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Purpose: Subependymal giant cell astrocytoma (SEGA) is a brain tumor associated with tuberous sclerosis complex (TSC). It usually grows in a second decade of life, but may develop in the first months of life. The aim of this work was to establish the incidence, clinical features, and outcome of congenital SEGA in TSC patients., Methods: Cohort of 452 TSC patients was reviewed to identify cases with growing or hydrocephalus producing SEGAs in the first 3 months of life. Clinical presentation, size of the tumor, growth rate, mutational analysis, treatment applied, and outcome were analyzed., Results: Ten (2.2 %) patients presented with SEGA in the first 3 months of life. All of them had documented SEGA growth and all developed hydrocephalus. In eight patients, mutational analysis was done, and in all of them, TSC2 gene mutations were identified. Mean maximum SEGA diameter at baseline was 21.8 mm. Mean SEGA growth rate observed postnatally was 2.78 mm per month and tended to be higher (5.43 mm per month) in patients with TSC2/PKD1 mutation than in other cases. Seven patients underwent SEGA surgery and surgery-related complications were observed in 57.1 % cases. One patient was successfully treated with everolimus as a primary treatment., Conclusions: Congenital SEGA develops 2.2 % of TSC patients. Patients with TSC2 mutations, and especially with TSC2/PKD1 mutations, are more prone to develop SEGA earlier in childhood and should be screened for SEGA from birth. In young infants with SEGA, both surgery and mTOR inhibitor should be considered as a treatment option.

Background: Subependymal giant cell astrocytoma is a brain tumor associated with tuberous sclerosis complex. There are two treatment options for subependymal giant cell astrocytomas: surgery or mammalian target of rapamycin inhibitor. The analysis of outcome of subependymal giant cell astrocytoma surgery may help characterize the patients who may benefit from pharmacotherapy., Methods: Sixty-four subependymal giant cell astrocytoma surgeries in 57 tuberous sclerosis complex patients with at least a 12-month follow-up were included in the study. The tumor size, age of the patients, mutation in the TSC1 or TSC2 gene, indication for the surgery, and postsurgical complications were analyzed., Results: The mean age of patients at surgery was 9.7 years. Mean follow-up after surgery was 63.7 months. Thirty-seven (57.8%) tumors were symptomatic and 27 (42.2%) were asymptomatic. Patients with TSC2 mutations developed subependymal giant cell astrocytoma at a significantly younger age than individuals with TSC1 mutations. Four patients (6.2% of all surgeries) died after surgery. Surgery-related complications were reported in 0%, 46%, 83%, 81%, and 67% of patients with tumors <2 cm, between 2 and 3 cm, between 3 and 4 cm, >4 cm, and bilateral subependymal giant cell astrocytomas, respectively, and were most common in children younger than 3 years of age. The most common complications included hemiparesis, hydrocephalus, hematoma, and cognitive decline., Conclusions: Our study indicates that subependymal giant cell astrocytoma surgery is associated with significant risk in individuals with bilateral subependymal giant cell astrocytomas, tumors bigger than 2 cm, and in children younger than 3 years of age. Therefore, tuberous sclerosis complex patients should be thoroughly screened for subependymal giant cell astrocytoma growth, and early treatment should be considered in selected patients., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Subependymal giant cell astrocytomas (SEGAs) are rare brain tumors associated with tuberous sclerosis complex (TSC), a disease caused by mutations in TSC1 or TSC2, resulting in enhancement of mammalian target of rapamycin (mTOR) activity, dysregulation of cell growth, and tumorigenesis. Signaling via mTOR plays a role in multifaceted genomic responses, but its effectors in the brain are largely unknown. Therefore, gene expression profiling on four SEGAs was performed with Affymetrix Human Genome arrays. Of the genes differentially expressed in TSC, 11 were validated by real-time PCR on independent tumor samples and 3 SEGA-derived cultures. Expression of several proteins was confirmed by immunohistochemistry. The differentially-regulated proteins were mainly involved in tumorigenesis and nervous system development. ANXA1, GPNMB, LTF, RND3, S100A11, SFRP4, and NPTX1 genes were likely to be mTOR effector genes in SEGA, as their expression was modulated by an mTOR inhibitor, rapamycin, in SEGA-derived cells. Inhibition of mTOR signaling affected size of cultured SEGA cells but had no influence on their proliferation, morphology, or migration, whereas inhibition of both mTOR and extracellular signal-regulated kinase signaling pathways led to significant alterations of these processes. For the first time, we identified genes related to the occurrence of SEGA and regulated by mTOR and demonstrated an effective modulation of SEGA growth by pharmacological inhibition of both mTOR and extracellular signal-regulated kinase signaling pathways, which could represent a novel therapeutic approach.

