acm Advances in Clinical Medicine 2161-8712 2161-8720 beplay体育官网网页版等您来挑战! 10.12677/acm.2024.1472090 acm-91879 Articles 医药卫生 各种示踪技术在乳腺癌前哨淋巴结的应用进展
Application Progress of Various Tracer Techniques in Sentinel Lymph Node of Breast Cancer
牛向阳 1 冯其贞 2 2 济宁医学院临床医学院,山东 济宁 济宁医学院附属医院乳腺外科,山东 济宁 02 07 2024 14 07 870 876 19 6 :2024 13 6 :2024 13 7 :2024 Copyright © 2024 beplay安卓登录 All rights reserved. 2024 This work is licensed under the Creative Commons Attribution International License (CC BY). http://creativecommons.org/licenses/by/4.0/ 乳腺癌是全球范围内最常见的癌症,且发病率逐年上升,非常严重影响女性身体和身心健康。而前哨淋巴结(sentinel lymph node, SLN)为乳腺癌淋巴结转移的第一个或第一组淋巴结,可反映腋窝淋巴结的病理状态,是影响患者预后的重要因素。目前,前哨淋巴结活检(sentinel lymph node biopsy, SLNB)已成为临床淋巴结阴性乳腺癌患者腋窝分期的标准,随着示踪技术的进步,各种示踪技术在乳腺癌前哨淋巴结检查中得到广泛应用,可提高检查准确率。本文对各种示踪技术在乳腺癌前哨淋巴结检查中的应用进行综述。
Breast cancer is the most common cancer in the world, and its incidence is increasing year by year, which seriously affects women’s physical and mental health. Sentinel lymph node (SLN) is the first or first group of lymph node metastasis in breast cancer, which can reflect the pathological state of axillary lymph nodes and is an important factor affecting the prognosis of patients. At present, sentinel lymph node biopsy (SLNB) has become the standard of axillary staging in patients with clinical lymph node-negative breast cancer. With the progress of tracer technology, various tracer techniques have been widely used in sentinel lymph node examination of breast cancer, which can improve the accuracy of examination. This article reviews the application of various tracer techniques in sentinel lymph node examination of breast cancer.
乳腺癌,示踪方法,前哨淋巴结
Breast Cancer
Tracing Method Sentinel Lymph Node
1. 引言

近几年来,乳腺癌的发病率越来越高,2020年世界癌症统计显示:在全部癌症病人中,女性乳腺癌的发病率已经超过肺癌,严重威胁了女性的身体健康 [1] 。前哨淋巴结是乳腺癌向淋巴池引流的第一个淋巴结,SLN的解剖学位置对腋窝淋巴结的状态起到重要作用。美国国家综合癌症网络指南 [2] 提出,前哨淋巴结活检已逐步应用于临床实践成为临床乳腺癌淋巴结阴性患者腋窝分期的标准评估方案。自从将SLNB技术确立为临床淋巴结阴性乳腺癌腋窝分期的标准程序以来,腋窝淋巴结清除的数量已显著减少 [3] 。欧洲乳腺癌专科医师协会调查结果显示,从2010年到2016年,ALND的比例从89%降至46% [4] 。SLNB的实现是基于淋巴网络的连接和淋巴液的流动理论 [5] 以及示踪剂,目前临床定位SLN的常用方法为蓝色染料(blue dye, BD)法和放射性同位素(radioactive isotope, RI)法。除此之外,SLN的示踪技术还包括纳米碳、吲哚菁绿(indocyanine green, ICG)荧光染色法、超声造影(contrast-enhanced ultrasound, CEUS)、超顺磁性氧化铁(superparamagnetic iron oxide, SPIO)以及盐酸米托蒽醌注射液(mitoxantrone hydrochloride injection, MHI)示踪,这些方法在临床应用中各有利弊。本文拟对示踪技术在乳腺癌SLN的研究进展进行阐述。

