Immunohistochemical Assessment of Neuroepithelial Markers and Hamartin/Tuberin Expression in Subependymal Giant Cell Astrocytoma (SEGA): Further Evidence for Ambiguous Differentiation and mTOR Signal Transduction Dysregulation.
Brad D Barrows, Martin J Rutkowski, Humayun Gultekin, Andrew Parsa, Tarik Tihan. UCSF, San Francisco, CA; OHSU, Portland, OR
Background: The exact nature of subependymal giant cell astrocytoma (SEGA) has been debated due to evidence of divergent differentiation and the uncertainty about the cell of origin. Mutations and subsequent biallelic inactivation of either TSC1 encoding hamartin, or TSC2 encoding tuberin have been demonstrated in SEGAs. This inactivation is suggested to lead to the loss of proteins that inhibit mammalian target of rapamycin (mTOR) disrupting a large number of tightly regulated cell functions.
Design: In order to determine their practical diagnostic value and help in identifying the mutated protein, we analyzed the expression of tuberin and hamartin proteins as well as neuroepithelial markers in 9 patients with SEGAs. In addition, RPS6 and 4EBP1 regulatory proteins that are downstream to the heterodimer in the mTOR pathway were also evaluated. Normal brain tissue and other glial tumors obtained from neuropathology files were used as controls.
Results: Hamartin and tuberin expression levels were found to be relatively decreased in the SEGA specimens when compared to controls, while the expression levels of RPS6 and 4EBP1 were increased. Interestingly, GFAP was strongly positive in only 5 of the cases (in addition to 3 negative and 1 weakly positive), while Synaptophysin positivity was found in all tumors. Staining for CD34 (a marker often observed in well differentiated glioneuronal tumors) and Olig2 (a nuclear marker present in most gliomas) were entirely negative in all tumor cells. Ki67 (MIB-1) showed a low proliferation rate ranging from 2% to 8%.
Conclusions: Our results suggest that staining for either hamartin or tuberin is unlikely to be of diagnostic value due to positivity in almost all tumors and normal tissues, even if the expression is relatively decreased in SEGAs as expected. Increased expression of RPS6 and 4EBP1 further confirms the activation of mTOR pathway and the possible role these molecules may have in the growth of these tumors. Staining with neuroepithelial markers further supports the suggestion of ambiguous differentiation. SEGAs do not appear to have the typical expression profiles of astocytic tumors, under which they have been classified.
Tuesday, March 1, 2011 1:00 PM
Poster Session IV # 226, Tuesday Afternoon