Subependymal giant cell astrocytoma pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Ifeoma Odukwe, M.D. [2], Sujit Routray, M.D. [3]

Subependymal giant cell astrocytoma is almost exclusively associated with tuberous sclerosis complex, which is an autosomal dominant disorder. It is associated with inactivation of the tumor suppressor genes, TSC1 and/or TSC2. It is also believed to arise from a subependymal nodule present in the ventricular wall of a patient with tuberous sclerosis. Some of the common findings seen on microscopic pathology include pleomorphic multinuleated eosinophilic cells, streams of elongated tumor cells with abundant cytoplasm, and clustered cells arranged in a perivascular pseudopallisading pattern. On immunohistochemistry, the tumor cells are positive for glial fibrillary acidic protein, microtubule-associated protein 2, synaptophysin, S-100, neurofilament, and neuron-specific enolase.

• Subependymal giant cell astrocytoma is a rare, benign tumor predominantly associated with tuberous sclerosis complex, although a few cases have been reported in patients without evidence of tuberous sclerosis.^[1]
• It is classified as a WHO grade I central nervous system tumor.
• It is of glioneuronal origin and typically arises from the caudothalamic groove adjacent to the foramen of monro.^[2][3]
• The inactivation of the tumor suppressor genes TSC1 (on chromosome 9q34) and/or TSC2 (on chromosome 16p13) results in the formation of subependymal giant cell astrocytoma in people with tuberous sclerosis.^[1]
• TSC1 and TSC2 encodes the proteins tuberin and hamartin, respectively. The tuberin/hamartin complex suppresses Ras homolog enriched in brain (RHES) which functions as a direct activator of the mammalian target of rapamycin (mTOR). The complex also inhibits cyclin-dependent kinase inhibitor 1B, which regulates cell cycle progression. The activation of mTOR and progression of the cell cycle from the loss of upstream inhibition leads to protein translation, cell growth, and proliferation.^[1]
• It is believed that a subependymal nodule, which are common brain masses seen in tuberous sclerosis, can transform to subependymal giant cell astrocytoma.
• It is commonly located in the ventricles but a few may have extraventricular locations.^[2]
• Subependymal giant cell astrocytoma is a major cause of tuberous sclerosis complex-related morbidity and mortality during the pediatrics age, as it is seen in 10 to 20% of these patients.^[4]
• It is believed to arise from a subependymal nodule but this is controversial because subependymal giant cell astrocytomas are located in the caudothalamic groove while subependymal nodules are located in the ependymal lining of the lateral ventricles along the caudate nucleus.^[4]
• On immunohistochemistry, the tumor cells test positive for the glial fibrillary acidic protein and microtubule-associated protein 2.^[4]

Genes involved in the pathogenesis of subependymal giant cell astrocytoma include:^[5]

• TSC1
• TSC2

Conditions associated with subependymal giant cell astrocytoma include:^[5]

• Tuberous sclerosis

On microscopic histopathological analysis, subependymal giant cell astrocytoma is characterized by:^{[4][6][7][8][1][9][9]}

• Pleomorphic multinuleated eosinophilic cells
• Streams of elongated tumor cells with abundant cytoplasm
• Clustered cells arranged in a perivascular pseudopallisading pattern
• Evenly distributed granular chromatin
• Frequent binucleation and multinucleation
• Vesicular nuclei
• Occasional distinct to prominent nucleoli
• On rare occasions, there can be atypical features such as vascular endothelial proliferations, mitosis, and necrosis
• Tumor cells are positive on immunohistochemistry for glial fibrillary acidic protein, microtubule-associated protein 2, synaptophysin, S-100, neurofilament, and [[neuron-specific enolase

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