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2012, Volume 28, Number 2, Page(s) 095-103     
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DOI: 10.5146/tjpath.2012.01107
Evidence of Ambiguous Differentiation and mTOR Pathway Dysregulation in Subependymal Giant Cell Astrocytoma
Brad D BARROWS1, Martin J RUTKOWSKI2, Şakir Humayun GÜLTEKİN3, Andrew T PARSA2, Tarık TİHAN1
1Department of Pathology, University of California San Francisco, SAN FRANCISCO, USA
2Department of Neurosurgery, University of California San Francisco, SAN FRANCISCO, USA
3Department of Pathology, Oregon Health Sciences University, PORTLAND, USA
Keywords: Subependymal giant cell astrocytoma, Hamartin, Tuberin, mTOR complex, IDH1, IDH2, Olig2

Objective: The exact cell of origin of subependymal giant cell astrocytoma is debated but most currently consider the tumor in the astrocytic category. Mutations and subsequent biallelic inactivation of TSC1 encoding hamartin, or TSC2 encoding tuberin appear to be the underlying genetic aberrations. Inactivation leads to loss of proteins that inhibit mammalian target of rapamycin (mTOR ) disrupting tightly regulated cell functions.

Material and Method: We analyzed the expression of tuberin and hamartin along with an array of neuroepithelial markers in 9 subependymal giant cell astrocytomas. In addition, RPS6 and 4EBP1 regulatory proteins that are downstream in the mTOR pathway were also evaluated.

Results: While hamartin and tuberin expression levels were relatively decreased compared to control tissue, this was not of particular practical use to detect the mutated gene since low levels of positivity could be detected throughout the central nervous system. As expected, the levels of RPS6 and 4EBP1 were increased, further confirming the activation of the mTOR pathway. GFAP was positive in 5 cases, while Synaptophysin positivity was found in all tumors. CD34 (a marker often observed in well differentiated glio-neuronal tumors), Olig2 (a nuclear marker present in most gliomas), IDH1 and IDH2 were entirely negative in all tumor cells. Ki67 (MIB-1) showed a low proliferation rate ranging from 2% to 8%.

Conclusion: Staining with neuroepithelial markers supports the suggestion of ambiguous differentiation. Subependymal giant cell astrocytomas do not appear to have the typical expression profiles of astrocytic tumors, under which they have been classified.

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