第二军医大学学报  2021, Vol. 42 Issue (9): 1044-1051   PDF    
支气管腔内超声技术的临床应用及进展
王健男, 黄海东, 白冲     
海军军医大学(第二军医大学)长海医院呼吸与危重症医学科, 上海 200433
摘要: 随着胸部CT筛查的普及,肺外周、纵隔病灶的检出率大大提高。为了提高传统支气管镜的诊断率,新的技术不断出现。支气管腔内超声(EBUS)是一种同时结合了支气管镜和超声的微创诊疗技术,可以提供气道壁和支气管树邻近结构的超声图像及实时引导活检,类型主要包括凸探头式支气管腔内超声(CP-EBUS)和径向微探头导管支气管腔内超声(RP-EBUS)。CP-EBUS主要应用于大气道及肺中央型病变,在肺癌纵隔分期中发挥重要的作用,RP-EBUS综合导引技术主要用于诊断肺周围型病变,此外EBUS也可用于一些肺外毗邻脏器疾病的微创诊断和治疗。EBUS具有风险低、诊断良恶性病灶灵敏性高、重复性好等优势,已在全世界范围内广泛应用于临床并不断发展。本文就EBUS的发展史和临床应用及进展进行综述。
关键词: 超声支气管镜    肺肿瘤    微创诊断    经支气管针吸活检    肺周围型病变    
Clinical application and progress of endobronchial ultrasound
WANG Jian-nan, HUANG Hai-dong, BAI Chong     
Department of Respiratory and Critical Care Medicine, Changhai Hospital, Naval Medical University (Second Military Medical University), Shanghai 200433, China
Abstract: With the popularization of chest computed tomography (CT) screening, the detection rates of pulmonary peripheral lesions and mediastinal masses have been greatly increased. Novel technologies are emerging to improve the diagnostic rate of traditional bronchoscopy. Endobronchial ultrasound (EBUS) is a minimally invasive diagnosis and treatment technology combining bronchoscopy and ultrasound. It can provide ultrasound images and guide biopsy of airway wall and adjacent structures of bronchial tree in real time. The main types include convex probe-endobronchial ultrasound (CP-EBUS) and radial probe-endobronchial ultrasound (RP-EBUS). CP-EBUS is mainly used in the major airway and central lung lesions, and plays an important role in mediastinal staging of lung cancer. RP-EBUS comprehensive guidance technology is mainly used in the diagnosis of peripheral lung lesions. In addition, EBUS can also be applied to the minimally invasive diagnosis and treatment of some extrapulmonary adjacent organ diseases. With the advantages of low risk, high sensitivity to benign and malignant lesions and good repeatability, EBUS has been widely used in clinical practice all over the world. This paper reviews the development history, clinical application and progress of EBUS.
Key words: endobronchial ultrasound    lung neoplasms    minimally invasive diagnosis    transbronchial needle aspiration biopsy    peripheral pulmonary lesions    

近年来,随着内镜临床应用的推广和超声设备的微型化发展,超声内镜用于人体腔道内疾病的诊治已成为一项日趋成熟的技术。支气管镜技术作为气道和肺部常见疾病的常规诊疗手段,是每位从事呼吸与危重症医学专业的医师必须掌握的技术之一。自20世纪末21世纪初,随着支气管腔内超声(endobronchial ultrasound,EBUS)设备的研发,EBUS技术逐步被专业从事呼吸介入的内镜医师掌握,经过近30年的发展,现代EBUS技术的临床应用已不仅局限于大气道腔内及管壁外病灶,在肺周围型病变甚至邻近脏器的诊治中也有了极为广泛的应用[1]。本文就EBUS的发展史及在肺部疾病、肺外邻近脏器中的应用与进展进行综述。