<xref></xref>2. SLNB的应用

乳腺癌治疗策略的选择,包括手术、放疗和化疗,与腋窝淋巴结的状况密切相关,而腋窝淋巴结是乳腺癌临床分期的重要指标,由于乳腺癌跳跃淋巴结转移的发生率较低,引流链中的第一个淋巴结SLN的病理状态通常代表乳腺癌区域所有引流淋巴结的状态 [6] 。无前哨淋巴结转移的患者一般不需要腋窝淋巴结清扫术 [7] 。这简化了治疗程序,还减少了组织创伤,可以避免过度治疗。因此,及时、准确地诊断SLN转移对于改善乳腺癌患者的预后和及时治疗至关重要。乳腺癌SLN转移的诊断对于选择适当的治疗策略至关重要。

3. SLNB的示踪技术 3.1. 蓝色染料法

蓝色染料具有操作简单、无辐射危害、易于获取等优点,主要包括异硫蓝(IB)、专利蓝(PB)的异构体以及亚甲基蓝(MB)。MB的显色相对于PB和IB来说更淡。然而,由于PB和IB相对于MB价格昂贵且在中国尚未上市,MB因其价格便宜且易于获得而成为中国最常用的蓝色染料示踪剂。亚甲蓝染色法有大量循证医学证据支持,成本低、疗效高、手术并发症发生率低,已成为乳腺手术前哨淋巴结活检的重要工具,但可能会导致皮肤出现蓝色染色,皮内注射后皮肤坏死的病例也有报道 [8] [9] 。在放射性分子获取不足的低收入和中等收入国家,符合SLNB条件的患者的手术治疗通常依赖于单独的蓝色染料,这逊色于单独的锝99m (99mTc)以及标准的双RI + BD技术 [10] 。根据一份调查报告 [11] 显示,中国有63% (69/110)的医院使用亚甲蓝作为示踪剂来定位SLN。单独使用蓝色染料进行前哨淋巴结活检的主要问题在于其仅有70%~92%的检出率 [12]

3.2. 放射性同位素法

使用锝99m (99mTc)是SLNB治疗乳腺癌的首选放射性示踪剂。硫胶体是国内常用的核素载体,由于胶体是一种不稳定的体系,因此制备胶体需要严格的质量控制。术前将医院自制的胶体注射于乳晕四周或瘤周皮下,术中在γ探测器下识别前哨淋巴结。核素法在手术中检测前哨淋巴结的准确率可达97.2% [13] 。然而,该方法价格昂贵,需要核医学设施,患者和手术室工作人员都受到影响,并且还有放射性剂供应和排放等问题。手术标本的处理必须严格按照相关规定执行 [14] ,且大众对放射安全性的担忧以及核素载体硫胶体的准入问题,对核素在国内的推广应用产生了影响 [15] 。在我国放射性同位素的临床应用受到严格管理,因此难以广泛使用 [16]

3.3. 联合法

目前,联合放射性同位素和蓝色染料的双重映射技术被认为是提供最高前哨淋巴结识别率(>90%)和最低假阴性率(<5%~10%)的金标准技术 [17] [18] 。蓝色染料和放射性核素联合示踪前哨淋巴结是具有充分循证医学证据支持的标准示踪方法 [19] 。有研究表明两者联合使用的敏感度高达96%~99% [20] 。不过它也存在着蓝染法和核素法的不足之处,比如蓝色染料的过敏反应,放射同位素的核污染问题等,因此临床使用率仍较低。

3.4. 纳米碳

纳米炭是一种大分子染色剂,其直径大约为150 nm,不容易穿透血管内皮,但小于毛细淋巴管,因此,纳米碳可以穿过毛细淋巴管,容易在淋巴结中留存,将淋巴结染成黑色,可作为示踪剂染料 [21] 。使用纳米炭法标记前哨淋巴结时,无需其他设备的辅助,染色结果可直接肉眼观察到,在手术中有助于直观地识别和清除淋巴结,从而减少组织损伤、缩短手术时间,且识别淋巴结的准确性较高。一项Meta分析 [22] 显示,在SLNB中,纳米碳的灵敏度和假阴性率与亚甲蓝相当,然而其SLN检出率和检测准确度却有所不同,均优于亚甲蓝。但是纳米碳在淋巴管中的染色较弱,且纳米碳价格昂贵。中国抗癌协会乳腺癌诊治指南与规范(2021年版)不建议在临床中常规使用 [23]

