肝细胞癌微血管侵犯的术前诊断与评估

蒋涵羽， 陈婕， 张晗媚， 刘曦娇， 黄子星， 宋彬

肝细胞癌(hepatocellular carcinoma，HCC)是世界范围内最常见的恶性肿瘤之一，其发病率在所有恶性肿瘤中位居全球第五，肿瘤相关死因更高居全球第三[1]。外科手术肝切除(liver resection,LR)和肝移植(liver transplantation,LT)是HCC根治性治疗的主要手段。然而，肿瘤高复发率严重影响了HCC患者的预后及远期疗效[2,3]。目前，肿瘤大小、数目、血管侵犯等被认为是影响HCC复发和总生存期(overall survival,OS)的主要危险因素[2, 4-10]。

HCC血管侵犯一般包括大血管侵犯(macrovascular invasion)和微血管侵犯(microvascular invasion,MVI)[5]。其中，大血管侵犯系指通过无创影像学检查或术后病理检查能够用肉眼辨识的血管侵犯，主要累及大到中等大小血管、二级或二级以上肝静脉或门静脉。MVI为仅在显微镜下可见的血管侵犯，主要累及如门静脉小分支、癌旁肝组织中央静脉、肿瘤包膜或纤维分隔中的小静脉等小分支血管，偶可侵犯肝动脉、胆管和淋巴管分支[11]。

与大血管侵犯不同，使用CT、MRI等常规的术前影像技术目前难以直接准确识别和评估MVI[1,12,13]。然而，HCC患者一旦发生大血管转移，则基本丧失了根治性治疗的可能。因此，早期识别MVI可以为HCC的诊断、分期和预后判断提供极为重要的信息；而针对MVI的及时处理也能显著延长HCC患者的术后生存期，降低患者复发和转移风险。同时，随着分子生物学、核医学以及功能MRI等的发展与进步，越来越多的研究发现，部分血清学和影像学征象可间接提示MVI的存在。本文总结了近年来HCC相关MVI的诊断与评估研究进展，并探讨了未来可能的发展方向。

MVI的病理生理学基础

新生血管生成是肿瘤发生的重要标志[14]。在HCC中，癌细胞可以产生组织蛋白酶H等蛋白酶降解细胞外基质[15]。其次，肿瘤组织中E-钙粘蛋白的过低表达降低了细胞间连接的稳固性[16-18]，其他黏附分子的异常高表达可能进一步促进了上皮组织向间叶组织的化生过程[19, 20]。此外，通过将自己包裹在内皮细胞内，癌细胞团块逃避了机体正常的免疫应答和凝血活化，从而使其能顺利通过血流进行播散[21]。HCC的新生血管生成和肿瘤转移正是上述过程的共同结果。在HCC中，MVI可累及门静脉分支，引起相应的肝内复发[22]；或累及肝静脉分支，导致相应的远处转移[23]。

MVI的病理学评估

在病理学中，MVI定义为影像学或标本解剖均未发现肉眼可见的血管内癌栓，仅显微镜下于内皮下查见部分或全部被覆内皮细胞的癌细胞栓子或息肉，或于管腔中查见自由漂浮的、部分或全部被覆内皮细胞的癌细胞栓子，需除外无内皮细胞包裹、自由漂浮的小簇肿瘤细胞团；累及血管可包括门静脉分支、肝静脉分支、肿瘤内部血管、癌旁血管及肿瘤包膜血管，偶可见动脉及淋巴管累及[6,24-29]。多项研究发现，HCC的肿瘤分化程度越低，MVI发生的可能性越大[30-32]。MVI与HCC的大体形态密切相关，根据Kanai等[33]提出的HCC形态学分类标准，单结节结外生长型和连续多结节型HCC的MVI发生率显著高于单结节型，是MVI的独立预测因素[34-37]。

然而，术前HCC组织活检取样难度大、出血及肿瘤播散风险高、肿瘤异质性导致针吸活检难以避免取样误差等困境，目前MVI的临床应用主要局限于术后的组织病理学评估[38]。因此，进一步提高MVI术前活检取样准确度、建立完善而标准的诊断及分级标准、探索新的免疫组织化学染色方式、明确术后组织病理学检查所需的标本数量及大小等，对于MVI的术前识别、提高MVI诊断的准确度具有重要意义。