1 EBUS发展史

超声技术应用在支气管镜中的源动力为20世纪90年代经典经支气管针吸活检术(conventional transbronchial needle biopsy,C-TBNA)在肺部疾病中的应用,美国约翰·霍普金斯医院内镜中心的Kopen Wang教授早在20世纪80年代就依据胸部CT制定了纵隔和肺门肿大淋巴结患者气道腔内C-TBNA穿刺点图谱,并研发了穿刺针,总结了行之有效的穿刺方法;在他的努力下,C-TBNA对纵隔及肺门肿大淋巴结的穿刺阳性率达72%[2-4]。为了进一步提高C-TBNA穿刺诊断率和减少并发症,20世纪90年代初,德国海德堡大学医院胸腔内镜科Heinrich Becker教授首先引入EBUS概念,他发明了一种末端有径向微探头导管的支气管腔内超声(radial probe-endobronchial ultrasound,RP-EBUS),该微探头经支气管镜工作孔道进行气道腔内超声检查[5]。1992年,德国胸科医师Hürter和Hanrath首先使用美国波士顿公司生产的带引导鞘管(guided sheath,GS)的RP-EBUS(EBUS-GS),在74例大气道中央型病变患者和26例肺周围型病变患者中验证了该技术的安全性和有效性,首次揭示人体大气道管壁及周围血管、肺实质、病灶的腔内超声内镜图像,并且对26例气道腔内不可见的肺周围型病变获得了19例(73.1%)的病理诊断结果,这一发现奠定了RP-EBUS技术在肺周围型病变中推广应用的基础[6]

1996年,丹麦医师Pedersen等[7]采用末端带有线阵超声探头的消化超声内镜对9例患者共13枚纵隔肿大淋巴结实施了超声内镜下的针吸活检术。受此启发,日本肺科专家和Olympus内镜公司合作,共同研发了可用于气道的超声支气管镜,2004年,Yasufuku等[8]首次采用凸探头式支气管腔内超声(convex probe-endobronchial ultrasound,CP-EBUS)通过实时超声图像观察病灶和周围血管的位置,并对病灶开展实时穿刺活检取样,这项技术即为支气管腔内超声引导针吸活检术(endobronchial ultrasound-guided transbronchial needle aspiration,EBUS-TBNA),此后其主要用于大气道管壁及管壁外相邻病灶的超声诊断和穿刺活检[9]

2 CP-EBUS在大气道及肺中央型病变中的应用与进展 2.1 CP-EBUS设备介绍

CP-EBUS系统主要包括内镜主机、超声主机、超声支气管镜、连接配件和穿刺针。新近的内镜超声主机基本都配备了B模式、彩色多普勒和弹性成像等功能。超声支气管镜在插入段末端设置了微型超声探头,到达目标区域可采用直接接触法或水囊法实施超声扫描,超声探头探测深度约为5 cm,扫描频率为5~12 MHz,发现目标病灶后通过支气管镜工作孔道置入专用的穿刺针,在超声实时引导下穿刺[10]。超声支气管镜采用针吸活检穿刺针,目前21、22 G的穿刺针在国内外应用广泛,近期25 G的超细穿刺针和19 G的组织穿刺针也即将在国内应用[1, 11]

2.2 CP-EBUS临床应用进展

CP-EBUS常见的适应证包括不明原因纵隔、肺门病灶的诊断,肺癌的纵隔分期和再分期,大气道壁、纵隔及周边解剖结构的观察与治疗;禁忌证同可弯曲式支气管镜检查[12]。EBUS-TBNA不需要X射线透视辅助即可诊断第1、2、3P、4、7、10、11及12组纵隔及肺门旁淋巴结,该技术相比C-TBNA的优势在于可直视病变并实时穿刺、评估更多部位的淋巴结、有效避开血管穿刺、可以取得更多的肿瘤细胞,其相比纵隔镜的优势在于创伤小、无须全身麻醉、操作时间短、可评估更多部位的淋巴结、节省费用、呼吸内科医师可实施操作[13]。目前广泛应用的CP-EBUS先端部外径一般为6.3~6.9 mm,可弯曲部最大角度为向上120°、向下90°,可进入直径7 mm左右的叶支气管和部分段支气管,新近有直径更小的CP-EBUS研发,有利于进入更远端的肺叶段探查,据报道直径5.9 mm的CP-EBUS几乎可到达所有段支气管[14]。EBUS-TBNA可以在单次操作中同时完成肺内病灶活检诊断和淋巴结分期,缩短诊断时间,并且可以检出PET-CT为假阴性的淋巴结,从而提高分期的准确率。EBUS-TBNA对于胸内淋巴结分期的诊断准确度为98%,灵敏度为92.3%,特异度为100%,远高于CT(60.8%、76.9%、55.3%)和PET-CT(72.5%、80%、70.1%)[15]。EBUS-TBNA的上述优势使之成为确定肺癌患者纵隔及肺门淋巴结诊断和分期的标准工具。

