Congenital subependymal giant cell astrocytomas in patients with tuberous sclerosis complex

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.     

Solitary subependymal giant cell astrocytoma: a forme fruste of tuberous sclerosis complex?]

Subependymal giant cell astrocytoma (SEGA) is usually associated with tuberous sclerosis (TS) and believed to originate from subependymal nodules. We report a rare case of SEGA in a patient lacking symptoms of TS. Radiological findings, including CT and MRI, were characteristic of SEGA, but the preoperative diagnosis was difficult due to the fact that no other features of TS were present. TS has been classically characterized by the clinical presence of Vogt's triad of seizure, facial angiofibroma and mental retardation, however, few cases present with all of these manifestations. In 1998, Roarch et al. proposed new clinical diagnostic criteria for the TS complex based on the clinical and radiographic features of TS. According to these criteria, our case is classified as a "possible" TS complex. There have been previous reports of SEGAs without any obvious features of TS, but it is still controversial as to whether these reports represent a forme fruste of TS. To determine a strict diagnosis of SEGA, additional genetic studies are needed. The possibility of SEGA should be considered whenever an intraventricular tumor near the foramen of Monro is found, regardless of other clinical features of TS.     

Solitary subependymal giant cell astrocytoma incidentally found at autopsy in an elderly woman without tuberous sclerosis complex

Subependymal giant cell astrocytoma (SEGA) is a benign, slowly growing tumor typically occurring in the setting of tuberous sclerosis complex (TSC). However there are several reported cases in which patients with a solitary SEGA had no other stigmata of TSC. We describe a case of SEGA in a 75‐year‐old woman representing the oldest patient reported to‐date. The patient had a history of radical vulvectomy for malignant melanoma (MM), and died of autopsy‐confirmed widespread systemic metastasis. Postmortem examination of the brain revealed a single 2.1 × 1.0 × 0.8 cm intraventricular nodule in the lateral ventricle. Histologically, it was composed of interlacing bundles of spindle‐shaped tumor cells with thin delicate processes admixed with relatively large pleomorphic cells with abundant glassy eosinophilic cytoplasm, as seen in a SEGA. Immunohistochemically, GFAP, S‐100 protein, and neuron specific enolase were positive, and synaptophysin labeled a few tumor cells. Also noted were rare isolated MM cells within the tumor (i.e., tumor‐to‐tumor metastasis). Autopsy showed no manifestations of TSC systemically or intracranially. The histopathological differential diagnosis was limited and included giant cell ependymoma and, much less likely, giant cell glioblastoma and pleomorphic xanthoastrocytoma. This case illustrates that SEGA can be found incidentally in an elderly individual with no associated symptoms and also indicates that SEGA can occur outside the setting of TSC. Tumor metastasis to an occult SEGA is extremely rare.     

Subependymal giant cell astrocytoma with intratumoral hemorrhage in the absence of tuberous sclerosis.

Subependymal giant cell astrocytoma (SEGA) is an uncommon tumor that usually occurs in the setting of tuberous sclerosis (TS) syndrome. We report a rare case of an intratumoral and a small intraventricular hemorrhage complicating a SEGA in an adult patient without any signs of TS. Although pre-operative CT and MRI findings for the tumor were typical of SEGA, SEGA was not considered in the differential diagnosis because the patient was lacking any symptoms of TS. This is the second report of intraventricular and intratumoral hemorrhage complicating a SEGA and the first case in which these complications occurred in an adult patient in whom there was no previous suspicion of systemic disease.     

结节性硬化合并室管膜下巨细胞星形细胞瘤(附五例报告)

目的 探讨室管膜下巨细胞星形细胞瘤(SEGA)的临床表现、影像学特点、病理类型、治疗方法 及预后.方法 同顺性分析我院收治的5例经手术及病理证实的SEGA患者的临床特点、治疗方法 及预后情况并结合文献复习.结果 结节性硬化(TSC)伴SEGA足一种少见的常染色体显性遗传性疾病,多见于儿童.此病在临床上可表现为典型的Vogt三联征:皮脂腺瘤、癫痫发作和智力障碍.由于肿瘤多发生于室间孔附近,故极易阻塞室间孔及第三脑室引起梗阻性脑积水.本组5例患者均经显微手术全切肿瘤,无术后并发症,随访1～8年肿瘤无复发,临床症状消失.结论 SEGA属于级别低预后好的颅内肿瘤,显微外科手术全切肿瘤是目前主要的治疗方法 ,全切后无需放疗和化疗,亦很少复发.     

