Subependymal Giant Cell Astrocytomas in Tuberous Sclerosis Complex: History
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Contributor:
Chao Gao
,
Bernadeta Zabielska
,
Fuyong Jiao
,
Daoqi Mei
,
Xiaona Wang
,
Katarzyna Kotulska
,
Sergiusz Jozwiak

Tuberous sclerosis complex (TSC) is an autosomal-dominant disorder caused by mutations inactivating TSC1 or TSC2 genes and characterized by the presence of tumors involving many organs, including the brain, heart, kidneys, and skin. Subependymal giant cell astrocytoma (SEGA) is a slow-growing brain tumor almost exclusively associated with TSC.

  • subependymal giant cell astrocytoma (SEGA)
  • tuberous sclerosis complex (TSC)
  • mTOR inhibitors

1. Introduction

Tuberous sclerosis complex (TSC), also known as Bourneville–Pringle syndrome, is an autosomal dominant, potentially devastating, a neurocutaneous disorder characterized by the development of hamartomas in several organs, including the brain, kidneys, lungs, heart, eyes, and skin [1]. With an incidence of about 1:6000 in the general population TSC is the second most common neurocutaneous disorder [2].
TSC manifestations are caused by mutations in either TSC1 (on chromosome 9q34) or the TSC2 gene (on chromosome 16p13.3), both recognized as tumor suppressors. Loss of TSC1 or TSC2 gene function results in the overactivation of the mTOR (mammalian target of rapamycin) signaling pathway leading to impaired control of cell growth, differentiation, and proliferation [3]. In general, patients with the TSC2 mutation are characterized by a more severe course of the disease and earlier development of symptoms than individuals with TSC1 mutations [4]. There are many scientific studies based on animal studies showing that the mentioned mutation is also a more common cause of severe phenotypic features, including the intensity and frequency of epilepsy and other neurological symptoms. On a similar note, patients carrying a PKD mutation with an accompanying TSC2 mutation are at risk for an earlier onset of polycystic kidney disease and its more acute course.
The most common neurological manifestation associated with this condition is epilepsy, which appears in about 90% of patients. Early onset of epilepsy in the first year of life is frequently accompanied by TSC-associated neuropsychiatric disorders (TAND), especially intellectual disability and autistic behavior [5][6].
TSC2 gene mutations are four times more common than TSC1 gene mutations in the TSC population; however, in familial cases which comprise about one-third of all TSC individuals, the proportion is 1:1 [7].
TSC-related neoplasms are generally benign, non-infiltrative and classified by the World Health Organization as grade I, and the risk of mortality and morbidity is associated with their volume and location [8]. One of the characteristics of TSC is the development of age-specific tumors in various organs over time, starting from the prenatal period. Cardiac tumors and cortical brain tubers develop prenatally, skin lesions typically start to grow in toddlers, brain and kidney tumors in older children and adolescents, and lung involvement is present usually not earlier than in adults [9]. Interestingly, some of the tumors typically do not grow beyond a specific age: for example, cardiac tumors usually tend to regress in infants and brain tumors do not increase their size in adults. Other lesions, such as kidney and liver AMLs, skin manifestations, or pulmonary lymphangioleiomyomatosis (LAM) are characterized by a constant tendency to grow. Despite the benign nature of the tumors, TSC is associated with increased mortality in children and young adults [10][11]. Analysis of the Tuberous Sclerosis Alliance TSC Natural History Database of 2233 TSC patients revealed that the median age of death of 31 decedents was 28 years [10].
The diagnosis of TSC is established on the basis of clinical manifestations or pathological genetic findings. The newest diagnostic criteria of TSC have been recently published (Figure 1) [12]. In 2021, the International TSC Clinical Consensus Group reaffirmed the importance of independent genetic diagnosis. Identification of a pathogenic variant in TSC1 or TSC2 is sufficient for the diagnosis of TSC regardless of clinical findings. The diagnosis may be also established if two major or one major and two minor clinical criteria are present. Currently, more and more patients are diagnosed prenatally due to cardiac and brain lesions which may be revealed in routine fetal ultrasonography and magnetic resonance imaging (MRI) [13]. Disclosure of a cardiac tumor and a brain lesion specific for TSC is consistent with a prenatal diagnosis of TSC.
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Figure 1. Updated Diagnostic Criteria of Tuberous Sclerosis Complex According to Northrup et al. (2021).