EBUS-TBNA获取的组织标本可用于肺癌的分子标志物检测,在中晚期肺癌的靶向治疗和免疫治疗中发挥着重要作用[10]。一项回顾性研究中对于直径>5 mm的淋巴结用22 G针穿刺3针,对取样结果进行高通量测序、荧光原位杂交和程序性死亡因子配体1(programmed death ligand 1,PD-L1)免疫组织化学染色等检测,结果显示50例诊断为非小细胞肺癌的患者中有41例(82%)获得了足够的样本用于以上3项辅助检查[16]。另有研究表明,EBUS-TBNA穿刺标本与外科活检样本的PD-L1表达一致率为82%~87%,淋巴结穿刺取样与原发病灶的PD-L1表达也较为相符[17]。在肿瘤的治疗过程中,对于肿瘤复发患者可以再次取材活检,并检测新的基因突变位点[18]

EBUS-TBNA也可有效评估或取样良性胸内淋巴结肿大和纵隔病灶,如结节病和结核病等感染性疾病,EBUS-TBNA对结节病的诊断率高于传统支气管镜,诊断结核病的灵敏度为80%,但淋巴结穿刺样本的病原学检测灵敏度欠佳[10]。在一项140例倾向良性的不明原因纵隔病灶患者的回顾性研究中,131例(93.6%)通过EBUS-TBNA获得诊断[19]

2.3 CP-EBUS超声影像学技术进展

CP-EBUS观察病灶的超声影像特点有助于良恶性疾病的诊断。2010年Fujiwara等[20]总结了EBUS-TBNA技术在肺癌纵隔淋巴结分期中的超声影像特点,其中6个超声影像特点有助于恶性淋巴结的预判,即淋巴结直径>10 mm、圆形、边界清晰、内部异质性、中央窦门结构缺失、凝固性坏死。2013年EBUS引入弹性超声成像,其作为一种非侵入性手段有助于诊断淋巴结的良恶性。弹性成像能够显示组织的相对硬度,蓝色代表组织偏硬,红色代表组织偏软[21]。Izumo等[22]提出了一项简易EBUS弹性图像分类法,1型(非蓝色为主)提示良性淋巴结,2型(部分蓝色,部分非蓝色)提示不确定,3型(蓝色为主)提示恶性淋巴结,94.6%(35/37)的3型淋巴结确诊为恶性,但估算面积百分比容易受主观影响。Fujiwara等[23]在一项回顾性研究中将B模式超声影像同时观察到椭圆形、边界不清晰、均匀回声、无凝固坏死征判定为良性,采用ImageJ 1.45s软件计算的弹性超声成像硬质组织区域大于整个淋巴结面积的31%判定为恶性,转移性淋巴结的硬质组织区域比例显著高于良性淋巴结(0.487 vs 0.216),结合B模式和弹性成像的超声结果,恶性淋巴结的诊断率为83.1%(59/71),良性诊断率为96.2%(101/105),显示了良好的灵敏性和较高的阴性预测值,能够帮助选择最可疑的淋巴结进行活检,提高EBUS-TBNA的诊断效率。此外,研究表明人工智能也有助于EBUS超声图像中良恶性的鉴别,运用人工神经网络技术对EBUS淋巴结超声图像进行深度学习和测试后其诊断准确率为82%,灵敏度为89%,特异度为72%[24]。由上述可见,EBUS的B模式和弹性成像可以作为诊断淋巴结良恶性的重要补充,但判定标准尚需统一。