Successful everolimus therapy for SEGA in pediatric patients with tuberous sclerosis complex

Purpose

Tuberous sclerosis complex (TSC) is associated with hamartomatous growths including subependymal giant cell astrocytomas (SEGAs). Although, SEGAs are slow-growing glioneuronal tumors, they represent a significant cause of morbidity and mortality due to the risk of sudden death from acute hydrocephalus. Neurosurgical resection has been the mainstay of therapy, since radiotherapy and chemotherapy were proved inefficient in those tumors. Recent studies support the use of everolimus for subependymal giant cell astrocytomas associated with tuberous sclerosis and suggest it might represent a disease-modifying treatment for other aspects of tuberous sclerosis.

Methods

We describe the clinical and radiological progression of three pediatric patients with definitive diagnosis of TSC and SEGA, which have been treated with everolimus.

Results

Up to 34 % sustained SEGA decrease was observed in the three cases. All three patients have experienced seizure control and two of them have showed cognitive and behavioral improvement. Everolimus has been well tolerated by all. No severe adverse events have been observed to date.

Conclusion

Everolimus offers significant promise in treating SEGAs. Studies are required to explore optimal therapy duration and management upon discontinuing therapy.     

Congenital subependymal giant cell astrocytoma: clinical considerations and expression of radial glial cell markers in giant cells

Objects  Congenital Subependymal giant cell astrocytoma (SEGA), diagnosed in fetal and neonatal period, is extremely rare. Previous studies have reported poor surgical outcomes of this small group of patients. We encountered a patient diagnosed as congenital SEGA and report the surgical outcome along with interesting immuno-phenotypes of giant tumor cells. Case  Ventriculomegaly and a hypoechoic mass near the foramen of Monro were detected in a fetus on prenatal ultrasonography in the 35th week of gestation. Surgery was scheduled 2 months later to reduce the risk of operative complications. At postnatal 2 months, gross total resection of the tumor was achieved without complications. The patient had been followed up for 1 year without tumor recurrence. In double immunofluorescence, the prototype cells of SEGA expressed a variety of neural stem cell (nestin and Sox2) and radial glial cell markers (vimentin and brain lipid-binding protein), in addition to glutamate/aspartate transporter and glial fibrillary acidic protein. Conclusions  Congenital SEGA can be successfully treated with judicious use of observation period and careful evaluation of general conditions. Pathological findings support the concept that SEGA may originate from aberrant radial glial cells in the developing brain.     

室管膜下巨细胞型星形细胞瘤的临床分析

目的探讨室管膜下巨细胞型星形细胞瘤(SEGA)的临床特点、影像学表现、治疗方法及预后.方法回顾性分析12例经病理证实的SEGA病人的临床资料,其中经胼胝体入路8例,经额叶皮质入路4例.结果肿瘤均获全切除;本组无围手术期并发症,无死亡病例;术后均未行放化疗.随访9～112个月,无肿瘤复发,平均KPS评分为85分.结论SEGA是一种少见的神经上皮良性肿瘤,多与结节性硬化综合征并发;易发生于男性儿童,以侧脑室多见,影像学表现具有相对特异性,肿瘤全切除后预后良好.     

Tuber and subependymal giant cell astrocytoma associated with tuberous sclerosis: an immunohistochemical,ultrastructural, and immunoelectron microscopic study

