存在BRAF V600E突变的混合性多形性黄色星形细胞瘤和节细胞胶质瘤

目的回顾分析1例存在BRAF V600E突变的混合性多形性黄色星形细胞瘤和节细胞胶质瘤患儿的临床病理学和分子遗传学特征。方法与结果男性患儿,14岁,临床表现为发作性意识丧失伴四肢抽搐6年,头部MRI显示左侧颞叶海马类圆形异常信号,考虑占位性病变。手术全切除肿瘤,术中可见颞叶深部局部脑回粉红色,肿瘤组织呈灰红、灰白色,质地较韧,内有钙化,伴囊性变,血供较丰富,无包膜,与周围脑组织界限清晰。组织学形态表现为肿瘤细胞弥漫性生长,肿瘤具有异质性:部分区域呈节细胞胶质瘤结构,部分区域呈多形性黄色星形细胞瘤结构。免疫组织化学染色和特殊染色,节细胞胶质瘤区域胶质纤维酸性蛋白(GFAP)和神经微丝蛋白(NF)散在阳性,神经节细胞样细胞微管相关蛋白-2和神经元核抗原阳性,Ki-67抗原标记指数约2%;多形性黄色星形细胞瘤区域梭形肿瘤细胞GFAP和NF散在阳性,黄瘤样细胞CD163和CD68阳性,Ki-67抗原标记指数3%~5%,网织纤维丰富。基因检测显示两部分区域均存在BRAF V600E突变。术后未予放射治疗和药物化疗,口服抗癫药物(丙戊酸钠1.20 g/次、2次/d和左乙拉西坦0.50 g/次、2次/d)1年,临床症状明显改善。随访18个月未见肿瘤复发。结论混合性多形性黄色星形细胞瘤和节细胞胶质瘤是临床少见的中枢神经系统肿瘤,具有多形性黄色星形细胞瘤和节细胞胶质瘤的组织学形态特征,但具有BRAF V600E突变的相同分子遗传学特征。该病例对混合性胶质瘤和混合性神经元-胶质肿瘤的组织学形态、组织来源和分子遗传学研究具有很好的提示意义。     

成人弥漫性低级别胶质瘤相关性癫痫发生机制与治疗的研究进展

癫痫是成人幕上弥漫性低级别胶质瘤(DLGG)最常见的临床症状,常常影响着DLGG患者的生活质量,致残致死率高。控制癫痫发作对于改善DLGG患者的生存质量尤为重要。该文总结了弥漫性低级别胶质瘤相关性癫痫的发作特点、发生机制及治疗方法,以期为弥漫性低级别胶质瘤相关性癫痫患者的个体化临床诊疗决策提供依据。[国际神经病学神经外科学杂志, 2022, 49(2):74-78.]     

青少年多形性低级别神经上皮肿瘤的临床病理及分子病理特征分析

目的 分析青少年多形性低级别神经上皮肿瘤（PLNTY）的临床病理及分子病理特点。 方法 选取 2021 年 5 月— 2023 年 5 月于首都医科大学附属北京天坛医院接受手术治疗的 16 例 PLNTY 患者为研究对象,收集患者临床及影像学资料。采用苏木精 - 伊红染色、免疫组织化学染色及基因测序 检测肿瘤组织形态学及分子遗传学变化,电话随访及查阅影像学资料了解患者的症状改善情况、有无 放化疗及肿瘤复发情况。结果 16 例 PLNTY 患者中位发病年龄 24 岁,男女比例相当（1∶1）;5 例（5/16） 呈急性起病（起病时间＜ 3 个月）;临床症状以不同程度的癫痫发作为主;8 例（8/16）肿瘤位于颞叶,5 例 （5/16）位于顶枕叶。增强磁共振成像扫描显示,11例（11/16）无明显强化,3例（3/16）出现轻度不均匀强化, 2 例（2/16）明显不均匀强化。14 例（14/16）患者术后癫痫症状改善,其中 1 例复发。组织病理学结果显 示肿瘤呈浸润性生长,位于皮层及皮层下白质,可见多形性和少突样细胞形态,并见枝芽状细小血管, 12 例（12/16）伴钙化;其中 1 例复发再次手术切除的标本中呈现恶性转化,表现为局部细胞密度增高, 可见核分裂象、微血管增生和栅栏样坏死。16 例肿瘤免疫组织化学染色结果显示,胶质纤维酸性蛋白 （GFAP）、少突胶质细胞转录因子 2（Olig2）及 CD34 弥漫阳性,突触素呈阴性表达,其中 14 例 ki67 增殖指 数≤ 4%,恶性转化病例的 Ki67 增殖指数为 20%。7 例 PLNTY 二代测序结果显示,以BRAF或FGFR分子 变异为主,其中 3 例（3/7）存在 O6- 甲基鸟嘌呤 -DNA 甲基转移酶启动子（MGMT）甲基化;1 例原发及复发 的病例中均检测到FGFR3：：TACC3融合,伴 TERT 启动子突变,且在复发病例中出现了 10 号染色体缺 失及CDK4、MDM2扩增。结论 PLNTY 好发于青少年,为一种长期癫痫相关肿瘤,多见于颞叶及顶枕 叶;肿瘤呈浸润性生长,可见多形性细胞和少突样细胞成分,CD34 弥漫阳性,分子改变以BRAF或FGFR 变异为主。大部分预后良好,术后癫痫症状改善;个别病例复发后可发生恶性转化,分子病理结果显示 FGFR3：：TACC3融合并 TERT 启动子突变;临床医生需要对 PLNTY 临床病理及分子病理特征进行综合 评估并提高警惕。     

