多b值DWI在WHOⅡ～Ⅲ级脑星形细胞瘤IDH基因型的诊断价值

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• 临床研究 •

多b值DWI在WHOⅡ~Ⅲ级脑星形细胞瘤IDH基因型的诊断价值

邓晓琳张辉王效春谭艳秦江波

Cite this article as: Deng XL, Zhang H, Wang XC, et al. The diagnostic value of multi b-values diffusion weighted imaging in the genotypes of WHO grade Ⅱ—Ⅲ astrocytomas. Chin J Magn Reson Imaging, 2019, 10(5): 327-330.本文引用格式：邓晓琳，张辉，王效春,等.多b值DWI在WHOⅡ~Ⅲ级脑星形细胞瘤IDH基因型的诊断价值.磁共振成像，2019，10(5)：327-330. DOI:10.12015/issn.1674-8034.2019.05.002.

摘要

[摘要] 目的探究多b值扩散加权成像(diffusion weighted imaging，DWI)对WHO Ⅱ~Ⅲ级脑星形细胞瘤异柠檬酸脱氢酶(isocitrate dehydrogenase，IDH)基因型的诊断价值。材料与方法 收集经手术病理确诊为WHO Ⅱ~Ⅲ级星形细胞瘤、且有IDH基因型的患者资料，术前均行颅脑常规MRI扫描及多b值DWI扫描，测量肿瘤实质区及同一层面对侧正常脑实质区的各参数值：水通道蛋白相关扩散系数(aquaporines related diffusion coefficient，AQP-ADC)、纯扩散系数(true diffusion coefficient，D)、灌注相关扩散系数(perfusion related diffusion coefficient，D^*)、灌注分数(perfusion fraction，f)，计算校正参数值(瘤体参数值除以对侧正常脑实质参数值)：相对AQP-ADC (relative AQP-ADC)、相对D (relative D)、相对D^* (relative D^*)、相对f (relative f)等，应用两样本t检验分析IDH突变组与野生组之间的参数值差异，绘制受试者工作特征(receiver operating characteristic，ROC)曲线计算阈值、敏感性及特异性。结果脑星形细胞瘤IDH突变组rD值高于野生组，D^*、rD^*、rf值低于野生型，差异有统计学意义(P<0.05)。瘤体rD值ROC曲线下面积、阈值、敏感性及特异性分别为0.706、1.839、64.71%、80.00%，D^*值分别为0.814、0.00267、88.24%、66.67%；rD^*值分别为0.759、0.969、58.82%、93.33%，rf值分别为0.710、1.875、88.24%、53.33%。结论多b值DWI对于诊断WHO Ⅱ~Ⅲ级脑星形细胞瘤IDH基因型具有一定价值，瘤体D^*和rf值诊断IDH基因的敏感性较高，rD^*值的特异性较高。

[Abstract] Objective: To investigate the value of multiple b-values diffusion weighted imaging (DWI) in predicting the genotype of isocitrate dehydrogenase1 (IDH) in WHO grade Ⅱ—Ⅲ astrocytomas.Materials and Methods: Patients' data of WHO grade Ⅱ—Ⅲ astrocytomas with IDH genetic information were collected. All routine magnetic resonance imaging (MRI) and multiple b-values DWI were performed before surgery. Measuring the parameters of the astrocytoma's parenchyma and the contralateral normal brain's parenchyma: aquaporines related diffusion coefficient (AQP-ADC), true diffusion coefficient (D), perfusion related diffusion coefficient (D^*) and perfusion fraction (f). Then calculate the calibrated parameters (tumor parameters values divided by parameters values measured in the contralateral normal brain's parenchyma): relative AQP-ADC (rAQP-ADC), relative D (rD), relative D^* (rD^*), relative f (rf). A t-test of two samples was used to analyze the difference in parameters between different gene states, and the receiver operating characteristic (ROC) curve was plotted to calculate the threshold, sensitivity and specificity.Results: For astrocytomas, the rD value of IDH mutation group was higher than the IDH wild-type, while the D^* value, rD^* value and rf value of the mutation group were lower than the wild type, the difference was statistically significant (P< 0.05). The area under the ROC curve, the threshold, the sensitivity and the specificity of the rD were 0.706, 1.839, 64.71%, 80.00%. The D^* were 0.814, 0.00267, 88.24%, 66.67%. The rD^* were 0.759, 0.969, 58.82%, 93.33%. The rf were 0.710, 1.875, 88.24%, 53.33%.Conclusions: Multi b-values DWI has certain application value for diagnosis of IDH genotype in WHO grade Ⅱ—Ⅲ astrocytomas. The values of D^* and rf are more sensitive to diagnose the genotypes of astrocytoma, while the value of rD^* has higher specificity.