3.5. 吲哚菁绿荧光染色法

荧光成像法ICG是一种水溶性染料,在近红外光谱中具有荧光特性,ICG通常用于血管造影和肝脏清除测试,它与血浆蛋白结合并吸收波长约800 nm的光以产生荧光信号。目前,ICG已被批准用于对多种肿瘤的淋巴引流途径进行成像,例如前列腺癌、皮肤卡西波肉瘤和直肠癌皮肤转移 [24] 。ICG已被证明作为乳腺癌SLNB期间的示踪剂是安全有效的,并且越来越多的证据表明ICG优于BD [25] 。Wang [26] 等人进行了一项前瞻性研究,比较ICG的准确性和MB的准确性,得出ICG和MB的SLN检出率分别为100%和93%。值得注意的是,与BD相比,当ICG用作示踪剂时,SLN的平均数量明显更大。也有越来越多的证据表明ICG优于RI,有一项研究报告称,RI的检出率为73.4%,ICG的检出率为98.1% [27] 。此外,Wang [28] 等人在荟萃分析中纳入了11项研究,涉及2137名患者,得出的结论是,与单独使用BD相比,ICG + BD联合技术的特点是检出率显着更高,检测到的SLN数量显着更高。ICG也有一些缺点,ICG含有碘,因此,对碘或造影剂过敏的患者必须慎用。此外,对于肥胖患者,ICG作为SLNB示踪剂的效果也可能较差。ICG的另外的显著缺点是手术野的污染,当发射荧光信号的淋巴管受损时,导致ICG渗漏到周围组织中,从而损害SLN的准确检测。总之,ICG是新型示踪剂中最有前途的,最可能作为SLNB传统示踪剂的可行替代方案。

<xref></xref>3.6. 超顺磁性氧化铁法

在正常淋巴结中,吞噬细胞可以摄取并分解SPIO,通过外界磁场的影响,无信号强度变化,但在转移性淋巴结中,这种示踪剂的降解速度较为缓慢,SPIO在SLN内聚集,导致SLN在MRI T2加权成像中显示出显著的高信号变化,增强了MRI在检测淋巴结受累方面的敏感性 [29] 。SPIO法最大的优势是一种无创性示踪法。一项研究表明 [30] ,磁性技术是SLNB的一种可行方法,其识别率不低于标准技术。Vivian [31] 等人研究发现单示踪剂SPIO引导的SLNB并不劣于双重技术(放射性同位素和蓝色染料),并且可以安全地取代早期乳腺癌SLN定位的金标准。但SPIO技术也存在不足之处,比如皮肤色素积聚时间长,也可能导致一些患者出现色素脱落的现象。Krischer [32] 等研究人员观察到,一半的患者在乳房MRI测试中的结果受到损害,这将对患者后续的诊疗产生严重影响。总之,磁性技术为标准技术提供了合适的替代方案,避免了核医学辐射的危害以及蓝色染料的过敏风险。然而,SPIO示踪剂在中国还无法获得,而且其技术也存在缺陷,仍需进一步研究。