2.4 EBUS穿刺针及穿刺方法进展

EBUS-TBNA采用专用针吸活检穿刺针,可以灵活弯曲,深度可控,穿刺针有21 G和22 G 2种选择,带有安全锁,可以防止穿刺针意外伸出鞘管、损伤内镜。穿刺针已从第一代细胞穿刺针(21~22 G)发展到19 G组织穿刺针,在临床广泛应用的穿刺针多为21、22 G,插入部最大径分别为1.9 mm和1.8 mm,常规针长20 mm,最大针长40 mm。25 G的超细穿刺针和19 G的组织穿刺针也即将在国内应用,前者更细、更柔,可以取得更多大角度管外病变组织,还可以在保证组织样本量的同时更易到达远端分支支气管管外目标淋巴结站,所获取样本更不容易被血污染。19 G穿刺针为第一款真正意义上的组织穿刺针,能够取得更多的组织,提高良性疾病和淋巴瘤的诊断率;新的材质同时增加了柔韧性,使EBUS-TBNA弯曲角度更大,有助于对纵隔第10L组和第10R组淋巴结大角度穿刺[11, 25]。此外,19 G及更粗的穿刺针可以进入直径 < 1 mm、分辨率为3.5 μm的AQ-Flex 19共聚焦激光微探头进行实时光学活检。针型共聚焦激光显微内镜的探头十分细微,可以通过穿刺针的针孔,结合安全的荧光染色技术或利用肺部自体荧光进行表面成像,能高分辨率实时显示肿瘤细胞,并可检查从支气管树到肺泡的所有结构。针型共聚焦激光显微内镜显示的恶性细胞表现为变暗增大的多形性细胞、重叠的暗细胞团和定向细胞流,诊断恶性肿瘤的灵敏度和特异度分别为0.90和0.89[26]。针型活检钳可获取较穿刺针更多的淋巴结组织,兼具穿刺针和活检钳的特点,其直径1.5 mm,远端15 mm硬质,由1个尖端呈锐利斜面的长齿和1个短齿组成,在EBUS引导下经支气管镜工作孔道穿刺气管壁到达目标淋巴结进行活检[27]。或使用直径1 mm的微型活检钳在EBUS-TBNA穿刺后经过气管黏膜穿刺缺口进入目标淋巴结,打开活检钳,获取组织样本;文献报道的300次淋巴结活检钳活检操作中,总体并发症发生率为1.5%,其操作与EBUS-TBNA一样安全,并且可以提供更充足的组织样本,对结节病、淋巴结结核和淋巴瘤的诊断率显著高于EBUS-TBNA[28-29]

2.5 安全性

EBUS-TBNA操作总体安全可控,一项纳入了9项临床研究的meta分析表明EBUS-TBNA的总体并发症发生率为1.44%(19/1 317),最常见并发症包括严重出血(发生率为0.2%)、气道损伤(< 0.1%)、呼吸衰竭(0.23%)、缺氧(0.3%)、低血压(< 0.1%)和气胸(0.53%);高风险因素包括年龄>70岁、住院患者、采用深度镇静或全身麻醉实施操作和同步开展经支气管肺活检[30]。多项研究表明第5组和第6组淋巴结也可以使用22 G穿刺针在EBUS引导下经肺动脉旁或主动脉旁进行穿刺,且安全、有效,无明显操作相关并发症出现[31-32]

3 RP-EBUS在肺周围型病变中的应用与进展 3.1 常用的RP-EBUS设备介绍

RP-EBUS所需设备包括内镜主机系统、电子支气管镜、超声主机EU-ME1/EU-ME2、超声探头UM-S20-17S/ UM-S20-20R、探头驱动器及支架支臂、GS套装、虚拟支气管软件、C臂机和引导装置(可选)。2种超声小探头均为B模式超声影像,提供360°径向超声成像,超声频率均为20 MHz。一次性GS套装包括卡锁、细胞刷、活检钳、外鞘管[33-34]

3.2 RP-EBUS综合导引技术诊断肺周围型病变的应用进展

随着肺部CT筛查的普及,肺周围型病变的检出率大大提高,但这类病灶的活检诊断具有一定挑战性。诊断肺周围型病变的方法包括痰细胞学、可弯曲支气管镜检查、CT引导下经胸穿刺活检术(transthoracic needle aspiration,TTNA)等。传统可弯曲支气管镜对肺周围型病变的诊断率仅为30%~60%[34]。为了提高传统支气管镜的灵敏性,新的技术手段不断研发,如虚拟支气管镜导航(virtual bronchoscopic navigation,VBN)、电子束计算机断层扫描(conebeam computed tomography)技术、VBN联合超细支气管镜(ultrathin bronchoscopy,UTB)、电磁导航支气管镜(electromagnetic navigation bronchoscopy,ENB)及EBUS技术[35]