MVI血清学评估

MVI是HCC患者预后不良的重要危险因素，与多种物质的血清水平密切相关。维生素K 缺乏或拮抗剂Ⅱ诱导的蛋白质(protein induced by vitamin K absence/antagonism Ⅱ,PIVKA-Ⅱ)，也称脱-γ-羧基凝血酶原( Des-γ-carboxy-prothrombin，DCP)，是一种高特异性的HCC相关血清标志物，其γ-羧基谷氨酸结构中1 个或多个谷氨酸残基不完全羧化为γ-羧基谷氨酸，导致其失去正常凝血功能[39-41]。相关研究发现，血清PIVKA-Ⅱ的异常增高可用于预测MVI的发生，但对于PIVKA-Ⅱ血清水平的最佳临界值，目前仍有较多争议[37,42-44]。Poté等[42]及Kaibori[43]等提出，血清PIVKA-Ⅱ≥200 mAU/ml是MVI的独立预测因素；而其他研究则认为，血清PIVKA-Ⅱ>100 mAU/mL是预测MVI的最佳界值[37,44]。

甲胎蛋白(Alpha fetoprotein,AFP)是目前诊断和评估HCC最重要的血清标志物，但对于AFP在术前预测MVI的能力，目前仍有较多争议。Zhao等[45]发现，血清AFP水平高于400 ug/L是MVI的独立预测因素(OR= 3.732,P=0.016)。然而，其他相关研究却发现，AFP与MVI的发生无明显关联，而PIVKA-Ⅱ是预测MVI更好的血清标志物[42,43]。此外，Zhao[45]等也发现，血清谷氨酰转肽酶(gammaglutamyltransferase,GGT)水平的异常升高也可以用于预测MVI。然而，尽管使用血清标志物于术前预测MVI具有操作简便、快捷、经济等优点，但目前仍需更多大样本、多中心的高质量研究来证实和进一步评估上述血清学标志物在预测MVI中的作用。

MVI的影像学评估

目前，HCC术前常规的影像学检查手段难以直接显示MVI，但CT、MRI、正电子发射断层显像-计算机断层显像(positron emission tomography-computed tomography,PET-CT)等无创影像检查手段的部分征象可以为术前预测MVI提供有力的间接证据。

HCC的肿瘤边缘是肿瘤组织与周围正常肝组织的分界面，其形态特征与肿瘤血管生成密切相关。多项研究发现，CT或MRI图像中HCC肿瘤边缘不清与MVI的发生密切相关[5,8,9]。Chou等[9]发现，CT显示肿瘤边缘不清是MVI发生的独立预测因素(OR=28.828，95%CI：7.718～107.680,P<0.001)。上述研究结果表明，对于影像学检查表现出肿瘤边缘不清的HCC患者，应该考虑使用如大范围手术切除、辅助化疗等更积极的治疗措施。

HCC的肿瘤大小可影响MVI的发生[46-48]。Kim等[49]发现，MRI显示MVI阳性的HCC患者的肿瘤直径[(4.09±2.43 ) cm]显著大于MVI阴性的HCC患者[(3.00±1.58) cm，P=0.030)。Chou等[8]也发现，CT显示MVI阳性的HCC患者肿瘤直径[(4.6±2.6) cm]显著大于MVI阴性的患者[(3.6±2.1) cm，P=0.036]。Ahn等[50]回顾性纳入了51例HCC患者，发现肿瘤直径>5 cm与MVI的发生密切相关 (OR=12.091,P=0.001)。Eguchi等[7]也在其连续纳入了229例接受了根治性LR的HCC患者的回顾性研究中发现，肿瘤直径>5 cm是MVI的高危因素(OR=1.678，P<0.01)。

