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综述
钆塞酸二钠在结直肠癌肝转移瘤诊断及评估中的应用进展
黄小兰 彭婕

Cite this article as: Huang XL, Peng J. Progress of Gd-EOB-DTPA in the diagnosis and evaluation of CRLM[J]. Chin J Magn Reson Imaging, 2021, 12(10): 112-114, 124.本文引用格式:黄小兰, 彭婕. 钆塞酸二钠在结直肠癌肝转移瘤诊断及评估中的应用进展[J]. 磁共振成像, 2021, 12(10): 112-114, 124. DOI:10.12015/issn.1674-8034.2021.10.029.


[摘要] 钆塞酸二钠(gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid,Gd-EOB-DTPA)是肝脏局灶性病变的重要影像诊断工具,其对于早期结直肠癌肝转移瘤(colorectal liver metastasis,CRLM)的诊断及化疗后CRLM的评估均具有较高的敏感度和准确性,同时为CRLM治疗方案的调整及治疗后疗效评估提供重要参考,本文就Gd-EOB-DTPA增强MRI在CRLM诊疗过程中的应用进展进行综述。
[Abstract] Gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA) plays an important role in the diagnosis of colorectal liver metastasis (CRLM). It is highly accurate in the diagnosis of early CRLM and CRLM after chemotherapy, and provides a significant reference for the adjustment of CRLM treatment plan and the evaluation of curative effect after treatment. This paper describes the application progress of Gd-EOB-DTPA enhanced MRI in CRLM diagnosis and treatment.
[关键词] 钆塞酸二钠;结直肠癌;肝转移瘤;消失;磁共振成像
[Keywords] Gd-EOB-DTPA;colorectal cancer;liver metastases;disappear;magnetic resonance imaging

黄小兰    彭婕 *  

长江大学附属第一医院放射科,荆州 434000

彭婕,E-mail:pengjie-77@163.com

全部作者均声明无利益冲突。


收稿日期:2021-05-11
接受日期:2021-06-28
DOI: 10.12015/issn.1674-8034.2021.10.029
本文引用格式:黄小兰, 彭婕. 钆塞酸二钠在结直肠癌肝转移瘤诊断及评估中的应用进展[J]. 磁共振成像, 2021, 12(10): 112-114, 124. DOI:10.12015/issn.1674-8034.2021.10.029.

       肝脏是结直肠癌发生血行远处扩散的主要器官,约四分之一的结直肠癌患者在初次确诊时便合并有肝转移,称为同时性肝转移;另外,多达一半的患者在后续疾病发展过程中发生肝转移,即异时性肝转移[1]。绝大多数的结直肠癌肝转移瘤(colorectal liver metastasis,CRLM)是多发的,并且通常累及肝脏多个叶,只有10%左右的肝转移瘤是单发的[2],肝转移也是造成此类患者死亡的最主要因素。早期监测结直肠癌患者是否发生肝转移以及明确转移瘤准确数目、大小、分布部位及其与周围的正常肝组织毗邻关系,对于临床医生为患者制订最佳治疗方式以及提高患者生存率均具有重要临床意义。

       Gd-EOB-DTPA是在钆喷酸葡胺(gadolinium diethylenetriamine pentaacetic acid,Gd-DTPA)的基础上添加乙氧基苯甲基基团而成的[3],经静脉注射后迅速扩散至细胞外间隙,EOB基团的脂溶性使得约50%的药物由正常肝细胞膜上表达的有机阴离子转运多肽介导摄取,而后经由细胞膜上的多药抵抗相关蛋白(multidrug resistance protein 2,MRP2)介导排泄入胆管,经胆道清除,其余50%的Gd-EOB-DTPA则通过肾脏途径排出体外。双重排泄途径使得Gd-EOB-DTPA具有双重特性,一方面具有与Gd-DTPA相似的多期动态增强效果,但钆含量和使用剂量要明显低于普通细胞外钆对比剂;另一方面,在注射药物后约15~20 min,肝实质达到最大限度增强,胆系也因药物排入而显影,此时期称为肝胆特异期(hepatobiliary phase,HBP),可提供病变以及肝功能的更多信息。正常肝组织或含有正常摄取功能肝细胞的良性肝脏病变中,如局灶性结节增生、低级别异型增生结节[4],可在HBP摄取Gd-EOB-DTPA而表现为高信号,而CRLM等病变组织中由于缺乏正常肝细胞,对Gd-EOB-DTPA的摄取功能显著降低,HBP呈低信号,从而区分出病变部位,甚至可能发现常规序列未能发现的微小隐匿病灶(d<1.0 cm)[5],因此Gd-EOB-DTPA对肝脏病变的检出及鉴别诊断具有优势。

