Immunohistochemical and molecular genetics study of a granular cell astrocytoma: A case report of malignant transformation to a glioblastoma

Abstract

We treated a 56-year-old woman who had a right temporal lobe tumor found by chance after a traffic accident. MRI confirmed a heterogeneously enhanced tumor in the temporal lobe with large peritumoral edema extending to the superior parietal lobe. The patient underwent tumor resection. The tumor consisted largely of distinct cells with discrete borders and granular cytoplasm. In granular cells, the accumulation of PAS-positive granules was observed. Immunohistochemical analysis demonstrated positive staining for GFAP, S-100, and oligodendrocyte transcription factor 2 and negative staining for synaptophysin. CD68 was negative in granular cells, but positive in stromal cells. Ki-67 labeling index was quite low. The tumor was diagnosed as a granular cell astrocytoma (GCA). Postoperative radiotherapy combined with temozolomide was administered. One month after chemoradiotherapy, the tumor occurred in the parietal lobe, and a tumorectomy was performed. The tumor was composed of poorly differentiated astrocytic tumor cells with prominent microvascular proliferation and necrosis. A small number of granular cells were locally observed and the tumor was diagnosed as a glioblastoma. O6-methylguanine-DNA methyltransferase promoter methylation was detected in the GCA but not in the glioblastoma. Isocitrate dehydrogenase mutations were not detected in either tumor. Comparative genomic hybridization analysis demonstrated that no chromosomal abnormality was found in the GCA; however, a gain of chromosomes 7 and 19 and a loss of chromosomes 10 and 9p21 (CDKN2A) were found in the glioblastoma. p53 was strongly expressed in both the GCA and glioblastoma. The tumor progressed despite extensive chemotherapy, and the patient died 1 year after the initial treatment. Our immunohistochemical, genetic and chromosomal analyses indicate that the glioblastoma was transformed from the GCA.

Mesenchymal/radioresistant traits in granular astrocytomas: evidence from a combined clinical and molecular approach

“…reported a molecular analysis of a GCA that progressed into a GBM 1 month after chemoradiotherapy: MGMT promoter methylation was found in the GCA, whereas gain of chromosome 7 (gain of EGFR ), loss of chromosome 10 ( PTEN ) and a p16 INK4A deletion were observed in the GBM. All of these studies failed to support a unique molecular signature for this subgroup of granular tumours, leading the authors to exclude the hypothesis of a peculiar/specific genotype . In accordance with these observations, our GCA series did not show a unique molecular trait, and showed similar genetic alterations as the control cohort of conventional high‐grade gliomas; indeed, no statistically significant differences were found among the two series.…”

“…Interestingly, the only patient still alive showed MGMT promoter methylation, in accordance with the favourable predictive and prognostic value of this feature, although 10 months is too short a follow‐up for any assumptions to be made. Only two cases of MGMT ‐methylated GCA have been reported in the literature to date . Deletion of CDKN2A and 1p.36 was also observed in two of our GCAs, highlighting the high frequency of allelic loss in this subgroup .…”

“…Even though recently reported data suggest that the role of expression signatures in defining GBM subclasses may need better assessment, our findings could help to characterize this tumour variant and provide a molecular basis associated with its aggressive behaviour. In fact, considering the extensive molecular profile of GCA subsets, different studies had previously failed to identify a unique molecular signature, leading the authors to exclude the hypothesis of a peculiar/specific genotype . Castellano‐Sanchez et al .…”

“…[2][3][4][5][6] Although the aggressive behaviour of GCAs has been associated with a high frequency of allelic losses in previous studies, a specific molecular trait of these uncommon lesions has been investigated by only a few authors, with conflicting results. 2,[7][8][9][10] Therefore, the question of whether the granular appearance is merely a rare phenotypic change or a marker that could be used to identify a distinct and genetically defined subgroup of astrocytomas remains unanswered.…”

A rare differentiation pattern of a common tumor arising in the frontal lobe in an elderly woman

“…Besides the well characterized morphologic variants recognized by the 2007 WHO classification, the emerging variants include: glioblastoma with oligodendroglial component, lipidized cells, granular cells, epithelial structures and glioblastoma with primitive neuroectodermal features . Glioblastoma exhibiting granular cell differentiation is a rare infiltrative astrocytoma that has been intermittently reported in the literature as single case reports and short series ever since its first description by Markesbery . These tumors are characterized by a distinctive histomorphology of large polygonal cells with abundant granular cytoplasm, although there is no established cut‐off percentage for the fraction of tumor demonstrating such differentiation.…”