Clinicopathological and genetic association between epithelioid glioblastoma and pleomorphic xanthoastrocytoma
Clinicopathological and genetic association between epithelioid glioblastoma and pleomorphic xanthoastrocytoma
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DOI：
10.1111/neup.12459
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发表时间：
2018-06-01
期刊：
影响因子：
2.3
通讯作者：
Sugita, Yasuo
中科院分区：
文献类型：
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作者：
Furuta, Takuya;Miyoshi, Hiroaki;Sugita, Yasuo
上皮样胶质母细胞瘤(EGBM)是2016年WHO分类中采用的一种罕见的GBM变体。EGBM和多形性黄色星形细胞瘤(PXA)在组织学和遗传学上有时表现出重叠的特征，如vRAF小鼠肉瘤病毒癌基因同源B1(BRAF)基因上皮样模式和高频率的V600E突变。根据修订后的2016年世卫组织分类中的新标准，对这些罕见肿瘤的准确诊断具有挑战性。阐明肿瘤的生物学特性，选择合适的治疗方法是当务之急。对连续20例经组织学诊断为PXA或eGBM的病例进行了分析。20例中12例为PXA，8例为EGBM。形态上可见有丝分裂活动、细胞内脂肪堆积、嗜酸性颗粒小体、网状纤维沉积等坏死和变性改变。免疫组织化学和分子生物学方法检测异柠檬酸脱氢酶1和2、-thalassemia/mental-retardation-syndrome-X-linked基因、p53、BRAF、端粒逆转录酶启动子、H3F3A和整合酶相互作用蛋白1的表达。EGBM缺乏PXA所特有的退行性改变。BRAF基因T1799>；A(V600E)突变在4/12(33.3%)PXA和4/8(50.0%)eGBM中检测到，而TERT-p突变在2/12(16.7%)PXA和1/8(12.5%)eGBM中检测到C228和GT；12/12(100%)PXA和6/7(85.7%)eGBM有核ATRX残留，2/10(20%)PXA和7/7(100%)eGBM有P53突变。所有肿瘤均在细胞核内保留INI1的表达。所有肿瘤均未发现H3F3A突变。1例无BRAF突变的PXA在复发时获得TERT-p突变，1例eGBM同时存在BRAF和TERT-p突变。提示eGBM与PXA具有分子生物学相似性，而退行性改变反映了PXA的特点。推测eGBM和PXA发生和发展的常见基因改变可能包括BRAF和TERT-p突变。
Epithelioid glioblastoma (eGBM) is a rare variant of GBM which was adopted in the 2016 WHO classification. eGBM and pleomorphic xanthoastrocytoma (PXA) sometimes show overlapping features histologically and genetically, such as epithelioid pattern and a highly frequent V600E mutation in the gene for vRAF murine sarcoma viral oncogene homolog B1 (BRAF), respectively. Accurate diagnosis of these rare tumors is challenging according to the new criteria in the revised 2016 WHO classification. It is an urgent task to elucidate the biological properties of the tumors and to select appropriate treatment. Twenty consecutive cases diagnosed as PXA or eGBM histologically were investigated. Twelve of the 20 cases were PXAs and eight were eGBMs. Morphologically, mitotic activity, necrosis and degenerative changes such as intracellular lipid accumulation, eosinophilic granular bodies and reticulin fiber deposits were scored. Immunohistochemical and molecular biological assessment for isocitrate dehydrogenases 1 and 2 (IDH1/2), -thalassemia/mental-retardation-syndrome-X-linked gene (ATRX), p53, BRAF, telomere reverse transcriptase promoter (TERT-p), H3F3A, and integrase interactor 1 (INI1) were performed. eGBM tended to lack the degenerative changes characteristic for PXA. Of the 20 cases tested, Sanger technique showed no mutation in IDH1/2. BRAF mutation at T1799>A (V600E) was detected in 4/12 (33.3%) PXA and 4/8 (50.0%) eGBM, while TERT-p mutation was detected at C228>T in 2/12 (16.7%) PXA and at C250>T in 1/8 (12.5%) eGBM. Retained nuclear ATRX was observed in 12/12 (100%) PXA and 6/7 (85.7%) eGBM while p53 mutation was observed in 2/10 (20%) PXA and 7/7 (100%) eGBM. All tumors retained INI1 expression in their nuclei. None of the tumors harbored H3F3A mutation. One PXA without BRAF mutation acquired TERT-p mutation at recurrence and one eGBM harbored both BRAF and TERT-p mutation. Molecular biological similarity between eGBM and PXA was suggested in our series, while degenerative changes reflected the features of PXA. It was speculated that the common genetic alterations for development and progression of eGBM and PXA might include BRAF and TERT-p mutations.