太赫兹技术在胶质瘤诊疗中的应用: 从组织分级到分子分型

穆宁; 杨川艳; 马康; 全玉莲; 王诗; 赖颖; 李飞; 王与烨; 陈图南; 徐德刚; 冯华

doi:10.7498/aps.71.20212419

摘要

太赫兹波(terahertz, THz)是位于微波和红外之间介观尺度波长的电磁波, 因其低电离性和指纹性的特点, 在生物医学领域有着巨大的应用潜力, 尤其是在肿瘤的术中定位定性诊断方面. 而对于定位定性诊断需求最迫切的肿瘤为胶质瘤, 因其侵袭性和异质性, 切除后极易复发且对临近脑区神经功能有显著影响, 快速确定瘤体边界以及肿瘤病理学特征, 是开展胶质瘤精准诊疗和临床研究的重要前提. 本文总结了胶质瘤诊断的生物物理技术, 梳理了太赫兹波这一新兴技术在胶质瘤诊断方面所取得的研究成果. 进一步, 基于胶质瘤组织病理和分子病理整合诊断研究进展, 提出不同分子分型肿瘤组织在太赫兹波段可能具有不同 “特异性蛋白组成”的太赫兹肿瘤亚型识别机制假说, 结合脑组织生物学特点与体液中胶质瘤标志物检测潜力, 全面设想了未来太赫兹波在胶质瘤临床诊疗中的应用模式和发展前景.

关键词:

Abstract

Terahertz wave is an electromagnetic wave, whose wavelength is located between microwave wavelength and infrared wavelength. Based on low ionization and fingerprint characteristics, it has great potential applications in biomedical field, especially in the intraoperative localization and qualitative diagnosis of tumors. Glioma is the most urgent tumor for positioning qualitative diagnosis. Owing to its invasiveness and heterogeneity, it is easy to relapse after resection and has a significant influence on the nerve function of adjacent brain regions. Therefore, rapid determination of tumor boundary and pathological characteristics is an important prerequisite for accurate diagnosis, treatment and clinical research of glioma. Here, we summarize the biophysical technology of glioma diagnosis, and expound the new technique of terahertz wave and its research results in diagnosis of glioma. Furthermore, based on the research progress of integrated diagnosis of glioma histopathology and molecular pathology, we propose a hypothesis that different molecular subtypes of tumor tissue may have a consistent 'differential terahertz wave protein composition' of terahertz tumor subtype recognition mechanism. Finally, combining the biological characteristics of brain tissue and the potential of glioma marker detection in body fluids, we discuss the clinical application model and prospects of terahertz technologies in glioma detection.

Keywords:

作者及机构信息

1.
陆军军医大学(第三军医大学)第一附属医院神经外科, 重庆　400038

2.
天津大学精密仪器与光电子工程学院, 天津　300072

通信作者: 王与烨, yuyewang@tju.edu.cn ; 陈图南, ctn@tmmu.edu.cn ;

基金项目: 国家自然科学基金(批准号: 82173388)、国家重点基础研究发展计划(批准号: 2015CB755405)和陆军军医大学人才培养方案(批准号: 2019MPRC021/XZ-2019-505-051)资助的课题.

Authors and contacts

1.
Department of Neurosurgery, The First Affiliated Hospital of Army Military Medical University (Third Military Medical University), Chongqing 400038, China

2.
School of Precision Instrument and Optoelectronics Engineering, Tianjin University, Tianjin 300072, China

Corresponding author: Wang Yu-Ye, yuyewang@tju.edu.cn ; Chen Tu-Nan, ctn@tmmu.edu.cn ;

Funds: Project supported by the National Natural Science Foundation of China (Grant No. 82173388), the National Basic Research Program of China (Grant No. 2015CB755405), and the Talents Training Program of Army Military Medical University, China (Grant No. 2019MPRC021/XZ-2019-505-051).

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施引文献

图 1 基于“组织病理”和“分子病理”联合诊断标准　(a) 肿瘤细胞形态学特征; (b) 胶质瘤分子分型

Fig. 1. Based on a combination of histopathology and molecular pathology: (a) Morphological characteristics of tumor cells; (b) molecular typing of gliomas.

下载: 全尺寸图片幻灯片

图 2 胶质瘤诊断方法

Fig. 2. Diagnostic methods for glioma.

下载: 全尺寸图片幻灯片

图 3 太赫兹光谱检测技术　(a) 透射式太赫兹光谱系统; (b) 反射式太赫兹光谱系统; (c)衰减全反射太赫兹光谱系统

Fig. 3. Terahertz spectral detection technology: (a) Transmitted THz spectral system; (b) reflected THz spectral system; (c) attenuated total reflection THz spectral system.

下载: 全尺寸图片幻灯片

图 4 近10年太赫兹技术在胶质瘤诊断研究中的发文情况

Fig. 4. Publication of THz technology in glioma diagnosis in recent 10 years.