弥漫性半球胶质瘤临床病理特征及分子病理特征分析

目的 探讨弥漫性半球胶质瘤（DHG）的临床病理特征及分子病理特征。方法 选取 2021 年 1 月— 2023 年 5 月于首都医科大学附属北京天坛医院神经外科接受手术切除或立体定向活检 的 27 例 DHG 患者为研究对象,收集患者临床资料并进行随访。采用苏木素 - 伊红染色及免疫组织化 学染色检测肿瘤细胞特征性的蛋白表达;采用二代测序 + 焦磷酸测序的方法检测肿瘤分子病理学特征。 结果 27 例 DHG 患者的中位发病年龄为 22.5 岁;男性占 59.3%（16/27）;24 例肿瘤主要位于单侧额、顶、 颞叶,仅 3 例位于双侧大脑半球。组织病理学结果显示,27 例肿瘤形态学上 5 例呈星形细胞瘤形态, 17 例呈胶质母细胞瘤形态,1 例呈胶质母细胞瘤伴节细胞样分化,4 例呈原始神经外胚层肿瘤形态。免 疫组化染色结果显示,27 例肿瘤胶质纤维酸性蛋白染色均为弥漫阳性,少突胶质细胞转录因子 2 蛋白阴 性表达,α- 地中海贫血 / 精神发育迟滞综合征 X 染色体相关基因表达缺失,p53 蛋白呈错义突变或无义 突变表达,异柠檬酸脱氢酶 1 R132H、异柠檬酸脱氢酶 2 R172K、H3K27M、BRAF V600E 蛋白均呈阴性 表达,24 例肿瘤细胞核不同程度地表达 H3.3G34R 蛋白,3 例肿瘤弥漫性表达 H3.3G34V 蛋白。Ki67 增殖 指数 3%～80% 不等。分子病理学检测结果显示,所有肿瘤均出现H3F3A基因H3.3 G34（35）突变,23 例 伴ATRX缺失,27 例均伴TP53突变。随访 2～24 个月,其中 5 例在确诊 10～24 个月后死亡,中位无进展 生存期为 6.5 个月,中位总生存时间为 11 个月,5 例失访。结论 DHG恶性程度高,尽管全切或近全切 病变加放疗或化疗,患者仍很快复发进展或死亡。因此,对于DHG进行免疫组化及分子病理检测是必 要的,更有利于对DHG患者的积极治疗和预后评估。     

低级别胶质瘤临床治疗现状

<正>胶质瘤是颅内最常见的原发性恶性肿瘤。根据病理学特点,世界卫生组织将胶质瘤分为I-IV级,其中I-II级为低级别胶质瘤(low-grade gliomas,LGGs),III-IV级为高级别胶质瘤(high-grade gliomas,HGGs)。LGGs约占颅内胶质瘤的15%,生长缓慢,平均生存时间比HGGs长,会发生间变或去分化形成致命性的HGGs。故对于那些年轻的,症状不明显的,靠近功能区的LGGs患者,是否应积极     

低级别胶质瘤的显微手术治疗

中枢神经系统低级别胶质瘤侵及范围广泛且发病早期多无明显症状及体征，作出临床诊断时肿瘤体积已经较大，肿瘤活检加放疗的效果很不满意。作者自1998年3月至2005年1月应用显微外科技术治疗低级别胶质瘤17例，术后进行放射治疗，取得了良好效果，现报道如下：     