[关键词] 星形细胞瘤；脑肿瘤；磁共振成像；基因型

[Keywords] astrocytoma；brain neoplasms；magnetic resonance imaging；genotype

作者信息

邓晓琳 山西医科大学医学影像学系，太原　030000

张辉^* 山西医科大学第一医院影像科，太原　030000

王效春 山西医科大学第一医院影像科，太原　030000

谭艳山西医科大学第一医院影像科，太原　030000

秦江波 山西医科大学第一医院影像科，太原　030000

通信作者：张辉，E-mail：zhanghui_mr@163.com

利益冲突：无。

出版信息

收稿日期：2019-02-10

接受日期：2019-04-20

中图分类号：R445.2; R739.41

文献标识码：A

DOI: 10.12015/issn.1674-8034.2019.05.002

本文引用格式：邓晓琳，张辉，王效春,等.多b值DWI在WHOⅡ~Ⅲ级脑星形细胞瘤IDH基因型的诊断价值.磁共振成像，2019，10(5)：327-330. DOI:10.12015/issn.1674-8034.2019.05.002.

正文

星形细胞瘤(astrocytoma)是颅内最常见的原发性肿瘤，具有进展快、预后差、复发率高等特点^[¹^]。2016版世界卫生组织(World Health Organization，WHO)中枢神经系统(central nervous system，CNS)肿瘤分类中，依据分子学特征，将其分成IDH突变型、IDH野生型及NOS三种类型^[²^]。有学者研究发现胶质瘤IDH基因突变能作用于体内免疫微环境进而影响患者的预后^[³^]，IDH突变是提示胶质瘤预后较好的因素之一^[⁴^]，目前检测IDH突变主要是DNA直接测序、焦磷酸测序、抗体法等^[⁵^]，存在诊断滞后、成本昂贵等不足。因此无创诊断星形细胞瘤IDH基因型对于治疗方式的选择和预后的评估具有重要临床意义。多b值扩散加权成像(diffusion weighted imaging，DWI)可以量化肿瘤组织的灌注和扩散信息，检测组织微观结构变化。本研究旨在探讨多b值DWI对WHO Ⅱ~Ⅲ级星形细胞瘤IDH基因型的诊断价值。

1　材料与方法

1.1　临床资料

回顾性分析我院2015至2018年经病理确诊的WHO Ⅱ~Ⅲ级共32例，标本送至北京泰普舜康医学检验所进行Sanger (双脱氧末端终止法)测序得到IDH基因型，将其分成IDH突变组和IDH野生组，患者术前均行颅脑常规MRI平扫、增强扫描及多b值DWI扫描。本研究已获得伦理委员会批准，所有受试者均签署知情同意书。

1.2　图像采集

使用GE Signa HDx 3.0 T MR超导型，采用8通道相控阵线圈收集图像。常规MRI扫描序列包括：轴位、矢状位T1WI：TR 1674 ms，TE 20 ms，FOV 24.6 cm× 24.6 cm；轴位T2WI：TR 6820 ms，TE 1.6 ms，FOV 22 cm×22 cm；轴位T2FLAIR：TR 8024 ms，TE 126.8 ms，FOV 22 cm×22 cm，层厚均为6.0 mm。增强扫描：TR 1500 ms，TE 14.5 ms，FA 90°，激励次数1，视野240×255，矩阵128×128。