下载: 全尺寸图片幻灯片

图 5 THz技术在临床胶质瘤诊断方面的新模式

Fig. 5. New models of THz technology in clinical glioma diagnosis.

下载: 全尺寸图片幻灯片

表 1 当前胶质瘤临床诊断方法

Table 1. Current clinical diagnosis of glioma.

	诊断方式	标记物	对健康组织损伤	局限性	应用效果对比	检测信息
影像学诊断	CT	¹⁸F; ¹¹C; ⁶⁴Cu	微量辐射暴露	对软组织的分辨率和敏感性相对较低, 成像参数少	适用于术后早期病人的检查及因手术银夹不能行MRI检查者	实现定位, 部分定性
	PET-CT	碘剂; 钡剂; 金	辐射引起微量组织损伤	辐射大、价格昂贵, 缺乏解剖相关性	特异性高, 具有较高阳性预测值与准确性, 阴性预测值较CT和MRI低
	SPECT	放射药物	辐射剂量小, 价格低廉	空间分辨率、特异性低	可应用于判断胶质瘤恶性程度
	MRI	顺磁性或超顺磁性粒子钆	无创、需造影剂	检查时间长、费用高, 对患者自身因素有限制	敏感性高, 具有较高的诊断准确性
病理学诊断	术中冰冻病理	HE试剂	有创、局部组织	取材局限、容易漏诊, 图像解释具有主观性	可用于术中胶质瘤形态观察, 确定手术范围	实现定性
病理学诊断	术后免疫组化	标记物抗体	有创、病灶组织	周期长、滞后	为后期胶质瘤治疗提供指导建议
分子生物学技术	生物芯片、基因检测和测序	依赖检测平台	有创、局部病灶组织、血液	准入门槛高、滞后性、价格昂贵	提供药物筛查、靶向精准治疗
其他新型技术	拉曼光谱	—	抗干扰强, 结果重复性好	散射效率低, 单次检测面积小	介观尺度胶质瘤病灶精准检测及分级识别	可同时获取“定位定性”信息
其他新型技术	太赫兹波	—	无创、非电离	穿透深度低, 水敏感	宏观到介观尺度病灶分布与肿瘤边界, 肿瘤组织与正常组织, 肿瘤分子分型特异性识别	可同时获取“定位定性”信息

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表 2 近10年太赫兹技术在肿瘤诊断中的工作模式

Table 2. Patterns of THz technique in tumor diagnosis over the last 10 years.

年份	癌症种类	辐射源	工作模式	参考文献
2011	肝癌(兔)	脉冲式	反射式光谱成像系统	[46]
2011	结肠癌(人)	脉冲式	反射式成像系统	[47]
2011	基底细胞癌(BCC)	连续式	光纤扫描近场显微镜透射成像系统	[61]
2011	乳腺癌	脉冲式	透射式成像系统	[38]
2011	结肠癌	脉冲式	反射式成像系统	[48]
2011	宫颈癌	脉冲式	反射式成像模式	[49]
2011	皮肤癌	连续式	透射式成像模式	[41]
2011	胶质瘤	脉冲式	反射式成像模式	[62]
2013	结肠癌	连续式	反射式成像模式	[63]
2013	肝癌	脉冲式	光纤扫描近场显微镜透射成像系统	[64]
2013	恶性黑色素瘤	脉冲式	反射式成像模式	[65]
2013	乳腺癌	连续式	反射式成像模式	[51]
2013	口腔癌	脉冲式	反射式成像模式	[50]
2014	结肠癌	连续式	反射式成像模式	[66]
2014	皮肤病	脉冲式	反射式成像模式	[52]
2014	皮肤癌	脉冲式	反射式成像模式	[67]
2014	皮肤癌	连续式	反射式成像模式	[68]
2014	胶质瘤	脉冲式	反射式成像模式	[69]
2014	肠癌	脉冲式	反射式成像模式	[70]
2014	胶质瘤	脉冲式	透射式光谱模式	[42]
2015	结肠癌组织	脉冲式	透射式近场成像模式	[71]
2015	结肠癌组织	脉冲式	透射式光谱模式	[39]
2015	胃癌	脉冲式	透射式光谱模式	[72]
2015	乳腺癌	脉冲式	反射式成像模式	[73]
2015	肝癌组织	连续式	透射式同轴全息成像模式	[74]
2016	结肠癌	连续式	反射式光谱及成像模式	[40]
2015	胃癌	脉冲式	反射式光谱及成像模式	[75]
2016	NMSC组织	连续式	反射式成像模式	[76]
2016	胶质瘤	脉冲式	反射式光谱模式	[53]
2016	皮肤癌	连续式	反射式光谱及成像模式	[77]
2016	胶质瘤	脉冲式	反射式光谱及成像模式	[78]
2016	胶质瘤	脉冲式	反射式成像系统	[79]
2017	胃癌	脉冲式	透射式光谱模式	[43]
2017	乳腺癌	脉冲式	反射式成像模式	[80]
2017	乳腺癌	脉冲式	透射式光谱及反射式成像模式	[44]
2018	肝癌	脉冲式	反射式光谱模式	[81]
2018	乳腺癌	脉冲式	透射式成像模式	[82]
2018	乳腺癌	连续式	反射式成像模式	[83]
2018	乳腺癌	脉冲式	反射式光谱及成像模式	[84]
2019	胃癌	脉冲式	反射式光谱模式	[85]
2019	胶质瘤	连续式	反射式成像模式	[58]
2019	乳腺癌	脉冲式	反射式成像模式	[86]
2019	胶质瘤	脉冲式	反射式光谱及成像模式	[87]
2020	乳腺癌	脉冲式	反射式光谱及成像模式	[88]
2020	胶质瘤组织	连续式	反射成像模式	[59]
2020	胶质瘤组织	连续式	反射式成像模式	[89]
2021	皮肤癌	脉冲式	透射式光谱模式	[45]
2021	胶质瘤	脉冲式	—	[90]
2021	胶质瘤	脉冲式	反射式光谱及成像系统	[91]
2021	胶质瘤组织	连续式	反射式光谱及成像系统	[60]

