Contributed by Lin Liu, MD, PhD and Geoffrey Murdoch, MD, PhDFINAL DIAGNOSIS
SUBEPENDYMAL GIANT CELL ASTROCYTOMA
DISCUSSION
General introduction of SubEpendymal Giant cell Astrocytoma (SEGA): SEGA is one of the major criteria in diagnosis of tuberous sclerosis complex (TSC) (Table 1), with a prevalence ranging from 6 - 14% in these patients (1), and most commonly occurring in the first two decades of life. SEGA is a WHO grade I, slow growing tumor, typically arises in the brain lateral ventricles, frequently in the region of the foramen of Monro, which may cause obstructive hydrocephalus and increased intracranial pressure. Lesions are sharply demarcated, multinodular sometimes with a cystic component and frequent calcifications. Histology is characterized by large, polygonal or rounded cells, with abundant eosinophilic glassy cytoplasm. The nuclei are eccentric, pleomorphic, finely granular with some having distinct nucleoli, resembling ganglion cells; others may resemble gemistocytic astrocytes. Immunohistochemistry studies (2, 3) reveal only patchy and variable GFAP positive element. Some of the tumor cells may show positivity of neurofilament proteins and neuronal-associated class III -tubulin; however, Synatophysin, another neuronal marker, is usually non-reactive. In contrast, Vimentin, the intermediate filament present in immature astrocyte precursors, are consistently positive in these tumor cells. Ultrastructural studies have demonstrated features of both neuronal cells and astrocytes (2, 3). Due to these conflict findings, the cellular origin of SEGA is still an open question to date. Treatments include surgical resection and medications, such as rapamycin and derivatives, based on genetic studies and molecular mechanisms, which will be further discussed below.
Tuberous Sclerosis Complex (TSC): TSC is a genetic disorder with an autosomal dominant pattern of transmission, however with high sporadic case rate up to 50-60% (1). TSC is characterized by the formation of hamartomas and benign neoplasms in multiple organs including brain, kidney, heart, and lung etc. and frequently with various skin manifestations. Major CNS lesions include cortical hamartomas (tubers), subcortical glioneuronal hamartomas, subependymal glial nodules and subependymal giant cell astrocytomas. These malformative lesions have a strong association with mental retardation and epilepsy. Histologically, giant cells are characteristic in all these CNS lesions (3). Two distinct genetic loci have been identified to be associated with TSC. One is on chromosome 9q34 (TSC1), encoding Hamartin protein; the other is on chromosome 16p13 (TSC2), encoding Tuberin protein. Typical patients with TSC carry a mutation in either TSC1 or TSC2, and tumors arise with a subsequent loss of the functional allele (LOH). Mutations in TSC2 are found to be more common and in general cause more severe diseases than those in TSC1. As a matter of fact, TSC may present with widely different phenotypes and variable disease mechanisms. For example, a few cases have reported disease penetrance in the patients' first-degree relatives demonstrating minor signs and a forme fruste of the disease, and were theoretically considered as having somatic mosaicism. On the other hand, in cerebral tubers (which are not neoplasms), molecular studies in patients and animal models so far have failed to demonstrate LOH (4) or mutations in TSC1 and TSC2 genes, suggesting additional mechanisms for tuberogenesis, likely related to different cellular compartment localizations of these proteins in this particular lesion (5). However, in SEGA, majority of the tumor cases consistently show either reduced tuberin or hamartin expression. Diagnosis of TSC is based on clinical findings of CNS and extraneural manifestations, and is divided into definitive, probable and possible TSC categories (Table 1).
Hamartin and tuberin signaling pathway in disease pathogenesis and molecular based medication for SEGA: In response to energy stress or low nutrient levels, tuberin is phosphorylated via LKB1/AMPK and Wnt/GSK3 pathways and form complex with hamartin. The tuberin/hamartin complex down regulates the mammalian Target Of Rapamycin (mTOR) protein function, and subsequently regulates the activities of two effector molecules: the eukaryotic initiation factor 4E-binding protein 1 (4E-BP1) and ribosomal protein S6 kinase 1 (S6K1) that are essential for G1 to S phase transition, thereby decrease cell proliferation and cell size (6, 7, 8). Inhibition of tuberin phosphorylation upon insulin or growth factor stimulation, or mutations/deletions of either tuberin or hamartin, will disrupt the complex formation, leading to increased mTOR activity and thus increased cell proliferation and enlarged cell sizes (6, 7, 8). Rapamycin is an mTOR inhibitor, and was previously shown to induce apoptosis and reduce cell proliferation in tuberin null cells. Oral rapamycin or rapamycin mimicker Everolimus have been shown to effectively induce regression of renal angiomyolipoma and CNS astrocytomas associated with TSC. However, regrowth of tumor has been reported once mTOR inhibitor therapy is stopped. In addition, adverse effects such as immunosuppression and hypercholesterolemia also limit the long term use of these medicines. Therefore, surgery resection is still considered to be the most effective therapeutic strategy for SEGA. Close clinical follow-up including image surveillance is also strongly recommended (9, 10).
Follow-up of the case: Genetic studies using the patient peripheral blood showed normal female microarray results, with no loss or gains in the genomic DNA copy numbers identified. Although uncommon, solitary SEGAs with no other TSC manifestations have been reported previously, and most of which were considered as forme fruste of TSC with somatic mosaicism. However, there was case report of isolated SEGA with two hit of somatic mutations of TSC2 gene identified in the tumor tissue, with no somatic mosaicism found in any other organs after extensive exploration (11). In our case, the patient does not inherit any disease alleles, based on negative family history and negative genomic studies, thus extensive search of somatic mutations of TSC1 and TSC2 genes in tumor tissue and in other organs may be helpful for the interpretation of SEGA development as well as for the prognosis of potential occurrence of other TSC phenotypes in the future.
REFERENCE
Contributed by Lin Liu, MD, PhD and Geoffrey Murdoch, MD, PhD
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