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Article Navigation >  Journal of Clinical Hepatology  > 2018  >  34(7): 1492-1496

Specific magnetic resonance imaging of vascular endothelial growth factor-C targeted molecular probe and its clinical significance in a rat model of hepatocellular carcinoma

DOI: 10.3969/j.issn.1001-5256.2018.07.025

  • Department of Radiology, The Second Affiliated Hospital of Xi'an Medical College

Research funding:

 

  • Received Date: 2018-01-25
  • Published Date: 2018-07-20
    Abstract
  • Objective To investigate the magnetic resonance ( MR) imaging features of the targeted molecular probe with vascular endothelial growth factor-C ( VEGF-C) antibody and superparamagnetic iron oxide ( USPIO) , VEGF-C-USPIO, in a rat model of hepatocellular carcinoma ( HCC) and its clinical significance. Methods The induction method was used to establish a rat model of in situ HCC, and30 Sprague-Dawley rats were randomly divided into experimental group with 20 rats and control group with 10 rats. The rats in the experimental group were treated with tail vein injection of the targeted molecular probe VEGF-C-USPIO, and those in the control group were treated with tail vein injection of the non-targeted probe USPIO. MR scanning was performed before injection and at 1 hour after injection;the intensity of T2 WI signal in liver tumor and adjacent liver tissue was measured; contrast-to-noise ratio ( CNR) was calculated, and the two groups were compared in terms of CNR before and after enhancement. Liver tissue was collected after scanning, and HE staining was performed to clarify the pathological type of liver cancer in rats; Prussian blue staining was performed to analyze the content of iron in tumor cells; immunohistochemical staining was performed to investigate the expression of VEGF-C in liver cancer tissue. The independent samples t-test was used for comparison between the experimental group and the control group, and the paired samples t-test was used for comparison within each group after the injection of contrast agent. Results Cancer was successfully induced in all 30 rats; the pathological diagnosis was HCC, and the tumor formation rate was 100%. The experimental group had a significant change in CNR at 1 hour after the injection of the targeted contrast agent VEGF-C-USPIO ( 2. 11 ± 0. 23 vs 3. 47 ± 0. 45, t =-13. 15, P < 0. 001) , while the control group had no significant change in CNR at 1 hour after the injection of the non-targeted contrast agent USPIO ( 3. 51 ± 0. 14 vs 3. 82 ± 0. 61, t =-1. 40, P = 0. 192) ; there was a significant difference in CNR between the two groups after injection ( t = 17. 60, P < 0. 001) . HE staining performed for liver tissue samples showed a pathological type of HCC; immunohistochemical staining showed that VEGF-C was mainly expressed in the membrane and cytoplasm of hepatoma cells; Prussian blue staining showed that compared with the control group, the experimental group had a significant increase in iron particles in tumor tissue. Conclusion The synthesized targeted molecular probe VEGF-C-USPIO has a good active targeting effect on a rat model of HCC and can realize the specific imaging of HCC through the change in MR signal intensity. Therefore, it provides an imaging basis for the early diagnosis of HCC.

     

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  • 自身免疫性胰腺炎(autoimmune pancreatitis, AIP)是由自身免疫异常引起的一种特殊类型的胰腺炎[1]，根据影像学表现，将其分为弥漫性AIP和肿块型AIP，弥漫性AIP表现为胰腺整体弥漫性肿大，而肿块型AIP则表现为胰腺内异常局灶性肿块[2]，在常规影像学上与胰腺导管腺癌(pancreatic ductal adenocarcinoma, PDAC)鉴别非常困难，在常规超声检查上亦是如此，而这两种疾病的治疗方式及预后截然不同[3-4]，因此，准确鉴别诊断肿块型AIP可避免不必要的手术，使患者得到及时、准确的治疗，本研究回顾性分析了经病理证实的11例肿块型AIP的超声造影表现特点，旨在探讨超声造影对肿块型AIP的诊断价值及与PDAC鉴别的要点。

