DIAGNOSIS: SUBEPENDYMAL GIANT CELL ASTROCYTOMA WITH MALIGNANT PHENOTYPE AND AXIAL SPREAD
Exon scanning for germline mutations of the tumor specimen was performed. 20 exons of the TSC1 and 41 exons of the TSC2 gene were analyzed by SSCP as described (1). Sequence alterations corresponded to shifts in exon 3 of the TSC1 gene in all samples. In addition, the spinal metastasis harbored a further shift in exon 23 of the TSC 1 gene. Herein, a silent mutation was detected in exon 23 with substitution of G to A at nucleotide no. 140273. In both exons, further mutations were absent.
We report on a patient with clinically definitive TSC (2) who suffered from a recurrent SEGA of the right lateral ventricle that displayed a frankly elevated mitotic activity, and who developed a spinal metastasis within two years and six months after diagnosis.
SEGA is a benign tumor of the CNS that generally occurs in the setting of TSC. Although increased mitotic activity, endothelial proliferation or necrosis may be present, these features are considered as not indicative of malignant progression of this tumor entity (3). Additionally, even the rare recurrences do not show malignant transformation (3). There is one recent report on a SEGA with elevated mitotic activity and a presumed spinal seeding (4). The reports on anaplastic SEGAs are scarce, and few cases of glioblastoma have been published in patients with tuberous sclerosis (5-7), one of these was probably irradiation induced as it developed from a typical WHO Grade I SEGA (6). In the presented case, the main differential diagnosis was glioblastoma multiforme (GBM), because of necrosis, vascular proliferates and high mitotic activity. However, the morphology of the tumor cells, the radiological features and the clinical picture were classical for a SEGA. In addition, the young age and the prolonged survival argue against a GBM. This diagnosis was confirmed by the Brain Tumor Reference Center, Bonn, Germany. Although primarily atypical but still compatible with a WHO Grade I SEGA, our tumor became frankly malignant, and metastasized shortly after the irradiation. Whether SEGA's with signs of anaplasia should be classified as high-grade gliomas is an important issue of debate. We strongly advise against radiotherapy, since currently there are no established guidelines on adjuvant therapy after surgical resection, which is considered the curative therapy.
Approximately one third of TSC cases are familial, and result in a dominantly inherited multisystem disorder, with mutations of the TSC1 gene at 9q34.3 or the TSC2 gene at 16p13.3 (8, 9). However, among sporadic individuals, the distribution of mutations on both loci is not precisely defined (10). The TSC1 and the TSC2 locus encode the 1164 amino acid protein hamartin, and the 1807 amino acid protein tuberin, respectively. Recently phosphorylation of tuberin, and the Akt kinase with subsequent inactivation has been described (11). Furthermore, mTOR activation as a central event in the pathogenesis of SEGAs was outlined (12). Although we did not have any fresh blood samples of the patient we performed a genetic analysis of the tumor specimen, but SSCP analysis and additional cloning experiments did not reveal functionally relevant mutations, except for a silent mutation in exon 23, showing that germline mutations were absent in these tumors.
Contributed by Werner Stenzel, Marek Franitza, Albert J. Becker, Manuel Montesinos-Rongen1, Mario Löhr, Jin-Yul Lee, Gabriele Röhn, Hrvoje Miletic, and Martina Deckert