Focal cortical dysplasia (FCD) type IIB is a malformation of cortical development characterized by presence of balloon cells. These cells share phenotypic features of giant cells found in tuberous sclerosis complex (TSC), but the relationship between FCD type IIB and TSC is not well established. TSC is an autosomal dominant disorder caused by mutation in either of two genes: TSC1, encoding hamartin, and TSC2, encoding tuberin. Both proteins form a complex inhibiting mTOR signalling pathway and thus regulate cell size and proliferation. In this study, tuberin and hamartin expression was evaluated under a confocal microscope in six cases of Taylor's balloon cell type FCD. Three patients met the clinical criteria for TSC. In three other patients, TSC was excluded based on a panel of clinical and radiological examinations. Additionally, two cases of FCD type I and 3 samples of normal brain tissue were used as a reference group. We found loss of tuberin and hamartin expression in FCD type IIB lesions from patients with TSC. In sporadic FCD type IIB cases, only a few tuberin and hamartin positive cells were detected in the white-grey matter junction and in deeper parts of the white matter. Cortical balloon cells showed loss of both tuberin and hamartin. In contrast, the expression of tuberin and hamartin in FCD type I samples was strong, similarly to normal brain tissue. In conclusion, loss of TSC1 and TSC2 products expression in balloon cells of both cortical dysplasia type IIB in TSC-related and sporadic patients suggests that FCD type IIB may represent the focal form of TSC.

Tuberous sclerosis (TS) is an autosomal dominant disease associated with the formation of usually benign tumors or hamartomas. The disease is connected with upregulation of mammalian target of rapamycin, central regulator of protein translation, which is usually regarded to be activated by Akt kinase. Here, we show for the first time that in all four brain lesions and one angiomyolipoma from TS patients both extracellular signal-regulated kinase (Erk) and p90 ribosomal S6 kinase 1 activation as well as Erk-dependent phosphorylation of p70 ribosomal S6 kinase 1 are markedly elevated whereas Akt, participating in the classical pathway of mammalian target of rapamycin activation is not always activated. Erk activation is also present in TS-derived cell lines. Importantly, Erk inhibition leads to the decrease of proliferation potential of such lines. These results show that Erk is specifically implicated in the pathogenesis of hamartomas.

Subependymal giant cell astrocytomas are distinctive brain tumors that are seen only in tuberous sclerosis complex. Although histologically benign, they cause both moribidity and occasional mortality owing to progressive growth in some patients. Tuberous sclerosis complex is an autosomal dominant genetic disorder with a high sporadic case rate that is due to mutations in either of two genes, TSC1 and TSC2, encoding hamartin and tuberin, respectively. The pathogenesis of subependymal giant cell astrocytomas in tuberous sclerosis complex is uncertain. In this study, we examined the expression of tuberin and hamartin in subependymal giant cell astrocytomas from nine patients with tuberous sclerosis complex by immunohistochemistry with confocal microscopy. Loss of hamartin expression was seen in all subependymal giant cell astrocytomas, including five from patients with germline TSC2 mutations and two from patients with germline TSC1 mutations. The subependymal giant cell astrocytomas of six of nine patients had no expression of tuberin as well, whereas three patients retained some tuberin expression. Tuberin expression was seen in one patient with a TSC2 germline mutation and two patients whose mutational status was not determined. Overall, these data indicate a loss of both tuberin and hamartin expression in the subependymal giant cell astrocytomas of patients with both TSC1 and TSC2 mutations and are consistent with a two-hit disease pathogenesis model for the development of subependymal giant cell astrocytomas.

Ten cases of subependymal giant cell astrocytoma associated with sclerosis tuberosa were reevaluated in order to assess their phenotyping and biologic features. All tumours were multifocal, located within lateral ventricles, often overlying the head of the caudate nucleus or protruding into the third ventricle. The phenotype of SGCA disclosed a complex pattern: giant cells were GFAP positive, some of them were stained with antibodies against neurofilament and NSE. Ultrastructurally, the cells of SGCA contained frequent dense bodies, numerous intermediate filaments and microtubules. Biologically SGCA is not malignant, although its appearance may suggest otherwise. No patient had an apparent recurrence within 3-5 years of observation.

Six children with intraventricular tumors associated with tuberous sclerosis (TS) were treated at the Children's Health Center, Department of Pediatric Neurosurgery, in the period 1987-1992. The age of the patients ranged from 7 to 15 years. TS was diagnosed according to Gomez diagnostic criteria. Computer tomography (CT) and magnetic resonance imaging showed intraventricular tumors associated with ventricular enlargement and multiple subependymal nodules commonly observed in cases of TS. All tumors were removed totally through frontal transcortical approach, with uneventful postoperative recovery. One patient, with two parallel tumors in the two frontal horns, underwent one-stage surgery with successful total removal. Histopathological examination in all cases showed subependymal giant cell astrocytoma (SGCA). The growth pattern of SGCA associated with TS, documented by sequential CT scans over several years, is described. The diagnosis and surgical treatment of the tumor are discussed, and periodic CT scanning, at least every 2 years, is recommended for patients with TS.

This article presents an abstract of the research paper "Pathology and Pathogenesis of Tuberous Sclerosis Subependymal Giant Cell Astrocytomas," which was discussed in the 13th Conference of the Polish Association of Neuropathologist. Subependymal Giant Cell Astrocytomas (SEGAs) are rare, histologically benign brain tumors associated with tuberous sclerosis complex (TSC). TSC is a neurocutaneus syndrome resulting from mutations in two genes, TSC1 and TSC2, encoding hamartin and tuberin, respectively. Recent studies show an important role for the TSC genes in a signaling pathway involving the mammalian target of rapamycin kinase.