3.7. 超声造影法

超声造影剂是一种微泡造影剂,其平均直径小于红细胞的平均直径,从而使得造影剂能够轻松进入毛细血管和淋巴管 [33] 。超声造影法是通过在乳晕周围进行经皮内或皮下注射超声造影剂。通过这种方式,可以找到造影剂汇聚的第一站淋巴结,即SLN,最终实现前哨淋巴结的定位和检查。各项研究对超声造影的增强模式没有统一的定义,一般可分为I类(均匀强化)、II类(不均匀强化或异质性)和III类(微弱或无增强) [34] 。目前多种超声造影剂已被临床使用,如羟乙基化淀粉、SonoVue、Sonazoid和Definity,它们均可通过皮下注射被淋巴管吸收,实现对淋巴结的实时成像。刘延兵 [35] 等研究发现CEUS定位前哨淋巴结的准确性为84.0%,而双标记技术(蓝色染料注射和放射性同位素示踪剂)的准确性为97.92%,研究还分析了CEUS与细针穿刺细胞学(FNAC)结合应用的效果,认为是诊断SLN转移的可靠技术。CEUS联合蓝色染料对临床阴性淋巴结患者SLNB的检出率可达100%,优于单纯蓝色染料,联合使用蓝色染料和CEUS可能为无法获得放射性同位素的中心提供SLNB的非放射性替代方法 [36]

<xref></xref>3.8. 示踪用盐酸米托蒽醌注射液

MHI是一种静脉注射抗肿瘤抗生素,主要通过胆道代谢,已用于治疗乳腺癌、前列腺癌、急性白血病和淋巴瘤等疾病。MHI是最新的替代技术,它对淋巴系统有很高的亲和力,最近被批准用于鉴定甲状腺癌相关的前哨淋巴结 [37] [38] 。在乳晕周围区域注射MHI后,它逐渐沉淀成100 nm的纳米晶体,进入毛细淋巴管,在区域淋巴结中积聚并停留相当长的时间,使淋巴结染成蓝色 [39] 。在剂量高达2.0 mL时,未观察到药物限制性毒性作用,并且可以安全地对乳腺癌患者进行SLN活检,且MHI与2mCi 99mTc标记硫胶体的淋巴结检出率无显着差异 [37] 。而Elzayat [40] 等人研究发现,MHI技术在SLN鉴定方面仍不如联合法,但是在放射性技术不可用的情况下,它可以作为安全可靠的替代方案。An [41] 等人进行的研究表明,MHI表现出肝脏、肾脏和血液毒性,此外,这项研究还表明任何毒性反应,包括乳腺水肿、溃疡和结痂,在停止使用MHI后两周内很快消失。MHI的起效时间比亚甲蓝更快,且持续时间比亚甲蓝长。此外,盐酸米托蒽醌是一种可以完全代谢的有机物质,降低了使用纳米碳作为淋巴示踪剂时可能发生的毛细血管堵塞的风险。因此盐酸米托蒽醌的优点明显,可作为早期乳腺癌患者前哨淋巴结活检的淋巴示踪剂。

4. 小结

亚甲蓝因操作简单、易于获取、价格廉价,在国内被广泛使用,而放射性同位素联合蓝色染料是目前所共识的金标准技术,然而国内很多医院都没有放射性同位素示踪剂,因此迫切需要开发新型淋巴示踪剂。尽管纳米碳不良反应较少,且与亚甲蓝的灵敏度相当,但其染色时间短且费用高等局限性使其不作为临床的常规使用;ICG作为一种新型的示踪剂,是安全有效的,并且越来越多的证据表明ICG优于BD,然而,迄今为止,关于在SLNB临床实践中实施ICG的最佳作用尚未达成共识,ICG是否有可能取代传统示踪剂的问题需要进一步的研究;SPIO费用低且无放射性的优点明显,而其技术目前不成熟,仍需进一步完善;超声造影法联合细针穿刺细胞学术前诊断SLN的转移优势明显,值得在临床推广;盐酸米托蒽醌注射液有着良好的安全性和有效性,但其研究时间较短,仍需大量的研究支持。尽管各种示踪技术取得了显著的进展,但仍然存在着一些挑战和限制。

课题名称

化疗相关认知功能障碍中亲环素D介导线粒体功能损伤的机制研究。

基金项目

山东省医药卫生科技发展计划项目202104080815。

NOTES

*第一作者。

#共同通讯作者。

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