1 CRLM的诊断

       肝转移瘤多在肝外原发恶性肿瘤的基础上出现肝区疼痛、消瘦、腹水等临床症状,甲胎蛋白多为阴性。肝转移瘤既可为富血供亦可为少血供,而来自结直肠癌的CRLM多为少血供病变。CRLM典型影像表现为在常规增强MRI动态扫描后肝内单发或多发、边界清楚的瘤灶,病灶边缘不规则环形强化;有时病灶周围T2WI可见高信号环,即晕征(halo sign),可能与瘤灶周围肝组织水肿或血供丰富有关[6]。常规增强MRI典型信号特征及强化方式具有较高的特异性和阳性预测值,但对于不典型或早期CRLM的检出仍有待提高[7]

       Gd-EOB-DTPA增强MRI可通过三期动态增强扫描提供CRLM病灶的血供情况;同时,由于缺乏OATP,CRLM摄取Gd-EOB-DTPA的能力减低,在HBP呈低信号,而周围正常肝实质摄取Gd-EOB-DTPA呈高信号,与病灶之间形成鲜明对比,使其显示更为清晰,可大幅提升微小病变的检出率。Zech、Granata[8, 9]等学者的研究表明,常规增强MRI对CRLM的诊断敏感度优于增强CT,而Gd-EOB-DTPA增强MRI的敏感度最高,尤其是对于d<1.0 cm的病变,Gd-EOB-DTPA增强MRI的检出率更具优势。Choi[10]的荟萃分析研究发现,对于CRLM的诊断性能,Gd-EOB-DTPA增强MRI检测CRLM的敏感度(93.1%)要显著高于增强CT (81.2%)和PET/CT (74.1%)。

       不仅是病灶的大小,病灶的位置同样影响着病灶检出率,常规增强MRI对于肝脏包膜下区域或血管周围的CRLM检出具有一定的困难,而扩散加权成像(diffusion weighted imaging, DWI)能够提供较好对比度背景下病变组织的定性图像和定量参数信息[11],对肝脏微小病变的检出和定性方面较T2WI有明显优势[12]。Schulz[13]的研究对比了单独DWI、DWI结合T2WI、DWI结合CT、单独CT以及Gd-EOB-DTPA对CRLM术前评估的检出效能,结果显示Gd-EOB-DTPA检出CRLM的敏感度最高,DWI可作为Gd-EOB-DTPA增强MRI的重要补充,Vilgrain等[14]的研究结果亦表明,DWI与Gd-EOB-DTPA增强MRI的结合显示病变的敏感度最高,可提高对上述部位病变的检出能力。

       CRLM还可能侵犯胆管系统,胆道的侵犯与较高的肿瘤负荷有关,代表了疾病进程的更晚期[15],术前若遗漏胆管侵犯将增加CRLM不被完全清除的可能性,CRLM术后局部复发的几率将大大增加。在Okano[16]的研究中,达40%以上患者的CRLM发生胆道系统侵袭。HBP可以清楚地显示胆道系统,CRLM周围胆管扩张或胆管内充盈缺损可以提示胆管侵犯,对改进手术具体制订方案具有重要作用,可降低局部复发的风险[17]。Reijonen[18]通过回顾性分析发现,伴胆管侵犯的CRLM患者,其复发率(61.3%)要远高于不伴有胆管侵犯的CRLM患者(33.3%),胆道侵犯与较高的复发率和较短的无复发生存期相关,同时其总生存率亦相对缩短[19]

2 CRLM患者术前评估

       根治性手术切除是治疗CRLM的有效手段,可延长患者的五年生存率,术后CRLM患者中位生存期为35个月,而未经手术治疗的CRLM患者中位生存期仅为6.9个月[20, 21]。值得一提的是,术后发生肿瘤复发的情况在经过根治性手术切除的患者中并不少见,据研究报道,超过34%的CRLM患者在接受根治性切除术后6个月内发生肝内肿瘤复发[22],其重要原因之一是肿瘤切缘阳性,仍有肿瘤细胞残留,仅达到R1切除(R1:microscopic residual tumor),未达到R0切除[the Residual Tumor (R) Classification,R0:no residual tumor]。同时,亦有文献表明,肿瘤切缘距离是根治性切除手术预后的独立危险因素,切缘距离>1 cm者其术后五年生存率更高[23]。因此,术前评估是否符合根治性手术治疗条件,并明确CRLM局部浸润范围,保证切缘与CRLM的距离>1 cm,尽可能达到R0切除,才能降低复发可能性,切实提高患者的生存率。