多b值DWI采用平面回波序列(echo-planar imaging，EPI)，扫描参数：采用总计13个b值(0、20、50、100、200、400、800、1200、1800、2500、3000、3500、4000 s/mm²)，TR 3000 s，TE 115.5 s，NEX为3，FOV 24 cm×24 cm，矩阵128×128，层厚6.0 mm，层间距为1.0 mm。

1.3　图像后处理及参数测量

将原始图像导入GE AW 4.4工作站，通过MADC及水通道蛋白(aquaporine，AQP)后处理软件得到AQP相关扩散系数(aquaporines related diffusion coefficient，AQP-ADC)、纯扩散系数(true diffusion coefficient，D)、灌注相关扩散系数(perfusion related diffusion coefficient，D^*)、灌注分数(perfusion fraction，f)伪彩图，结合患者平扫及增强图像，由2名经验丰富的影像科医师指导，笔者在肿瘤强化最明显区域和同一层面对侧正常脑实质勾画感兴趣区(region of interest，ROI)，ROI大小约20~30 mm²，选取时尽量避开坏死、囊变、出血、钙化等区域。每个ROI测量三次取平均值，计算校正后参数值：相对AQP-ADC (relative AQP-ADC)、相对D (relative D)、相对D^* (relative D^*)和相对f (relative f)。

1.4　统计学分析

使用统计学软件SPSS 22.0对数据进行分析，计量资料采用(±s)表示，对所得数据进行正态性检验，对于符合正态分布的数据，运用两样本t检验分析IDH突变组与IDH野生组肿瘤实质区各参数值差异，对具有统计学意义(P<0.05)的参数，进一步绘制受试者工作特征(receiver operating characteristic，ROC)曲线，并计算其敏感性、特异性。

2　结果

2.1　患者一般资料比较

所收集的32例脑星形细胞瘤患者中，IDH突变组17例(男9例，女8例)，IDH野生组15例(男9例，女6例)，突变组平均年龄为(44.41±12.28)岁，野生组平均年龄(58.20±12.57)岁，各组间年龄及性别差异均无统计学意义(P>0.05)。

2.2　多b值DWI参数比较

脑星形细胞瘤IDH突变组rD值高于IDH野生组，D^*、rD^*、rf值低于野生组，差异有统计学意义(P< 0.05)，两组间AQP-ADC、rAQP-ADC、D、f值差异无统计学意义(P>0.05)(表1；图1，图2)。rD、D^*、rD^*、rf值对于星形细胞瘤IDH基因型的诊断效能详见表2，ROC曲线见图3。

点击查看大图

图1 男，47岁，WHO Ⅲ级IDH突变型
图2 女，62岁，WHO Ⅲ级IDH野生型。A~E：分别对应同层面的增强、D^*、f、D、AQP-ADC图
Fig. 1 Male, 47 years old, WHO grade Ⅲ astrocytoma with mutation of IDH.
Fig. 2 Female, 62 years old, WHO grade Ⅲ astrocytoma with IDH wide-type. A—E: The image of enhancement, D^*, f, D and AQP-ADC at the same level.

点击查看大图

图3 瘤体的AQP-ADC、rD、D^*、以及rf的ROC曲线
Fig. 3 ROC curves of the rD, D^*, rD^* and rf.

