Subependymal Giant Cell Astrocytoma

The clinical presentation of patients with tuberous sclerosis and SEGA almost universally includes epilepsy, as 96% of patients report seizures that are frequent, severe and appear during the first few months of life [13]. Increased intracranial pressure (ICP) is seen in all patients [11], whereas learning difficulties, memory loss and behavioral changes may be observed [7], as well as autism [6]. Mental retardation is not uncommon, affecting 40-80% of TS patients. Headaches, vomiting, visual disturbances are often a manifestation of raised ICP.

A properly obtained patient history, including the onset of symptoms and positive family history may provide important clues for the physician. The mainstay of diagnosis, however, are imaging studies of the head, either CT or MRI. MRI that reveals a nodule of > 12 mm in diameter that obstructs normal CSF flow at the foramen of Monro is highly suggestive of SEGA [4]. Histology of the tumor, when possible, should be performed for further confirmation. Loosely cohesive clusters of cells with an oval-to-round nucleus without atypia and prominent nucleoli, binucleation or multinucleation with chromatin evenly distributed and an abundant eosinophilic cytoplasm "trapped" in numerous hairlike processes are some of the main features of SEGA [14].

Total surgical excision is the recommended mode of treatment, as this definite measure provides minimal rates of recurrence [6]. Indications for surgery are - presence of the tumor around the foramen of Monro, a diameter of > 5 cm, acute hydrocephalus, increased rate of seizures and significant growth on serial imaging studies [9] [12]. Although surgery is considered as first-line therapy, numerous complications have been observed, including neurological deficits, postoperative infections, epidural abscess and operative complications, whereas up to a third of patients develop tumor recurrence, primarily due to incomplete tumor excision [15]. Moreover, the need for ventriculoperitoneal shunting is not uncommon [16], which is a procedure that carries its own risks. In addition to surgery, the recent discovery of mTOR pathway inhibiting drugs, everolimus, has lead to their use in patients in whom surgery is not possible [6]. Everolimus can cause significant shrinkage of tumors in some patients, rising up to 50% shrinkage in certain reports [3] [8]. Despite fears of unknown long-term effects, its safety has been solidified through prolonged patient follow-ups [17]. The most significant adverse effects were determined to be mucosal ulcerations, stomatitis and convulsions [8]. Rapamycin (sirolimus) has also proven to be of benefit in certain patient groups and its use has been recently introduced for patients suffering from SEGA [9], but because it possesses immunosuppressive effects, not all patients are suitable candidates. Gamma-knife is a novel form of radiation therapy that is slowly becoming the mainstay of treatment of various malignant diseases and its efficacy against SEGA has been documented [9]. Gamma-knife, unfortunately, is not recommended for larger tumors, as a significant amount of time may pass before tumor shrinkage, thus predisposing patients to acute hydrocephalus and sudden death [9].

Even though SEGA is a benign tumor, its presence is a significant cause of mortality in patients suffering from tuberous sclerosis, primarily because they can obstruct normal CSF flow through the ventricular system and cause acute hydrocephalus [6] [11]. More importantly, the diagnosis is often delayed, with studies determining that up to 10 years may pass before the diagnosis, which is most commonly made around 13 years of age [11]. Other estimations, however, suggest that the mean age of diagnosis is 5 years [4]. Nevertheless, an early identification of tumors in their early stages, when they cause little or no symptoms, can surely lead to better patient outcomes. Moreover, an early surgical removal yields very good results [12], further strengthening the role of an early diagnosis.

SEGA arises from benign supependymal nodules (hamartomas) in the vicinity of the foramen of Monro in approximately 5-15% of patients suffering from TS, a genetic disease characterized by growth of hamartomas in the heart, kidneys, skin and brain [4]. Although TS is known for its autosomal dominant pattern of inheritance, it is estimated that 60-70% of mutations appear de novo [4], and the cause remains unknown. Mutations of the TSP1 and TSP2 genes that code for proteins involved in the formation of a tumor suppressor complex, are responsible for the development of SEGA [3], but the exact cause and trigger of these mutations remains unknown.

Prevalence rates of TS are estimated at 1 per 6,000-12,000 live births [4], and reports of SEGA among these individuals showed a rate of 5-10% [5], but as high as 20% was seen in other studies [10]. Symptoms can appear even at birth, but the diagnosis is often made at the end of first and the beginning of second decade of life. Neither gender nor ethnic prevalence is determined in this group of patients [7].