       患者术前肝功能储备评估在临床实践中同样很重要,特别是肝部分切除术后残余肝功能储备情况的预估,对于手术风险评估和完善制订相应的手术计划至关重要,以最大限度地降低发生术后肝功能不全(post-hepatectomy insufficiency,PHI)的风险,尤其是在患者合并有肝脏基础疾病如肝硬化、肝纤维化的情况下[24]。同时,结直肠癌患者的肝转移瘤往往是多发的,累及肝脏多个叶[2],因此考虑进行CRLM根治性切除时更加需要全面评估患者肝脏储备功能,才能保证患者术后功能性残留肝体积≥30%[20]以降低术后发生PHI的概率。临床上有多种方法可用于评估肝功能储备,如广泛使用的吲哚菁绿15 min清除率(indoncyanine green retention rate at 15 min,ICG R15)、Child-Pugh评分和终末期肝病模型等[25, 26, 27]。但上述方法仅可对患者整体肝功能储备情况进行初步评价,并不能评价肝段的储备能力,且当中的Child-Pugh评分所包含的评价指标中,如腹水、肝性脑病的评分具有主观性[28],对不同评分者所作评分的一致性有一定影响。

       多层螺旋CT和常规MRI检查可用于评估肝段的体积,但只能反映肝脏形态学上的变化[29]。而Gd-EOB-DTPA增强MRI不仅能用于整体肝功能储备的评估,也可用于评价各肝段的肝功能储备;同时,还可以根据手术方案评估残余肝脏的储备功能,预测PHI的发生[30]。肝实质信号强度(signal intensity,SI)可反映患者的肝功能储备,SI与肝细胞摄取Gd-EOB-DTPA的量有关,具有正常肝功能的肝细胞越多,则Gd-EOB-DTPA摄取量越多,SI越高。当前已有较多关于Gd-EOB-DTPA增强MRI评估肝功能的研究,Gd-EOB-DTPA的实际摄取量可以通过静态评估肝脏HBP信号强度、T1弛豫时间,以及动态评估肝脏摄取分数[31, 32]。其中最简单易行、最常用的方法是测量HBP信号强度,但不足之处在于HBP信号强度影响因素较多,如设备、扫描参数、场强、检查时间等,同时SI与对比剂浓度之间并非线性关系[33],因此可重复性和准确性欠佳。而T1弛豫时间受场强和B1不均匀性的影响相对较少,能够提供肝细胞功能的定量信息,可重复性和准确性俱佳。Haimerl[34]和Yoon[35]等学者的研究发现,HBP T1弛豫时间减低率(reduction rate of T1 relaxation time,ΔT1%)联合残余肝体积(residual liver volume,RLV)对肝功能储备的评估能力优于所有单一成像评价参数,评估结果更加准确。Duan等[36]的研究亦表明,以ICG R15作为评判标准时,ΔT1%联合RLV可以更加准确地评价患者的肝脏储备能力,并推荐该方法作为术前肝功能储备评估的首选方法。

3 CRLM患者化疗后评估

       术前化疗可提高潜在可切除CRLM患者根治性手术切除的机会,不仅可以检测CRLM对化疗的敏感性,同时可达到治疗潜在微转移灶的目的,提高治愈率[37, 38];再者,部分最初不能切除的CRLM经过化疗后可转化为可切除状态。值得注意的是,经过有效化疗后,部分CRLM在影像学上可能不再是可视化的,即在影像上出现原有CRLM消失(disappearing colorectal liver metastases,DLM)[39, 40]。同步性肝转移、CRLM的数量越多(≥3个)、体积越小、术前化疗持续时间越长[41, 42]以及将奥沙利铂作为基础化疗均与DLM的发生密切相关 [39,41, 42]。但DLM不一定等同于治愈,即DLM达到放射学完全缓解(radiologic complete response,RCR)并不意味着能够同时达到病理学完全缓解(pathologic complete response,PCR)。据报道,高达83%的DLM切除后组织病理学上仍可发现存活的癌细胞,或者在不切除的情况下出现原位复发[43]