点击查看表格

表1 不同IDH基因型的星形细胞瘤多b值DWI参数比较(

±s)
Tab. 1 Comparison of multi b-values DWI parameters in astrocytomas with different genotypes (

±s)

点击查看表格

表2 多b值DWI参数对星形细胞瘤IDH基因型的诊断效能
Tab. 2 Diagnostic efficacy of multiple b-values DWI parameters in genotypes of IDH on astrocytomas

3　讨论

3.1　临床资料分析

本次实验收集的32例脑星形细胞瘤IDH基因突变率为53.13%，证实在WHO Ⅱ~Ⅲ星形细胞瘤中IDH突变现象普遍存在^[⁶^]，与王川等^[⁷^]报道的Ⅱ级突变率54.6%和Ⅲ级突变率69.2%基本相符。研究发现脑星形细胞瘤患者IDH突变组平均年龄低于野生组，星形细胞瘤IDH发生突变现象在年轻患者中更加普遍，这与Metellus等^[⁸^]观点一致。

3.2　多b值DWI参数分析

DWI是一种反映水分子无规则运动的成像方式，已被广泛应用于中枢神经系统、腹盆等部位的疾病诊断。传统的DWI量化得到的ADC，仅反映了细胞间水分子自由扩散情况，忽视了微循环毛细血管血流量的影响，多b值DWI通过设定由低到高多个b值可以把扩散和灌注信息分开，得到D^*、D和f值，AQP与肿瘤细胞迁移、细胞骨架变化有关，超高b值(b>1700 s/mm²)时测得的AQP-ADC可以量化水孔蛋白进行主动转运的水分子信息^[⁹^,¹⁰^]，因此多b值DWI较传统DWI能更准确反映肿瘤组织微观变化。

在本研究中笔者发现星形细胞瘤IDH突变组中rD值高于野生组(P<0.05)，影响扩散的因素包括细胞密度、细胞膜的完整性、细胞内外间隙等，提示IDH突变型中肿瘤细胞数较少，细胞间隙大，水分子扩散受限程度轻，与武文杰等^[¹¹^]通过扩散峰度成像(diffusion kurtosis imaging，DKI)研究胶质瘤IDH基因型结果相符。推测原因可能有以下两点：(1) IDH发生突变使体内三羧酸循环途径受影响，肿瘤细胞处于低能量状态，细胞增殖呈相对不活跃，表现为rD值升高；(2) IDH的突变导致还原型辅酶Ⅱ生成下降，肿瘤细胞更易受外界氧化破坏^[¹²^]。

笔者还发现星形细胞瘤IDH突变型的D^*、rD^*和rf值低于野生组，D^*反映毛细血管灌注，f代表D^*所占的容积分数，二者主要与微血管密度、血容量及血流速度等有关，说明在IDH野生型中微循环灌注更加丰富。Kickingereder等^[¹³^]通过相对脑血容量(relative cerebral blood volume，rCBV)来定量分析IDH突变与HIF-1α的关系，发现IDH突变型中rCBV低于野生型，Xing等^[¹⁴^]通过联合扩散加权成像(DWI)和动态磁敏感对比增强(dynamic susceptibility contrast，DSC)研究星形细胞瘤基因突变情况，发现IDH突变型患者脑血容量下降，进一步证明IDH突变型中灌注减低。这可能是由于IDH突变型中α-酮戊二酸(α-ketoglutarate，α-KG)转变成2-羟基戊二酸(2-hydroxyglutarate，2-HG)，影响α-KG-脯氨酰羟化酶(prolyl hydroxylases，PHD) -缺氧诱导因子-1α(hypoxia induced factor-1α，HIF-1α)信号通路，改变体内HIF-1α含量^[¹⁵^,¹⁶^]，HIF-1α在缺氧环境下维持癌细胞的生长和繁殖，IDH突变型中2-HG的积聚能使HIF-1α的降解增加^[¹⁷^,¹⁸^,¹⁹^]，新生血管形成减少，表现为灌注的减低。

然而，本研究仍存在以下不足：收集的病例数较少，手工勾画感兴趣区存在一定误差。接下来笔者将继续收集病例，并结合其他功能磁共振技术进一步探究影像与胶质瘤IDH基因型的关系。

综上所述，多b值DWI的rD、D^*、rD^*、rf参数值能无创评估脑星形细胞瘤IDH基因型，其中rD和D^*的敏感度和特异度均较高，有助于指导脑星形细胞瘤IDH作用位点靶向药物治疗的研究以及对预后的评估。

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