2. Non-TSC Associated SEGA

In recent years there has been an increasing number of reports of SEGA diagnosis in “healthy” patients. The occurrence of SEGA in non-TSC patients is very rare, and those patients should undergo a detailed clinical workout for other features of TSC including TSC1/TSC2 genetic analysis in the search for “forme fruste” of TSC. The patients with TSC manifestations not sufficient for definite diagnosis of the disease may have low-level somatic mosaicism for TSC1/TSC2 mutations detectable only with deep sequencing methods [14].
However, SEGAs were reported also in otherwise healthy people, in whom all examinations for TSC, including genetic testing of DNA of epithelium of buccal mucosa, urine sediment, and blood cells, are negative. Ichikawa et al. [15], for example, described a 20-year-old woman with clinical manifestations of a brain tumor. She underwent brain surgery and a histological examination of the tumor was consistent with SEGA diagnosis. Molecular analysis of the tumor confirmed loss of heterozygosity and allelic mutation of TSC2 gene. The clinical workout for TSC manifestations was negative. Her DNA analysis from peripheral blood, buccal mucosa, urinary sediment, nail and hair revealed no TSC1/TSC2 pathogenic mutation. From a genetic point of view, these isolated SEGAs are thought to result from two purely somatic mutations in one of the TSC genes (TSC1 or TSC2) limited to the tumor. Similar mechanisms were reported in sporadic retinoblastoma and several other cancers. It must be emphasized that in such cases it is crucial to rule out low-level mosaicism in other tissues since its presence implies specific follow-up and a possible risk of transmission to offspring.

3. Clinical Presentation of SEGA and Patients’ Surveillance

Usually, SEGAs grow slowly and do not produce clinical symptoms for a long time, but on longer follow-up, by the occlusion of the foramen of Monro, they may lead to hydrocephalus and symptoms of increased intracranial pressure (Figure 2) [16][17][18]. These symptoms include headaches, nausea, vomiting, especially in the morning or during the night, blurred vision, changes in behavior, and new or worsened seizures. In patients with disabilities, early signs of increased intracranial pressure may be easily overlooked, so monitoring of SEGA with neuroimaging is now recommended.
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Figure 2. Growth of the SEGA in the proximity of foramen Monro during one year of follow-up (plates A, B, C). Pronounced hydrocephalus caused by growing SEGA is seen on plate C. This MRI image shows also a subcortical nodule in the right occipital lobe. (Courtesy of prof. Elzbieta Jurkiewicz, The Children’s Memorial Health Institute, Warsaw).
In the past, SEGAs were frequently diagnosed in patients presenting with symptoms of increased intracranial pressure. Nowadays, due to the implementation of MRI surveillance, the majority of tumors are diagnosed at an early stage allowing effective treatment [12][19]. In about 15–40% of patients, SEGAs may develop bilaterally or at several different locations [20].
In 2021, the International Tuberous Sclerosis Complex Consensus Group updated the diagnostic criteria and treatment recommendations [12]. Every TSC patient below the age of 25 years should undergo regular brain MRI examinations every 1–3 years to assess the presence of SEGA and evaluate a change in the size of the tumor. Patients with large or growing SEGA, or with SEGA causing ventricular enlargement who are asymptomatic, should undergo MRI scans more frequently and the patients and their families should be educated regarding the potential new symptoms [12]. Because the growth of tumors seems to slow down dramatically after 25 years of age, frequent MRIs are not recommended routinely but should be performed according to individual needs. However, in the adult TSC population included in the TOSCA study, the continued growth of SEGA was reported in 21% of patients, predominantly with the TSC2 genotype and 2.4% were newly diagnosed during adulthood, the oldest of whom was 57 years old. Most of the patients had mutations in the TSC2 gene [21]. Therefore, patients with SEGA diagnosed in childhood should undergo regular brain imaging also beyond the age of 25 years.
Today, there is a great variety of methods of tumor size assessment in MRI studies. The most popular, traditional manner is the planimetric methodology of volumetric analysis but there are also semi-automatic ways of tumor scanning. ITK-Snap (pixel clustering, geodesic active contours, region competition methods), 3D Slicer (level-set thresholding), and NIRFast (k-means clustering, Markov random fields) have proved to facilitate the appropriate assessment of SEGA growth [22].