低级别胶质瘤的分子遗传学研究进展

正脑胶质瘤是起源于脑部神经胶质细胞,是最常见的颅内肿瘤之一。近30年来,原发性恶性脑肿瘤发生率逐年递增,年增长率约为1.2%,中老年人群尤为明显。根据美国脑肿瘤注册中心统计,恶性胶质瘤约占原发性恶性脑肿瘤的70%,年发病率约为5/100 000,每年新发病率超过14 000例,65岁以上人群发病率明显升高[1]。尽管神经影像学及胶质瘤的治疗均取得了一定的进展,但胶质瘤的预后远不能使人满意。低     

低级别胶质瘤继发癫痫的手术治疗

目的 探讨低级别胶质瘤继发癫痫的手术治疗方法.方法 采用视频脑电、脑磁图定位致痫灶、功能区,手术中联合应用立体定向引导、术中B超、术中皮质电刺激等技术治疗继发癫痫的低级别胶质瘤13例.结果 全部患者在手术切除、保护神经功能的同时,控制了癫痫发作,临床效果良好.结论 多种定位技术的联合应用,可在最大程度切除肿瘤、致痫灶的同时减少脑组织损伤,保留脑功能区皮质,控制癫痫发作,提高患者生活质量.

Abstract：

Objective To explore the methods of surgical treatment of low-grade glioma with secondary epilepsy.Method Video-EEG,magnetoeneephalography ( MEG) were performed to localizated the epileptogenic zone and domain in 13 patients,and stereotactic technology,ultrasound,electrocorticogram (EcoG) were performed intraoperative combinating to treat the low-grade gliomas that lead to epilepsy.Results The seizure was controlled while the tumor was resected and the neural function were protected in all patients.The clinical effect was significant.Conclusions The combination of multiple technology to localize the epileptogenic can resect the tumor or the epileptogenic zone maximum, reduce the injury of normal brain tissue,protect the cortex of brain domain,control the epileptic seizure and improve the patients' quality of life.     

颞叶低级别胶质瘤继发顽固性癫痫的外科治疗

目的探讨颞叶低级别胶质瘤继发顽固性癫痫患者的临床特点、术前评估及外科治疗效果。方法对31例颞叶低级别胶质瘤继发顽固性癫痫患者术前进行MRI、视频脑电图（VEEG）、发作间期正电子发射断层扫描（PET）检查,综合分析检查结果,制定相应手术方案。术中行皮层脑电描记（ECoG）,术后对切除组织进行病理检查,并对患者进行术后随访。结果29例（93．5％）患者术后癫痫发作完全或部分缓解,2例（6．5％）患者无明显缓解。结论对于颞叶低级别胶质瘤继发顽固性癫痫的患者．术前进行综合评估,同时切除病灶及致痫灶是控制癫痫发作、改善预后的有效手段。     

纯岛叶低级别胶质瘤的显微外科治疗

目的探讨纯岛叶低级别胶质瘤的显微手术方法及疗效。方法回顾性分析17例纯岛叶低级别胶质瘤病人的临床资料。其中肿瘤位于左侧岛叶8例,右侧岛叶9例,均采用翼点外侧裂入路手术切除肿瘤。结果肿瘤全切除12例,近全切除5例。病理结果:星形细胞瘤8例,少枝胶质细胞瘤4例,少枝星形细胞瘤5例。无手术死亡,术后早期发生偏瘫、失语各2例。随访17例,时间6~12个月,均未见肿瘤复发,轻偏瘫1例,轻度失语1例。结论应用显微外科技术经翼点外侧裂入路治疗纯岛叶低级别胶质瘤安全、有效。了解岛叶解剖有助于最大程度切除岛叶低级别胶质瘤,减少病人术后神经功能障碍。     

A case of an epithelioid glioblastoma with the BRAF V600E mutation colocalized with BRAF intact low‐grade diffuse astrocytoma

Epithelioid glioblastomas are one of the rarest histological variants of glioblastomas, which are not formally recognized by the World Health Organization (WHO) classification. Epithelioid glioblastomas usually occur as primary lesions, but there have been several reports of secondary epithelioid glioblastomas or epithelioid glioblastomas with pre‐ or co‐existing lesions to date. The serine/threonine‐protein kinase B‐Raf (BRAF) V600E mutation has been found at a high frequency of 54% in epithelioid glioblastomas. We present a case of a 26‐year‐old female patient with an epithelioid glioblastoma with the BRAF V600E mutation in her right frontal lobe. In the present case, a low‐grade diffuse astrocytoma component had colocalized with the epithelioid glioblastoma. The component presented prominent calcification on neuroimages as well as by histology, and low‐grade diffuse astrocytoma was considered to be a precursor lesion of an epithelioid glioblastoma. However, the BRAF V600E mutation was detected only in epithelioid glioblastoma but not in low‐grade diffuse astrocytoma. To the best of our knowledge, this is the first report demonstrating a discrepancy in the BRAF V600E mutation states between epithelioid glioblastoma and colocalized low‐grade astrocytoma.     