    1.   资料与方法

    1.1   研究对象

    收集了2015年1月—2020年12月本院11例经病理证实的肿块型AIP患者的临床资料及病灶的常规超声、超声造影图像资料，其中男9例，女2例，年龄29~83岁，平均(56.2±9.2)岁，7例为穿刺活检、4例为手术切除病理证实。同时收集了23例经手术病理证实的PDAC患者的临床资料、常规超声及超声造影资料，其中男14例，女9例，年龄39~78岁，平均(61.3±8.5)岁。纳入标准：患者均做过常规超声及超声造影检查，并具有明确的病理结果; 排除标准：只进行了常规超声检查未做超声造影检查者，或未取得最终病理结果者。

    1.2   仪器与方法

    所有患者均行常规超声及超声造影检查，使用Philips iu22、GE Logiq E9、Siemens Helex OXANA超声诊断仪，采用常规腹部探头，探头频率为1~5 MHZ。患者检查前需空腹8 h以上，患者取仰卧位并深吸气后缓慢呼气，脐上横向扫查，通过下移的肝脏左叶扫查胰腺，观察病灶的位置、大小、形态、边界、回声、有无液化、胰管是否扩张及血供等情况，如果有肠道气体干扰显示不清，则采用坐位法或饮水法。然后切换至超声造影模式，超声造影剂使用Sonovue，5 mL生理盐水稀释，充分振荡，使其溶解均匀，经肘正中静脉快速团注1.5~2 mL，随后以5 mL生理盐水快速冲洗套管针，在注入造影剂瞬间开始计时，不间断观察病灶灌注过程，存储并记录2 min内病灶的动态增强-消退过程。

    1.3   图像分析

    将胰腺造影时相分为动脉期(注入造影剂开始后10~30 s为动脉期)，静脉期(注入造影剂开始后30~120 s为静脉期)，与正常胰腺实质增强程度相比，将病灶增强程度分为高增强(病灶强化程度高于周边正常胰腺实质)，等增强(病灶强化程度与周边正常胰腺实质一致)和低增强(病灶强化程度低于周边正常胰腺实质)，由2位有经验的副主任医师以上职称的超声医师(超声诊断工作时间均超过10年)对图像进行综合分析判断。

    1.4   统计学方法

    使用SPSS 20.0统计软件分析数据，计数资料两组间比较采用χ2检验。P＜0.05为差异有统计学意义。

    2.   结果

    2.1   常规超声表现

    11例肿块型AIP均为单发病灶，其中9例(81.82%)位于胰头，2例(18.18%)位于胰体，病灶最大径2.1~6.2 cm，常规超声均表现为低回声，6例(54.55%)边界较清，7例(63.64%)形态较规则，11例(100%)均无液化，2例(18.18%)存在胰管扩张，彩色多普勒显示，其中4例(36.36%)肿块内伴有点状血流信号，7例(63.64%)无明显血流信号(图 1、2)。

    图  1  肿块型AIP二维超声图像
    注：胰头部低回声肿块(粗箭头)，胰体部为正常胰腺组织(细箭头)。
    Figure  1.  Two-dimensional ultrasonic imaging of focal autoimmune pancreatitis
    下载: 全尺寸图片 幻灯片
    图  2  肿块型AIP彩色多普勒超声图像
    注：箭头示胰头部肿块内可见少许点条状血流信号。
    Figure  2.  Color doppler flow imaging of focal autoimmune pancreatitis
    下载: 全尺寸图片 幻灯片

    23例PDAC中，病灶均为单发，其中17例(73.91%)位于胰头，2例(8.70%)位于胰体，4例(17.39%)位于胰尾，肿瘤最大径1.9~5.7 cm，病灶均呈低回声，16例(69.57%)边界不清，15例(65.22%)形态不规则，4例(17.39%)伴有液化，18例(78.26%)伴有胰管扩张或截断，彩色多普勒显示，5例(21.74%)可见点状血流信号，18例(78.26%)肿块内无明显血流信号。