The cellular nature of the giant eosinophilic cells of tuber and of the cells comprising subependymal giant cell astrocytoma (SEGA) in tuberous sclerosis (TS) remains unclear. To assess the characteristics of these lesions, 13 tubers and 6 SEGA were immunohistochemically studied with glial and neuron-associated antigens. In addition to conventional ultrastructure, 6 tubers and 8 SEGA were fibrillary acidic protein (GFAP) and somatostatin. Eosinophilic giant cells of tubers were positive for vimentin (100%), GFAP (77%) and S-100 protein (92%); such cells were also found to a various extent to be reactive for neuron-associated antigens, including neurofilament (NF) proteins (38%) or class III -tubulin (77%). SEGA also showed variable immunoreactivity for GFAP (50%) or for S-100 protein (100%); NF epitopes, class III -tubulin, and calbindin 28-kD were expressed in 2 (33%), 5 (83%) and 4 (67%) cases, respectively. Cytoplasmic staining for somatostatin (50%), met-enkephalin (50%), 6-hydroxytryptamine (33%), -endorphin (33%) and neuropeptide Y (17%) was noted in SEGA, but not in tubers. Ultrastructurally, the giant cells of tubers and the cells of SEGA contained numerous intermediate filaments, frequent lysosomes and occasional rectangular or rhomboid membrane-bound crystalloids exhibiting lamellar periodicity and structural transition to lysosomes. Some SEGA cells showed features suggestive of neuronal differentiation, including stacks of rough endoplasmic reticulum, occasional microtubules and a few dense-core granules. Furthermore, in one case of tuber, a process of a single large cell was seen to be engaged in synapse formation. Intermediate filaments within a few cells of both lesions were decorated by gold particle-labeled GFAP antiserum. Within the tumor cells of SEGA, irregular, non-membrane-bound, electron-lucent areas often contained somatostatin-immunoreactive particles, whereas the latter could not be detected in tuber. The present study provides further evidence of divergent glioneuronal differentiation, both in the giant cells of tubers and the cells of SEGA. The findings of similar cells at different sites, including the subependymal zone, white matter (heterotopias), and cortex indirectly supports the idea that these lesions of TS result from a migration abnormality.     

Subependymal giant cell astrocytoma (SEGA): Is it an astrocytoma? Morphological,immunohistochemical and ultrastructural study

Subependymal giant‐cell astrocytoma (SEGA) is a rare intra‐ventricular low‐grade tumor which frequently occurs as a manifestation of tuberous sclerosis complex. The histogenesis of SEGA is controversial and its astrocytic nature has been doubted. First studies suggested the astrocytic nature of SEGA while several recent reports demonstrate its glio‐neuronal nature. In spite of this, in the recently revised WHO classification of the CNS tumors, SEGA has been still included in the group of astrocytomas. We studied nine tuberous sclerosis complex‐associated SEGAs. Patients were 1–18 years old. Eight patients (89%) had a solitary lesion located in the lateral ventricle close to of the head of the caudate nucleus, the remaining patient (11%) had two tumors, one located close to the head of the left caudate nucleus and the other in the central part of the right lateral ventricle. Histologically, tumors were composed of three types of cells: spindle, gemistocytic and ganglion‐like. Four tumors (44%) had a prominent vascularization and three (33%) showed an angiocentric pattern. Calcifications were observed in six cases (66%). By immunohistochemistry, the majority of the tumors were GFAP‐ (9; 100%), neurofilament‐ (8, 89%), neuron‐specific enolase‐ (9, 100%), and synaptophysin‐ (8; 89%) positive. Ultrastructural studies were performed on four cases. In all four there were glial cell processes filled with intermediate filaments. In one case dense core putative neurosecretory granules were appreciable. Our results emphasize the glio‐neuronal nature of SEGA. We suggest moving it into the group of mixed glio‐neuronal tumors under the denomination of subependymal giant cell tumor.     

Association between the growth rate of subependymal giant cell astrocytoma and age in patients with tuberous sclerosis complex

Purpose

The most common neurological complications associated with tuberous sclerosis complex (TSC) include intractable seizures that begin in infancy and subependymal giant cell astrocytoma (SEGA) complicated by hydrocephalus with increasing age. Information on SEGA growth of TSC patients is limited. This study aimed to examine the TSC-SEGA growth rates by periodic neuroimaging.

Methods

This study evaluated the TSC-SEGA growth rates by serial neuroimaging. Fifty-eight patients with TSC underwent systematic evaluation, including a review of medical history and serial brain neuroimaging.

Results

While magnetic resonance imaging was more sensitive in detecting cortical tubers than computed tomography (73.1 vs. 0 %, p?<?0.001), its efficacy in identifying intracranial lesions was comparable to that of computed tomography (96.2 vs. 100 %, p?=?0.658). Significant tumor growth was observed in children (p?=?0.012) and adults (p?=?0.028) during follow-up periods, respectively (median for children 23.5 months, interquartile range 18–40 months and median for adults 23 months, interquartile range 12–34 months). Further, the SEGA growth rate in children was significantly higher than that in adults (75.6 vs. 16.5 %, p?=?0.03).