4. Surgical and Pharmacological Treatment of SEGAs

Currently, two treatment modalities are available for growing SEGAs: surgical or pharmacological interventions with mTOR inhibitors (mTORi). Before the era of mTORis, neurosurgical resection of SEGAs was the standard therapy in patients with TSC [19]. Nowadays, according to recommendations of the International Tuberous Sclerosis Complex Consensus Conference surgical resection should be performed for acutely symptomatic SEGA (sometimes with cerebral spinal fluid shunt insertion). For growing but otherwise asymptomatic SEGA either surgical resection or medical treatment with mTORi may be used.
The most common resection routes are transfrontal transcortical and interhemispheric transcallosal [23]. Early and total removal of the tumor is associated with a better prognosis. The experience of the surgical team is also an important factor in favorable outcomes.
Postoperative morbidity and mortality increase when SEGA invades the neighboring structures as well as in bilateral and larger tumors. In a review of 263 TSC patients affected by SEGA gross total resection was achieved in 81.1% of cases, and mortality and permanent morbidity were 4.9% and 6.1%, respectively. A cerebrospinal fluid shunt was needed in 81 patients (30.8%). Tumors regrew in 11.5% of cases, and in most cases, the regrowth was seen when partial tumor resection was performed [24]. Subtotal resection results in a very high probability of regrowth, and medical treatment should be preferred in cases when total resection is not feasible or the size of tumors exceeds 4 cm [20][25]. In the largest series of 64 resected SEGAs surgical treatment of tumors >4 cm or bilateral tumors was associated with a very high risk of complications of 73% and 67%, respectively [20].
Endoscopic tumor removal has been more extensively considered in recent years; however, its main limitations are tumor size (<3 cm) and broad attachment of the tumor to the basal ganglia. The advantages of endoscopic management are also the possibility to add septostomy to tumor resection [26]. Among the less invasive surgical techniques, the keyhole concept method is also worth highlighting. It involves accessing deep intracranial lesions through the minimum craniotomy, which significantly reduces the operational risk and improves the cosmetic effect.
Laser interstitial thermal therapy (LITT) is the more recently considered option. It has similar limitations to the endoscopic approach (tumor size < 2 cm, broad attachment of the tumor to the basal); moreover, there is a risk of acute hydrocephalus and edema of basal ganglia, so active hydrocephalus is a contraindication to LITT in SEGAs [26]. This new minimally invasive technique is very promising; however, so far there are no data on the long-term results of LITT in SEGA. Given that radiation of tumors associated with Gamma Knife Stereotactic Radiosurgery (GK-SRS) may promote malignant malformation, the use of this therapy in the treatment of SEGA is very limited [27][28].
SEGAs were the very first manifestations of TSC, in which the mTORi have been used. Currently, two mTORi, everolimus and sirolimus, are widely used in the treatment of SEGAs. Several prospective trials documented successful SEGA regression with both agents, but only everolimus was used in a controlled, randomized study [29][30][31]. In the double-blind EXIST-1 study, everolimus significantly decreased the volume of SEGAs by at least 50% in 35% of patients after 6 months of treatment [31]. Longer follow-up of these patients) resulted in even higher numbers—62% of patients achieved at least a 50% reduction in the tumor volume after 4 years of treatment [32]. Everolimus is currently approved by FDA and EMA for the medical treatment of SAGAs in patients not eligible for surgical treatment.
Both mTOR inhibitors, everolimus and sirolimus, share the same main mechanism of reducing the activity of the mTOR pathway. However, due to their different clinical profile, patients may tolerate one drug better than the other and may have a greater response and/or fewer side effects with everolimus versus rapamycin or vice versa [33].
International Tuberous Sclerosis Complex Consensus Conference widely recommended the use of mTOR inhibitors for patients with asymptomatic and growing SEGA, as well as in patients with mild and moderate symptoms who are not eligible for surgery or prefer medical treatment. There are also several additional situations when the use of mTOR inhibitors may be particularly useful. There is an increasing number of reports on the presurgical administration of mTOR inhibitors in large SEGAs or in tumors invading deep brain structures such as the hypothalamus or thalamus. The neoadjuvant therapy may enable tumor size reduction and gross total resection. Moreover, intraoperative examination in such cases showed fewer features of hemorrhage and clearly differentiated borders of the tumor [34]. The use of mTOR inhibitors can also be found in the management of microscopic residual tumors. Such treatment is used as a neoadjuvant therapy in cases of poorly operated tumors or in the absence of absolute certainty as to their annihilation. Such a maneuver significantly reduces the patient’s risk of reoperation and the associated inconvenience.
Contrary to general indications, mTORi has been also reported to be used in acute obstructive hydrocephalus, including five patients who had clinical signs of increased intracranial pressure. Such an approach allowed significant tumor shrinkage and ventriculomegaly diminution without the use of a CSF shunt [35]. Other studies included patients with moderate hydrocephalus who were not eligible for surgery. Treatment with everolimus resulted in an improvement in ventricular dilatation [36][37].
Finally, mTORi was used for the prevention of tumor recurrence after subtotal resection of SEGA. Franz et al. reported persistent volume reduction in 3 out of 4 patients during long-term pharmacological treatment [38].
During the decision-making process on SEGA treatment, one should also consider the impact of mTOR inhibitors on other manifestations of TSC. Application of mTORi may also decrease seizure frequency in patients with refractory focal seizures, cause regression of cardiac rhabdomyomas in infants, as well as reduce the size of kidneys angiomyolipomas and improve facial angiofibromas [31][39]. Treatment with mTOR inhibitors can additionally improve autistic behavior. Yui et al. reported marked improvement in social interaction and verbal and non-verbal communication in four young TSC patients treated with an mTOR inhibitor [40]. A concomitant increase in ceruloplasmin and transferrin was observed.

This entry is adapted from the peer-reviewed paper 10.3390/jcm12030956

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