acute obstructive hydrocephalus in five, and intratu-moral hemorrhage in 1). In this series, death from brain tumor was most common at ages 10 to 19 years [10
]. In patients followed by a neurologist experienced in caring for patients with TSC, deaths from SEGAs are rare, but morbidity including vision loss, chronic ventriculoperitoneal shunting, and headache are still seen.