Conclusions

The results of the study show that SEGA has a significantly higher growth rate in children using serial follow-up brain imaging, suggesting the importance of performing follow-up neuroimaging at yearly intervals in childhood to identify and prevent potential comorbidities.

     

No chromosomal imbalances detected by comparative genomic hybridisation in subependymal giant cell astrocytomas

Eight subependymal giant cell astrocytomas (SEGA) were studied by comparative genomic hybridisation. These consisted of six primary SEGA and two recurrences gained from six paediatric patients suffering from tuberous sclerosis complex (TSC). No DNA copy number changes were found in any of the tumours. Our data show that chromosomal imbalances are absent or very rare events in primary and recurrent SEGA and that no aberrations were detected at the sites of the TSC-associated genes, thus indicating that mutational inactivation of one of the TSC genes is not followed by genomic instability.     

Resection of subependymal giant cell astrocytoma guided by intraoperative magnetic resonance imaging and neuronavigation

Purpose

Subependymal giant cell astrocytoma (SEGA) is a rare, benign tumor that occurs mainly in children; complete resection can achieve cure. Guidance of surgery by combined intraoperative magnetic resonance imaging (iMRI) and functional neuronavigation is reported to achieve more radical resection and reduced complications. However, reports about the resection of SEGA with such guidance are rare. We report here our preliminary experience of the resection of SEGA guided by iMRI and neuronavigation, focusing on the feasibility, benefits, and pitfalls of this combination of techniques.

Methods

We performed resection of SEGA guided by combined iMRI and functional neuronavigation in seven children. The first iMRI was performed when the surgeon believed that the tumor had been completely resected; the last iMRI was performed immediately after closure. Additional scans were performed as needed.

Results

Successful resection was achieved in all seven patients using this combination of techniques. The iMRI scans detected residual tumor in three patients and a large, remote epidural hematoma in one patient. Further resection or other surgery was performed in these four patients. Complete resection was eventually achieved in all patients. There were no cases of surgery-related neurological dysfunction, except transient memory loss in one patient. No recurrence of tumor or hydrocephalus was observed in any patients during the follow-up period.

Conclusions

Resection of SEGA in children guided by combined iMRI and neuronavigation is feasible and safe. This combination of techniques enables a higher complete resection rate and reduces brain injury and other unexpected events during surgery.     

Molecular Therapies for Tuberous Sclerosis and Neurofibromatosis

Neurofibromatosis type 1 (NF1) and tuberous sclerosis complex (TSC) are autosomal-dominant genetic disorders that result from dysregulation of the PI3K/AKT/mammalian target of rapamycin (mTOR) pathway. NF1 is caused by mutations in the NF1 gene on chromosome 17q11.2. Its protein product, neurofibromin, functions as a tumor suppressor and ultimately produces constitutive upregulation of mTOR. TSC is caused by mutations in either the TSC1 (chromosome 9q34) or TSC2 (chromosome 16p.13.3) genes. Their protein products, hamartin and tuberin, respectively, form a dimer that acts via the GAP protein Rheb (Ras homolog enhanced in brain) to directly inhibit mTOR, again resulting in upregulation. Specific inhibitors of mTOR are in clinical use, including sirolimus, everolimus, temsirolimus, and deforolimus. Everolimus has been shown to reduce the volume and appearance of subependymal giant cell astrocytomas (SEGA), facial angiofibromas, and renal angiomyolipomas associated with TSC, with a recent FDA approval for SEGA not suitable for surgical resection. This article reviews the use of mTOR inhibitors in these diseases, which have the potential to be a disease-modifying therapy in these and other conditions.     

Intracranial migration of Foley catheter--an unusual complication.

Profuse nasal bleeding in cases of severe head injury is mostly associated with facial and skull base fractures and various methods have been tried to control such bleeding. Anterior nasal packing, producing a tamponade effect with a Foley catheter and other inflatable balloon devices are time proven methods. We describe a case of severe head injury with such fractures where a Foley catheter tamponade was attempted to control the severe nasal bleeding and the CT brain scan revealed inadvertent malposition of the catheter into the cranial cavity. This rare entity is described to highlight the potential danger associated with a proven method of controlling severe nasal bleeding and suggestions are outlined as to how to avoid such a mishap, along with a brief review of the literature.     