    肿块型AIP与PDCA常规超声表现资料比较发现，两者在是否伴有胰管扩张或截断方面存在统计学差异(P＜0.05)，其他如病灶部位、边界、形态、是否伴有液化、有无血流信号等方面均无统计学差异(P值均＞0.05)(表 1)。

    表  1  肿块型AIP与PDCA常规超声表现比较
    Table  1.  Ultrasonographic characteristics between focal autoimmune pancreatitis and pancreatic ductal adenocarcinoma
    超声表现 肿块型AIP
    (n=11)    		 PDCA
    (n=23)    		 χ2值 P值
    病灶部位[例(%)] 2.543 0.280
    胰头 9(81.82) 17(73.91)
    胰体 2(18.18) 2(8.70)
    胰尾 0 4(17.39)
    病灶边界[例(%)] 1.832 0.176
    清晰 6(54.55) 7(30.43)
    不清晰 5(45.45) 16(69.57)
    病灶形态[例(%)] 2.531 0.113
    规则 7(63.64) 8(34.78)
    不规则 4(36.36) 15(65.22)
    是否伴有液化[例(%)] 2.168 0.141
    是 0 4(17.39)
    否 11(100) 19(82.61)
    胰管扩张或截断[例(%)] 11.089 0.001
    是 2(18.18) 18(78.26)
    否 9(81.82) 5(21.74)
    血流信号[例(%)] 0.818 0.366
    伴有 4(36.36) 5(21.74)
    不伴有 7(63.64) 18(78.26)
    下载: 导出CSV 
    | 显示表格

    2.2   超声造影表现

    在11例肿块型AIP中有7例(63.64%) 病灶在动脉期呈高增强，4例(36.36%)病灶呈等增强; 在静脉期，5例(45.45%)病灶呈高增强，6例(54.55%) 病灶呈等增强。通过超声造影诊断出其中的7例，诊断准确性为63.64%(7/11)(图 3、4)。在23例PDAC中，22例(95.65%)病灶在动脉期及静脉期均表现为低增强，1例(4.35%)病灶动脉期及静脉期表现为等增强(图 5、6)。肿块型AIP与PDCA的超声造影表现比较，动脉期、静脉期的增强方式均存在统计学差异(P值均＜0.001)(表 2)。

    图  3  肿块型AIP超声造影动脉期图像(24 s)
    注：a，超声造影显示胰头部肿块型AIP动脉期呈高增强(粗箭头)与胰体部正常胰腺组织(细箭头); b，常规超声显示胰头部低回声肿块型AIP(粗箭头)与胰体部正常胰腺组织(细箭头)。
    Figure  3.  Contrast-enhanced ultrasonography imaging of focal autoimmune pancreatitis in arterial phase (24 s)
    下载: 全尺寸图片 幻灯片
    图  4  肿块型AIP超声造影静脉期图像(38 s)
    注：a，超声造影显示胰头部肿块型AIP静脉期呈高增强(粗箭头)与胰体部正常胰腺组织(细箭头); b，常规超声显示胰头部低回声肿块型AIP(粗箭头)与胰体部正常胰腺组织(细箭头)。
    Figure  4.  Contrast-enhanced ultrasonography imaging of focal autoimmune pancreatitis in venous phase (38 s)
    下载: 全尺寸图片 幻灯片
    图  5  PDAC超声造影动脉期图像(16 s)
    注：a，常规超声显示胰头部低回声PDCA(箭头); b，超声造影显示胰头部PDCA动脉期呈低增强表现(箭头)。
    Figure  5.  Contrast-enhanced ultrasonography imaging of pancreatic ductal denocarcinoma in arterial phase (16 s)
    下载: 全尺寸图片 幻灯片
    图  6  PDAC超声造影静脉期图像(57 s)
    注：a，常规超声显示胰头部低回声PDCA(箭头); b，超声造影显示胰头部PDCA静脉期呈低增强表现(箭头)。
    Figure  6.  Contrast-enhanced ultrasonography imaging of pancreatic ductal denocarcinoma in venous phase (57 s)
    下载: 全尺寸图片 幻灯片
    表  2  肿块型AIP与PDCA超声造影表现
    Table  2.  Contrast-enhanced ultrasonography between focal autoimmune pancreatitis and pancreatic ductal adenocarcinoma
    期别 肿块型AIP(n=11) PDAC(n=23) χ2值 P值
    高增强 等增强 低增强 高增强 等增强 低增强
    动脉期(例) 7 4 0 0 1 22 30.345 ＜0.001
    静脉期(例) 5 6 0 0 1 22 30.084 ＜0.001
    下载: 导出CSV 
    | 显示表格