HCC癌组织周围强化是MVI的又一重要预测因素[5,49,51,52]。Renzulli等[5]回顾性纳入了125例HCC患者，由两位放射科医生根据患者的术前CT和MRI图像独立评估MVI发生情况，基于两位阅片者，癌周组织强化分别出现在58.9%和65.6%的MVI阳性的HCC患者中，而仅出现在10.0%和14.0%的MVI阴性的患者中(P<0.001)。对此可能的解释是，当HCC累及区域的门静脉分支被癌栓阻塞后，上述门静脉分支供给区域的门静脉血流灌注减少，这种血流动力学变化会引起相应区域的代偿性动脉灌注增加，在影像学上就表现为癌组织周围强化[53]。

HCC的纤维包膜主要由厚层的胶原纤维和薄层的血管结构组成，其完整程度也能反映肿瘤的微血管侵犯情况。Lim[54]等发现，CT显示包膜完整的HCC患者肿瘤周围肝实质发生门静脉分支或肝静脉MVI的概率明显小于包膜不完整的HCC患者(P<0.001)。然而，也有研究表明，MVI的存在与否与HCC肿瘤包膜的完整程度无关[4,8]，这可能与实验设计、纳入患者人群、扫描方案等因素的差异有关，但仍需进一步研究证实肿瘤包膜完整程度与MVI的关系。

此外，灌注CT、核医学、放射组学以及功能MR等的快速发展也为更好地预测和评估MVI提供了重要帮助。Wu[55]等发现，使用灌注CT评估HCC患者的肿瘤门静脉血流(PVFtumor)、肿瘤与肝组织门静脉血流差值(ΔPVF)以及ΔPVF与肝组织门静脉血流比(rPVF)，可以定量预测MVI的发生。Segal等[10]用放射组学的方法，发现肿瘤内部动脉、低密度环与MVI的发生有关，上述研究得到了Renzulli等[5]的证实。Banerjee[56]等发现，使用由肿瘤内部动脉、低密度环和肝组织-肿瘤差异这三个独立的影像学特征组成的影像基因相关的静脉侵犯(Radiogenomic venous invasion, RVI)这一放射组学标志，能够很好地预测HCC患者MVI发生(准确度89%，敏感度76%，特异度94%)、肿瘤复发以及整体预后。此外，多项研究表明，使用PET-CT评估HCC，肿瘤氟代脱氧葡萄糖(18F-fluorodeoxyglucose,18F-FDG)高摄取能够有效预测MVI的发生[50,57,58]。

钆塞酸二钠(gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid,Gd-EOB-DTPA)是一种肝细胞特异性MRI对比剂，能够特异性显示肝细胞功能和组织微血管的形成情况。相关研究发现，HCC患者肝胆期癌周Gd-EOB-DTPA摄取降低[59,60]和肿瘤边缘不清[49,61]与MVI的发生密切相关。此外，使用肝脏网状内皮系统特异性对比剂超顺磁性氧化铁(superparamagnetic iron oxid,SPIO)的增强MRI也能用于预测MVI[51]。不仅如此，磁共振扩散加权成像(diffusion weighted imaging,DWI)中HCC的表观扩散系数(apparent diffusion coefficient,ADC)值降低也与MVI的发生有关[62]。

目前的影像学检查手段虽难以在术前直接显示HCC肿瘤微血管的侵犯情况，但HCC肿瘤大小、数目、形态，肿瘤边缘不清与否，肿瘤包膜是否完整，癌组织周围强化情况，肿瘤内部是否存在动脉和低密度空洞等影像学征象可以为MVI的术前评估提供重要信息。

HCC是全球范围内最常见的恶性肿瘤之一，具有病死率高、易复发转移的特点[63]。目前，外科综合治疗是HCC最有效的根治性治疗手段。MVI是HCC患者术后复发的主要危险因素之一，其早期识别和评估对HCC的准确诊断、分期、治疗以及预后判断意义重大。MVI的诊断主要依赖于术后组织病理学检查，但近期的研究进展表明血清AFP、PIVKA-Ⅱ水平以及肿瘤边缘、大小、癌周组织强化、包膜完整程度等影像学征象可以为MVI的术前预测提供重要帮助。然而，目前仍需更多多中心、大样本的高质量研究来进一步验证上述指标或影像学征象在MVI的术前预测与评估中的作用。同时，建立涵盖多项MVI预测因素的综合评估系统能克服依靠单一因素进行评估的不足，提供更为全面、准确、可靠的MVI临床预测与诊断信息。

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