RP-EBUS在肺周围型病变的诊断中具有较高的诊断率和较低的并发症发生率。RP-EBUS诊断肺周围型病变恶性病灶的灵敏度为0.69~0.73,优于传统支气管镜(0.34~0.63)[36-37]。适合选择RP-EBUS活检的病灶特点包括最大径>2 cm、恶性、CT影像显示肺周围型病变存在支气管征、RP-EBUS探头在病灶内而不仅是毗邻的肺周围型病变、病灶位于肺野内2/3、预估到达支气管的路径较直[34, 38]。此外,在肺周围型病变的TBNA、经支气管镜肺活检过程中使用快速现场评价可以提高诊断准确率和灵敏性[39]。RP-EBUS并发症包括少量自限性出血和一般无须特殊干预的少量气胸,与RP-EBUS相比,TTNA的优势在于诊断率高,在挑选出的肺周围型病变中TTNA的诊断率可达82%,但其并发症的发生率也高,并且操作过程中医师和患者都会有较多射线暴露,TTNA的气胸发生率高达23%,显著高于RP-EBUS的气胸发生率(0.7%)[36, 40]

临床实践证明,在实施肺周围型病变的活检操作中联合应用以RP-EBUS为基础的多种导引技术可明显提高诊断率,据统计EBUS-GS、X射线透视、VBN 3项技术联用的诊断率可达67%~81%[41]。一项回顾性研究评估了基于RP-EBUS的多种技术联合应用对肺周围型病变的诊断阳性率、有效性和安全性,结果显示单独使用RP-EBUS的诊断阳性率为65.0%(13/20),联合VBN、EBUS-GS和X射线透视的综合导引技术对肺周围型病变的活检诊断率最高(91.7%,11/12),且94例患者均未发生严重并发症[34]。另外一项技术是利用UTB提高到达外周肺的能力,UTB(外径为3 mm)联合RP-EBUS、VBN及X射线透视能够到达更远段的(6级以上)亚段支气管,相比细支气管镜(外径为4 mm)有更高的肺外周结节诊断率[35, 42]

3.3 RP-EBUS超声影像学技术进展

RP-EBUS定位的肺周围型病变超声图像特点和病理结果同样具有一定的关联性,内部回声均匀、同心圆结构多提示良性病灶,而恶性病灶多表现为内部回声异质性、较多强回声点、无同心圆结构,可有连续强回声边缘或周围强回声弧线;肺炎或肺结核可表现为内部均匀回声、同心圆结构,肺炎的强回声点较小、分布均匀,肺结核和恶性病灶均可存在大量强回声点[43]。Izumo等[44]将116例诊断为恶性肺部磨玻璃影(ground glass opacity,GGO)患者的RP-EBUS图像与CT发现和外科组织病理进行比较,总结RP-EBUS影像特点如下:(1)雪花征,为正常肺组织;(2)暴风雪征,即轻微密度增加的弥漫的白色回声增强,为GGO;(3)混合性暴风雪征,即暴风雪征和一些散在不均匀分布的强回声点和血管,为偏实性GGO。组织学上暴风雪征为原位腺癌到高分化腺癌,混合性暴风雪征多以高分化侵袭性贴壁生长为主型,为中到低分化腺癌。

4 EBUS的扩展应用 4.1 心包积液或囊肿穿刺引流

EBUS-TBNA可对微量心包积液及纵隔、气道旁囊肿进行穿刺引流,帮助明确诊断和引流积液[45]。心包积液目前的常规处理方法是经胸壁心包穿刺术,而厚度 < 2 cm的心包积液暂无有效干预措施。Hohenforst-Schmidt等[46]应用EBUS-TBNA微创早期诊断和治疗了10例厚度 < 2 cm的心包积液患者,他们使用常规穿刺针,并结合X线C臂机和常规经胸超声,成功从左主支气管远端或下叶支气管近端穿刺抽取微量心包积液,所有患者均无严重并发症发生,60 d随访期内均无须再次穿刺。Christiansen等[47]报道了2例使用EBUS-TBNA经食管抽吸恶性心包积液进行肺癌分期的患者,结果表明EBUS可安全、有效地应用于肺癌治疗过程中心包积液的处理。