    3.   讨论

    AIP在临床上较为罕见，且临床表现不典型，患者一般无特殊临床症状，或仅有轻度上腹部疼痛[5-6]，实验室检查可伴有IGg4，血清γ球蛋白升高[7-8]。

    根据病变程度，AIP又分为肿块型AIP和弥漫型AIP[9]，以后者多见，前者罕见。肿块型AIP病灶多位于胰腺头部，本组11例肿块型AIP中9例位于胰头，占81.82%，与文献报道相符，在常规二维超声表现为低回声，边界清或不清，形态多较规则，液化少见，较少存在胰管扩张，伴或不伴血流信号，但这些常规超声表现与PDAC的超声特征相似[10-12]。本研究也发现在常规超声表现方面，只有在是否伴有胰管扩张或截断方面两者存在统计学差异，其余在病灶部位、边界、形态、是否伴有液化、有无血流信号等方面均无差异，所以单独应用常规超声对肿块型AIP及PDAC鉴别诊断存在一定困难。

    目前胰腺病变的临床上常用的影像学检查主要有超声检查、CT、MRI、PET/CT等，但CT检查存在射线，MRI检查不仅操作复杂并要求患者体内无金属等，PET/CT检查不仅存在放射性且价格昂贵，因此上述检查均无法实时动态观察病灶，超声造影检查在胰腺病变的诊断中显得越来越重要，临床应用也越来越广泛。随着超声造影技术的飞速发展，大大提高了超声的诊断能力[13]，超声造影剂能较好的渗入到肿瘤内毛细血管网，不进入组织间隙，并且可以始终位于血管内，能清晰地显示肿块内的微血管，较好的评估肿块内的血供情况，帮助分析和鉴别肿块的性质。

    研究[14-16]表明，PDAC在超声造影的整个时期始终表现为低增强，因为肿瘤内微血管少于正常胰腺组织，这可能与肿瘤内血管被肿瘤细胞侵犯破坏，形成血栓，动静脉短路等有关，以致造影剂不能很好的进入肿瘤内部，并且早廓清，使肿瘤始终呈低增强，大多数肿块型AIP在超声造影上表现为动脉期高增强或等增强，在静脉期无明显消退，仍表现为高增强或等增强，可能是因为肿块型胰腺炎的病灶病理改变主要是炎性淋巴细胞的浸润，间质纤维化，纤维组织增生，病灶内的微血管无明显破坏和增生，属于正常组织的血管，其分布特点与数量和正常胰腺大致相同，故病灶的超声造影表现与正常胰腺组织无明显差异。本组11例肿块型AIP患者中7例(63.64%)动脉期呈高增强，4例(36.36%)呈等增强，在静脉期，5例(45.45%)呈高增强，6例(54.55%)呈等增强，而23例PDCA患者中只有1例病灶在动脉期、静脉期表现为等增强，其余22例在动脉期及静脉期均表现为低增强，与以往研究结论一致，超声造影强化方式存在差异，从而能较好的鉴别肿块型AIP与PDCA。

    综上所述，超声造影可以在检查过程中动态观察病灶情况、进行实时显像，又具有高分辨率等优势，在肿块型AIP的诊断及与PDCA鉴别诊断方面能够提供病灶的血供信息，比常规超声要更加准确和客观，具有较高的临床价值及应用前景。

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    The first journal specializing in hepatobiliary and pancreatic diseases in China

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