       DLM的判断取决于将DLM定义为“消失”的成像方式及其检测CRLM的敏感性和特异性。迄今为止,多种成像方式已用于检测CRLM,包括平扫/增强CT、平扫/增强MRI、PET和PET/CT等。CT成像是CRLM患者的一线检查方式,在以往的研究中,大多采用CT来对化疗后CRLM进行评估,因此DLM一般是指CT成像上观察不到的CRLM[44]。当术前化疗引起肝脏的实质性改变时,如脂肪变性、非酒精性脂肪性肝炎和肝窦阻塞综合征,这些实质性改变会降低肝脏与CRLM之间的对比度,从而影响CT检测CRLM的敏感性[45]。在Vujic[46]的研究中使用CT成像评价化疗治疗后CRLM,最终发现并进行根治性切除的DLM中,术后病理结果显示仅18%达到PCR,而多达82%仍有存活的转移癌细胞。

       Park等[45]的回顾性分析表明,CT成像上发现的DLM达到PCR的为35.2%,而Gd-EOB-DTPA增强MRI成像上的DLM则有78.0%达到PCR,对DLM达到真正治愈的阳性预测值Gd-EOB-DTPA MRI成像要远远高于增强CT成像。Tani等[42]对比了Gd-EOB-DTPA增强MRI成像与术中超声造影(CE-IOUS)对化疗后增强CT未发现的DLM的检出率。在该研究中,69.2%的DLM经病理证实为残留病变,33.3%的未切除DLM经后续随访诊断为含残留病变,与CE-IOUS (70%)相比,Gd-EOB-DTPA增强MRI (90%)对DLM残留病变的预测准确性更高。

       根治性切除联合系统治疗正在逐步成为CRLM治疗趋势,随之而来的DLM也愈来愈多,指南[20]建议对DLM应进行根治性手术切除,但术中并无法保证对所有DLM都能进行精准定位并切除,而广泛切除则会增加术后肝衰竭的几率,因此,如何避免出现DLM以及在出现DLM时对其进行有效评价是一个重要的新兴问题。当CRLM在CT成像上消失,并在Gd-EOB-DTPA增强MRI成像上仍然观察不到时,该病灶达到PCR的符合率最高可达85%[47]。Muaddi等[48]对几种影像学方法进行荟萃分析,检测各种影像方法对DLM达到PCR的阴性预测值(negative predictive value,NPV),结果显示,Gd-EOB-DTPA MRI的NPV(73%)远高于IOUS (54%)、CT (47%)以及PET (22%),PET的NPV最低。综上所述,Gd-EOB-DTPA MRI成像不仅在CRLM术前评估具有较好的诊断性能,其在识别DLM和病变残留预测方面同样具有可信度较高的评估价值。

4 小结

       作为肝胆疾病高特异性对比剂,Gd-EOB-DTPA近年来已广泛应用于临床工作中,Gd-EOB-DTPA增强MRI成像能够提高CRLM及早期微小CRLM (直径<1.0 cm)的检出,与其他MRI功能序列相结合更能充分发挥出其诊断及鉴别诊断能力;同时,Gd-EOB-DTPA增强MRI成像还可评估整体以及各肝段的肝功能储备,预测术后残余肝功能储备,不失为CRLM术前评估的最佳成像方式。对于化疗后CRLM,Gd-EOB-DTPA增强MRI成像同样具有良好的评估效果,评价更加客观、准确,对DLM的检测及病变残留预测具有一定潜能,有助于临床医生全面评估患者病情、制订最佳治疗方案。总之,Gd-EOB-DTPA增强MRI可提供更多CRLM解剖学及生物学相关信息,在CRLM的诊断及鉴别诊断、术前评估及治疗后评估方面均具有良好的应用价值;另外,利用Gd-EOB-DTPA增强MRI影像学表现来预测患者的远期预后目前已处于初步探索阶段,与新兴影像组学的融合更是使其应用前景愈加广阔。但Gd-EOB-DTPA增强MRI仍有它的不足之处,在CRLM诊疗过程中的应用缺乏系统、完整的理论体系,尤其是对化疗后CRLM的定量分析以及预后评估方面,值得更进一步的探索及完善。

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