Intraoperative assessment of isocitrate dehydrogenase mutation status in human gliomas using desorption electrospray ionization-mass spectrometry
Intraoperative assessment of isocitrate dehydrogenase mutation status in human gliomas using desorption electrospray ionization-mass spectrometry
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DOI：
10.3171/2018.8.jns181207
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发表时间：
2020-01-01
影响因子：
4.1
通讯作者：
Cohen-Gadol, Aaron A.
中科院分区：
文献类型：
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作者：
Alfaro, Clint M.;Pirro, Valentina;Cohen-Gadol, Aaron A.
目的建立一种快速检测脑胶质瘤组织中异柠檬酸脱氢酶(IDH)突变的术中环境电离质谱仪(MS)方法。这种方法提供了新的胶质瘤治疗方案，并可能影响切除目标的范围。对IDH突变的评估是准确诊断胶质瘤的关键，特别是在区分弥漫性胶质瘤与其他肿瘤性和反应性炎症疾病方面，这对仅依靠形态学的标准术中诊断咨询是一个挑战。方法对37例保存的胶质瘤标本进行解吸电喷雾电离-质谱仪(DESI-MS)分析，以建立一种诊断方法来检测IDH突变的胶质瘤中已知的变化的肿瘤代谢物-2-羟基戊二酸(2HG)。该方法用于术中分析接受手术的胶质瘤患者的组织涂片，并快速诊断IDH突变状态(<；5分钟)。对25例脑胶质瘤患者(野生型14例，突变型11例)的51例肿瘤核心活检标本进行了检测，并用方差分析和受试者工作特征曲线分析进行了分析。结果优化的DESI-MS方法对IDH-WT和IDH-突变型胶质瘤的鉴别诊断的灵敏度和特异度均为100%。IDH突变脑胶质瘤的平均归一化Desi-MS 2HG信号比IDH-WT脑胶质瘤高一个数量级。DESI 2HG信号强度与独立测量的2HG浓度相关(R2=0.98)。1例IDH1R132H突变型胶质瘤在术中会诊时被冰冻切片组织学误诊为脱髓鞘，未行手术切除，等待最终的病理报告。在最终的病理提供与IDH突变的胶质母细胞瘤最一致的诊断后，进行了第二次开颅手术和肿瘤切除。在第二次开颅手术中，在肿瘤核心活检组织中检测到高水平的2HG。结论本研究证实了在肿瘤切除过程中利用DESI-MS快速鉴别IDH突变的胶质瘤和IDH-WT的能力。组织涂片的DESI-MS分析很简单，可以很容易地整合到标准术中病理咨询中。这种方法可能有助于解决与低级别胶质瘤相关的鉴别诊断问题，并可能影响术中关于切除范围的决定，最终改善患者的预后。研究正在进行中，以扩大患者队列，系统验证DESI-MS方法，并调查2HG与肿瘤异质性之间的关系。
OBJECTIVE The authors describe a rapid intraoperative ambient ionization mass spectrometry (MS) method for determining isocitrate dehydrogenase (IDH) mutation status from glioma tissue biopsies. This method offers new glioma management options and may impact extent of resection goals. Assessment of the IDH mutation is key for accurate glioma diagnosis, particularly for differentiating diffuse glioma from other neoplastic and reactive inflammatory conditions, a challenge for the standard intraoperative diagnostic consultation that relies solely on morphology.METHODS Banked glioma specimens (n = 37) were analyzed by desorption electrospray ionization-MS (DESI-MS) to develop a diagnostic method to detect the known altered oncometabolite in IDH-mutant gliomas, 2-hydroxyglutarate (2HG). The method was used intraoperatively to analyze tissue smears obtained from glioma patients undergoing resection and to rapidly diagnose IDH mutation status (< 5 minutes). Fifty-one tumor core biopsies from 25 patients (14 wild type [WT] and 11 mutant) were examined and data were analyzed using analysis of variance and receiver operating characteristic curve analysis.RESULTS The optimized DESI-MS method discriminated between IDH-WT and IDH-mutant gliomas, with an average sensitivity and specificity of 100%. The average normalized DESI-MS 2HG signal was an order of magnitude higher in IDH-mutant glioma than in IDH-WT glioma. The DESI 2HG signal intensities correlated with independently measured 2HG concentrations (R-2 = 0.98). In 1 case, an IDH1 R132H-mutant glioma was misdiagnosed as a demyelinating condition by frozen section histology during the intraoperative consultation, and no resection was performed pending the final pathology report. A second craniotomy and tumor resection was performed after the final pathology provided a diagnosis most consistent with an IDH- mutant glioblastoma. During the second craniotomy, high levels of 2HG in the tumor core biopsies were detected.CONCLUSIONS This study demonstrates the capability to differentiate rapidly between IDH-mutant gliomas and IDH-WT conditions by DESI-MS during tumor resection. DESI-MS analysis of tissue smears is simple and can be easily integrated into the standard intraoperative pathology consultation. This approach may aid in solving differential diagnosis problems associated with low-grade gliomas and could influence intraoperative decisions regarding extent of resection, ultimately improving patient outcome. Research is ongoing to expand the patient cohort, systematically validate the DESI-MS method, and investigate the relationships between 2HG and tumor heterogeneity.