Advances in the management of subependymal giant cell astrocytoma

Background

Subependymal giant cell astrocytoma (SEGA) is the most common central nervous system tumor in patients with tuberous sclerosis complex (TSC). Although these lesions are generally benign and non-infiltrative, they commonly arise in the region of the foramen of Monro, where they can cause obstructive hydrocephalus and sudden death.

Methods

Surgical resection has been, and presently remains, the standard treatment for SEGAs demonstrating serial growth on neuroimaging in the setting of symptomatic hydrocephalus or progressive ventriculomegaly.

Discussion

Surgery can be curative; however, not all SEGAs are amenable to safe and complete resection. Gamma Knife stereotactic radiosurgery provides another treatment option but has highly variable response rates with limited data demonstrating its efficacy. Newer medical therapy targeting mammalian target of rapamycin (mTOR), the key protein kinase that is constitutively activated in TSC, has demonstrated promising results in recent clinical trials. In both case reports and clinical trials, treatment with mTOR inhibitors results in a significant reduction in SEGA volume and improvement or resolution of ventriculomegaly. This has led to the approval of everolimus for the treatment of SEGA in tuberous sclerosis patients who are not candidates for surgery. This review summarizes the surgical and medical management of SEGA in patients with TSC.     

Subependymal giant cell astrocytoma: clinical and neuroimaging features of four cases.

The clinical history, neuroimaging features, treatments, and outcome of 4 patients with histologically verified subependymal giant cell astrocytomas (SEGA) were retrospectively reviewed. The average age at the time of surgery was 13.3 years. Headache related to raised intracranial pressure was the first and only sign in 2 patients, with the remaining 2 being admitted because of sequential neuroimaging studies over several years revealing the growth of 'subependymal nodules' into intraventricular tumours. In each case the tumour was in the region of Monro's foramen and was associated with ventricular dilatation. On computed tomography (CT), multiple subependymal nodules were found in 3 patients, and these well circumscribed isodense SEGAs were markedly enhanced by contrast medium. On magnetic resonance imaging (MRI), which was obtained in 3 patients, 2 SEGAs were isointense with the cerebral cortex and one with the white matter on T1-weighted images, and on T2-weighted images, 2 were isointense with the cortex and one with the white matter. At surgery the tumours appeared to originate from the inferolateral wall of the lateral ventricle in the region of the head of the caudate nuclei. Total macroscopic removal was achieved in 3 patients, and subtotal removal in one patient. Follow up ranged from 4.6 to 13.2 years, and all patients have exhibited similar physical and mental conditions to preoperative. So far there has been no evidence of any recurrences. The diagnosis and the surgical indications for SEGA are discussed, with periodic monitoring with neuroimaging studies being recommended even for asymptomatic patients with 'subependymal nodules'.     

室管膜下巨细胞型星形细胞瘤六例分析

目的 探讨室管膜下巨细胞型星形细胞瘤(SEGA)患者的临床、影像学、病理学特点以及诊断和治疗方法.方法 对自2000年2月至2007年8月收治的6例SEGA患者的临床和影像学表现、病理学特点、治疗及随访结果进行回顾分析.结果 6例SEGA的临床表现以高颅压和视力下降最为常见.CT显示肿瘤实体部分呈等或稍高密度,边界清楚,部分可见瘤内钙化.MRI扫描肿瘤实体部分T1WI多呈等信号,少数可呈稍低信号;T2WI呈等或稍高信号:增强扫描肿瘤实体部分呈不均匀强化.4例经胼胝体入路,2例经额叶皮质入路,肿瘤全切除均成功,无手术死亡.随访10月～8年,肿瘤无复发.结论 室管膜下病变如位于室间孔周围伴有结节性硬化,引起脑积水或呈现逐渐生长趋势者,应考虑SEGA的诊断,尽早手术治疗.SEGA为良性肿瘤,手术全切者预后良好.定期影像学检查对于跟踪室管膜下结节以及监测肿瘤复发是必要的.