Adult diffuse leptomeningeal glioneuronal tumour with limited leptomeningeal involvement,lack of 1p deletion and BRAF V600E mutation

Diffuse leptomeningeal glioneuronal tumours (DLGNT) are rare primary CNS tumours, traditionally characterised by leptomeningeal growth and usually affecting children. A recent large study defined DLGNT on a molecular basis, of which all demonstrated 1p deletions. The vast majority also demonstrated MAPK/ERK pathway activations, however BRAF V600E mutation has not been previously documented in adult cases. In this case report, we describe an unusual cerebral DLGNT, with limited leptomeningeal spread, intact 1p status and a BRAF V600E mutation.     

Spinal cord anaplastic astrocytoma with BRAF V600E mutation: A case report and review of literature

A 17-year-old female complained of lower extremity pain that progressed to low back pain accompanied by paraparesis. Magnetic resonance imaging revealed a mass in the conus medullaris of the spinal cord at the thoracic spine 11–12 level. The patient underwent resection of the mass. The pathological diagnosis was anaplastic astrocytoma based on the densely proliferating astrocytic tumor cells without necrosis or microvascular proliferation. The patient received chemoradiotherapy with oral temozolomide and a total of 54 Gy of local irradiation, followed by 24 courses of temozolomide as maintenance chemotherapy. The patient survived for 8 years without tumor recurrence following the initial treatment. Genetic analysis of the tumor revealed a BRAF V600E mutation that has not yet been reported in spinal cord high-grade gliomas (HGGs). In recent years, the molecular therapy targeting the BRAF V600E mutation has been applied in clinical practice for several cancer types. Although the frequency in spinal cord HGGs is uncertain, it is necessary to investigate BRAF V600E mutation as a potential therapeutic target in the future.     

BRAF V600E mutation is a significant prognosticator of the tumour regrowth rate in brainstem gangliogliomas

BRAF V600E mutations are progression factors in paediatric low-grade gliomas. Furthermore, a high percentage of paediatric brainstem gangliogliomas have BRAF V600E mutations. However, their clinical significance, including possible connections between the biomarkers and ganglioglioma’s clinical features, especially a brainstem counterpart, is unclear. To identify potential molecular features predictive of brainstem ganglioglioma’s clinical outcomes, a retrospective cohort of 28 World Health Organization (WHO) grade I brainstem gangliogliomas was analysed for BRAF V600E, IDH1 R132H, and IDH2 R172K mutations, TERT C228T/C250T promoter mutation, H3F3A K27M mutation and MGMT methylation. The volume of tumours was calculated accurately by using 3D Slicer software. The clinical data of these patients were retrospectively analysed. In tumours with BRAF V600E mutations, the tumour regrowth rate was significantly faster than that of the wild type group (p = 0.001). Moreover, the BRAF V600E mutant group had shorter progression-free survival (PFS) compared with wild type (p = 0.012). On multivariate analysis, no factor was found to be an independent prognostic factor; however, tumours with faster regrowth rates had a strong trend towards an increased risk for shorter PFS (HR = 1.027, p = 0.056). No statistical analysis could be performed to evaluate factors affecting overall survival (OS). These data suggest that BRAF V600E can predict the regrowth rate of brainstem gangliogliomas after microsurgery, and a BRAF V600E-targeted therapeutic may be a promising early intervention measure for patients who harbour BRAF V600E mutation after microsurgery.     

Response to combined BRAF/MEK inhibition in adult BRAF V600E mutant spinal pilocytic astrocytoma

Pilocytic astrocytomas are World Health Organisation (WHO) grade I tumors, occurring predominantly supratentorially and in the pediatric population. Although the mainstay of treatment is local therapies such as surgery, targeted systemic therapies may be necessary for recurrent or unresectable disease. The majority of sporadic pilocytic astrocytomas are associated with the BRAF-KIAA fusion gene, which results in constitutive activation of the MAP Kinase pathway. Less frequently, the BRAF V600E point mutation has been described, occurring in less than 10% of supratentorial pilocytic astrocytomas. Tumours with this mutation may respond to targeted therapy against the BRAF/MAP Kinase pathway. We report the first described case of a spinal pilocytic astrocytoma in an adult patient with a BRAF V600E mutation responding to targeted therapy using BRAF and MEK tyrosine kinase inhibitors, and share our experiences with the management of toxicity in this patient population.