Cheng Y, Ng H K, Ding M, Zhang S F, Pang J C, Lo K W
Department of Anatomical & Cellular Pathology, the Chinese University of Hong Kong, Shatin.
J Neuropathol Exp Neurol. 1999 Feb;58(2):120-8. doi: 10.1097/00005072-199902000-00002.
Glioblastoma multiforme (GBM) often displays morphological heterogeneity in that low-grade (LG) area with well-differentiated cells are commonly found adjacent to high-grade (HG) area with poorly-differentiated cells. This heterogeneity may cause difficulty in obtaining representative tumor samples. Nevertheless, the genetic composition of these cells has only been occasionally examined. In the present study, we examined 29 de novo glioblastomas in which distinct LG and HG areas of sufficient volumes could be identified. These areas were microdissected from paraffin-embedded tissues and analyzed for genetic alterations: p53 mutations and immunohistochemistry; allelic losses at 17p13.1, 9p21, and 10q23-25; and amplification of the epidermal growth factor receptor (EGFR) gene and immunohistochemistry. We also examined 14 paired astrocytic tumors, in which a primary Grade II astrocytoma progressed over a period of time to a Grade III or Grade IV tumor. Our findings showed that the LG areas of the de novo glioblastomas exhibited numerous genetic aberrations, the proportion of which was increased in the HG areas. Genetic abnormalities seen in the LG areas were conserved in the HG areas suggesting that these morphologically different cellular subsets were derived from a common transformed clone. Also, the LG areas were genetically different from Grade II astrocytomas of the paired tumor group, in spite of their morphological similarity. In particular, the LG areas had more deletions on 10q23-25 (75% vs 20%, p = 0.04), but fewer p53 mutations (24% vs 71%, p = 0.003) and less p53 protein labeling (45% vs 79%, p = 0.04). These differences suggest that LG and HG areas in de novo glioblastoma are genetically closer to each other compared with paired low- and high-grade tumors that have progressed over time. Moreover, only a small proportion (17%) of our de novo glioblastomas exhibited EGFR amplification while a high proportion (62%) showed either p53 mutations or allelic loss of 17p13.1. We speculate that some de novo GBMs with copious LG areas may constitute a separate group with rapid progression from Grade II astrocytomas.
多形性胶质母细胞瘤（GBM）通常表现出形态学异质性，即低级别（LG）区域（具有分化良好的细胞）通常紧邻高级别（HG）区域（具有分化不良的细胞）。这种异质性可能导致获取代表性肿瘤样本存在困难。然而，这些细胞的基因组成仅偶尔被检测。在本研究中，我们检测了29例原发性胶质母细胞瘤，其中能够识别出足够体积的明显LG和HG区域。这些区域从石蜡包埋组织中显微切割下来，并分析基因改变：p53突变和免疫组织化学；17p13.1、9p21和10q23 - 25处的等位基因缺失；以及表皮生长因子受体（EGFR）基因的扩增和免疫组织化学。我们还检测了14例配对的星形细胞瘤，其中原发性II级星形细胞瘤在一段时间内进展为III级或IV级肿瘤。我们的研究结果表明，原发性胶质母细胞瘤的LG区域表现出众多基因畸变，其比例在HG区域增加。在LG区域观察到的基因异常在HG区域得以保留，这表明这些形态学上不同的细胞亚群源自一个共同的转化克隆。此外，尽管LG区域与配对肿瘤组的II级星形细胞瘤形态相似，但其基因组成不同。特别是，LG区域在10q23 - 25处有更多缺失（75%对20%，p = 0.04），但p53突变较少（24%对71%，p = 0.003）且p53蛋白标记较少（45%对79%，p = 0.04）。这些差异表明，与随时间进展的配对低级别和高级别肿瘤相比，原发性胶质母细胞瘤中的LG和HG区域在基因上彼此更接近。此外，我们的原发性胶质母细胞瘤中只有一小部分（17%）表现出EGFR扩增，而很大一部分（62%）显示p53突变或17p13.1等位基因缺失。我们推测，一些具有大量LG区域的原发性GBM可能构成一个从II级星形细胞瘤快速进展而来的单独组群。