4.2 肺动脉栓塞(pulmonary embolism,PE)

PE通常需要通过增强肺部CT、核素灌注扫描等检查确诊,但患者可能存在造影剂过敏、肾功能不全、血流动力学不稳定、妊娠等禁忌证,这些情况下可以选择CP-EBUS进行有效诊断。肺动脉邻近气管支气管,CP-EBUS可以观察到主动脉弓、左右肺动脉干、奇静脉、叶动脉等,EBUS彩色多普勒可帮助辨认血管内栓子形状与栓塞程度,并且可以实时评估栓塞的治疗情况。PE的典型超声特点为血管内回声团块阻塞整个血管腔或贴附于血管壁[48]。Aumiller等[49]报道了一项前瞻性多中心临床研究,32例PE患者在增强CT确诊后24 h内进行CP-EBUS检查,增强CT定位了101处栓塞,CP-EBUS诊断了97处(96%),诊断出每例患者有至少1处栓塞,足以确诊,操作时间为3~5 min。但CP-EBUS超声图像质量稍低(5~10 MHz),必要时仍需CT血管造影确诊。也有研究者认为肺癌患者存在血液高凝因素,是PE的高风险人群,建议使用EBUS-TBNA开展纵隔淋巴结分期时应常规进行肺动脉探查以早期筛查PE[45]

4.3 气管壁探查及气道内新生物/血管鉴别

EBUS可以帮助大气道内黏膜下新生物、血管的判定,用于诊断和鉴别气道血管疾病,如支气管Dieulafoy病。支气管Dieulafoy病在气管镜下为黏膜光滑的结节状或突出的病变,可有白帽,容易误诊为支气管内肿瘤,盲目活检会导致致命的医源性大咯血,活检之前使用EBUS或血管造影检查可以避免活检引起的出血[50]。此外,RP-EBUS还可以测量气管壁厚度和识别气管壁层次,用于检测支气管哮喘和慢性阻塞性肺疾病气道重塑及测量肿瘤侵袭的深度,帮助制订治疗策略[51-52]

4.4 肿瘤等疾病的局部介入治疗

气管镜局部介入治疗为许多呼吸系统疾病难题的解决带来了更多选择,EBUS引导下气管镜介入治疗可以发挥更为精准、有效的作用。目前恶性肿瘤化疗存在着化疗药物瘤内分布不均匀的情况,使用EBUS引导下19 G穿刺针可以直接将抗肿瘤药物注射到瘤体内或转移性淋巴结内,其优点在于药物释放和分布精准、药物有效浓度高、全身毒性反应少,低剂量瘤内化疗可诱导树突状细胞抗原提呈和成熟,发挥免疫调节作用[10, 53]。Xu等[54]报道了EBUS引导下125I放射性粒子植入术治疗肺癌纵隔病灶或转移性淋巴结,6个月随访期内患者均耐受良好,总体反应率为85%(17/20)。Motooka等[55]报道了EBUS实时引导下射频消融电极插入肺部肿瘤和纵隔淋巴结内部,消融面积为0.6~3 cm2,无出血、气胸等并发症发生。因结核脓肿缺乏血供,抗结核药物不易到达病灶,EBUS也有助于肺周围及纵隔内难治性结核的局部治疗。Fang等[56]报道了在系统抗结核治疗的同时使用EBUS-TBNA穿刺、抽吸和局部应用药物,结果显示EBUS-TBNA能够促进病灶完全吸收,减少结核并发症的发生。

5 结语

经过数十年的发展,EBUS技术因微创、安全等优势目前已应用于大气道腔内及管壁外病灶、肺周围型病变及肺外毗邻脏器疾病的微创诊断。随着EBUS各项技术的日趋完善与普及推广、各项综合导引技术的发展和新的EBUS技术的改进,EBUS将在临床实践中发挥越来越大的作用。

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