The pathogenesis of TS involves mutations of TSC1 and TSC2 genes located on chromosomes 9 and 16, respectively [7]. These genes code for hamartin and tuberin, proteins responsible for proper cellular differentiation and energy utilization [7]. Hamartin and tuberin together form a tumor-suppressor complex that limits the activity of mTOR through the Ras homolog enriched in brain (RHEB) protein, an essential component of regular cell cycle [3]. When mutations of these proteins occur, the mTOR complex becomes up-regulated, resulting in abnormal protein synthesis, as well as cellular proliferation and differentiation [3]. Because of these changes, the tumor progressively grows and eventually causes compression of the ventricular system, causing acute hydrocephalus and other neurological deficits.

Although prevention of SEGAs is not possible due to the fact that the underlying cause of TSP mutations is not known, patients with TS should be regularly followed-up by imaging studies of the head in order to identify this tumor in its early stages.

Subependymal giant cell astrocytoma (SEGA) is a slow-growing, benign tumor of glioneural origin that develops in the ventricular system of the brain, most commonly in the lateral ventricle in close proximity to the foramen of Monro [1] [2]. It is exclusively a manifestation of tuberous sclerosis (TS), a genetic disease characterized by mutations of tumor suppressor genes TSP1 (hamartin) and TSP2 (tuberin) located on chromosomes 9 and 16, respectively [3]. Hamartin and tuberin are proteins that keep the mammalian target of rapamycin (mTOR) signaling pathway in check, but in the absence of their activity, up-regulation of this pathway leads to abnormal cellular division, proliferation and differentiation [3]. SEGAs develop from benign subependymal nodules (known as hamartomas) in either unilateral or bilateral fashion within the first two decades of life [2]. It is estimated that TS occurs in approximately 1 per 6,000-12,000 live births [4], and approximately 5-20% of those individuals will develop SEGA [5]. Mutations and the upregulation of mTOR signaling pathway causes a myriad of neurological deficits and changes in the brain parenchyma when it comes to TS, including SEGA [6]. The clinical triad of seizures, hydrocephalus and raised intracranial pressure (ICP) is a diagnostic hallmark of SEGA [2], together with cognitive, behavioral, memory and learning deficits [7]. Symptoms appear as early as infancy and all patients are diagnosed by the end of their second decade of life. Computed tomography (CT) and magnetic resonance imaging (MRI) of the endocranium are vital in the diagnostic workup, as they may reveal the presence of one or multiple SEGAs in the ventricular system [5]. Early and aggressive surgical treatment is considered as the primary method of treatment [2], as total surgical resection leads to minimal or even absent rates of recurrence. Not all patients may undergo surgery, for example those in whom large unresectable tumors are diagnosed and alternative treatment modalities include the use of mTOR inhibitors such as everolimus, rapamycin and Gamma-knife therapy [8] [9]. An early aggressive therapy carries a very good prognosis, but larger tumors may trigger acute hydrocephalus that is potentially fatal, which is why an early diagnosis is detrimental.

Subependymal giant cell astrocytoma (SEGA) is a rare tumor that develops in the brain in approximately 5-10% of patients suffering from Tuberous Sclerosis, a genetic disease distinguished by appearance of various tumors (known as hamartomas) in the brain, heart, kidneys and skin due to mutations of tumor suppressor genes on chromosomes 9 and 16. Tuberous sclerosis is seen in approximately 1 per 6,000-12,000 live births and is transferred through an autosomal dominant pattern of inheritance, meaning that if one parent is suffering from the disease, there is a 50% chance for the child to receive the copy of the mutated gene from that parent. However, mutations can also appear sporadically, meaning that positive family history for the diseases is not mandatory. Mutations of genes that are supposed to suppress abnormal cellular differentiation are the underlying cause of this tumor, but why do these mutations appear remains a mystery. This tumor grows slowly and has an insidious onset, but over time, the tumor compresses the structures through which cerebrospinal fluid passes, causing seizures, numerous neurological complaints and increased intracranial pressure due to acute hydrocephalus (accumulation of cerebrospinal fluid in the brain). Memory and language deficits, mental retardation and cognitive decline, together with headaches, vomiting and visual disturbances are encountered in the majority of patients. These complaints may appear within the first few months of life and the diagnosis is made before 20 years of age in all patients. To confirm SEGA as the cause of symptoms, imaging studies such as computed tomography (CT scan) or magnetic resonance imaging (MRI) of the head is necessary. Once the diagnosis is made, the choice of therapy depend on the size of the tumor, level of cerebrospinal fluid flow compression and overall condition of the patient, but complete surgical removal is performed whenever possible. Although brain surgery always carries a significant risk, it was shown to be most effective in preventing tumor recurrence, but only if the entire tumor is removed. In recent years, drugs that inhibit cellular pathways that cause tumor growth and development have been made and their use is becoming the mainstay of therapy in patients in whom surgery is not an option. The importance of an early diagnosis lies in ensuring patients the ability to undergo surgery, but also to prevent acute hydrocephalus that can be fatal if not recognized on time.

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