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表 3 当前基于太赫兹技术研究胶质瘤的结果

Table 3. Current results of glioma studies using the terahertz techniques.

	参考文献	年份	样本类型	THz 技术	研究特点	生物学对照	机理解释
组织	[62]	2011	SD大鼠胶质瘤模型	反射式太赫兹脉冲成像系统	首次开展THz胶质瘤成像	MRI, 可见光	水含量
	[69]	2014	SD大鼠胶质瘤及瘤旁 (石蜡3 μm)	反射式太赫兹脉冲成像系统	解释THz波生物组织成像机制	MRI, HE	除水含量外, 细胞密度、髓鞘分布
	[42]	2014	C57小鼠胶质瘤模型, 大脑组织石蜡1—2.5 mm	透射式太赫兹脉冲光谱系统	测量了石蜡包埋的脑胶质瘤和正常脑组织的折射率、吸收系数和复介电常数, 分析最佳太赫兹频率	—	脑胶质瘤具有更高的折射率、吸收系数和介电常数
	[78]	2016	SD大鼠胶质瘤模型(新鲜、石蜡)	反射式太赫兹脉冲光谱系统	定量解释THz光谱检测胶质瘤可行性	HE	细胞密度、含水量增加肿瘤折射率
	[76]	2016	SD大鼠胶质瘤模型(新鲜)	反射式太赫兹脉冲光谱成像系统	探究利用复折射率值获得太赫兹图像检测脑肿瘤的可能性	HE	水含量、细胞密度
	[79]	2016	Balb裸鼠原位异种移植、临床新鲜标本	反射式太赫兹脉冲成像系统	回答TRI解决临床组织移动性及无标记成像可能性	HE, 核磁	水、脂质
	[87]	2019	临床人脑胶质瘤(明胶包埋)	反射式太赫兹脉冲光谱成像系统	应用于临床分级组织	HE	水、细胞密度、血肿成分
	[58]	2019	C57胶质瘤组织	反射连续波太赫兹成像系统	反射连续波太赫兹成像系统应用与胶质瘤成像可能性	MRI, HE	血管、坏死碎片、水肿、细胞密度
	[59]	2020	大鼠/小鼠胶质瘤组织	衰减全反射连续波太赫兹成像系统	提高成像有效面积	HE	水、细胞密度、血管密度
	[89]	2020	大鼠胶质瘤	反射连续波太赫兹成像系统	提高分辨率	HE	水、细胞密度、血管密度
	[91]	2021	SD大鼠胶质瘤模型(新鲜)	反射式太赫兹脉冲光谱系统	胶质瘤异质性	HE	微血管生成、组织异质性
	[60]	2021	SD小鼠胶质瘤组织	反射式连续性太赫兹光谱成像系统	提高分辨率及扫描面积	HE、MRI	细胞、血管密度、组织坏死
	[90]	2021	临床胶质瘤样品(明胶包埋)	脉冲太赫兹光谱系统	验证介电常数的物理模型可靠性	—	—
细胞系	[98]	2021	胶质瘤细胞系	透射式太赫兹脉冲光谱系统	首次提出THz检测不同分子分型	—	细胞形态、大小、分子分型
细胞系	[97]	2019	神经胶质细胞和胶质瘤细胞	衰减全反射太赫兹脉冲式光谱系统	从细胞系角度解释THz可区分肿瘤组织	—	形态、含水量
分子标记物	[99]	2019	GABA/COC 1:15—1:18	透射式太赫兹脉冲光谱系统	率先推进了太赫兹神经递质检测	—	—
	[101]	2016	A-GLU/b-Glu	太赫兹时域光谱系统	区分不同构型谷氨酸	—	—
	[37]	2016	2-HG及其异构体	太赫兹时域光谱系统	区分不同构型代谢物	—	碳链质子转移
	[102]	2021	EGFR抗体结合	太赫兹时域光谱系统	提升EGFR检测灵敏性	—	—

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