肝細(xì)胞癌微血管侵犯的術(shù)前診斷與評(píng)估

蔣涵羽， 陳婕， 張晗媚， 劉曦嬌， 黃子星， 宋彬

肝細(xì)胞癌(hepatocellular carcinoma，HCC)是世界范圍內(nèi)最常見(jiàn)的惡性腫瘤之一，其發(fā)病率在所有惡性腫瘤中位居全球第五，腫瘤相關(guān)死因更高居全球第三[1]。外科手術(shù)肝切除(liver resection,LR)和肝移植(liver transplantation,LT)是HCC根治性治療的主要手段。然而，腫瘤高復(fù)發(fā)率嚴(yán)重影響了HCC患者的預(yù)后及遠(yuǎn)期療效[2,3]。目前，腫瘤大小、數(shù)目、血管侵犯等被認(rèn)為是影響HCC復(fù)發(fā)和總生存期(overall survival,OS)的主要危險(xiǎn)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，大血管侵犯系指通過(guò)無(wú)創(chuàng)影像學(xué)檢查或術(shù)后病理檢查能夠用肉眼辨識(shí)的血管侵犯，主要累及大到中等大小血管、二級(jí)或二級(jí)以上肝靜脈或門靜脈。MVI為僅在顯微鏡下可見(jiàn)的血管侵犯，主要累及如門靜脈小分支、癌旁肝組織中央靜脈、腫瘤包膜或纖維分隔中的小靜脈等小分支血管，偶可侵犯肝動(dòng)脈、膽管和淋巴管分支[11]。

與大血管侵犯不同，使用CT、MRI等常規(guī)的術(shù)前影像技術(shù)目前難以直接準(zhǔn)確識(shí)別和評(píng)估MVI[1,12,13]。然而，HCC患者一旦發(fā)生大血管轉(zhuǎn)移，則基本喪失了根治性治療的可能。因此，早期識(shí)別MVI可以為HCC的診斷、分期和預(yù)后判斷提供極為重要的信息；而針對(duì)MVI的及時(shí)處理也能顯著延長(zhǎng)HCC患者的術(shù)后生存期，降低患者復(fù)發(fā)和轉(zhuǎn)移風(fēng)險(xiǎn)。同時(shí)，隨著分子生物學(xué)、核醫(yī)學(xué)以及功能MRI等的發(fā)展與進(jìn)步，越來(lái)越多的研究發(fā)現(xiàn)，部分血清學(xué)和影像學(xué)征象可間接提示MVI的存在。本文總結(jié)了近年來(lái)HCC相關(guān)MVI的診斷與評(píng)估研究進(jìn)展，并探討了未來(lái)可能的發(fā)展方向。

MVI的病理生理學(xué)基礎(chǔ)

新生血管生成是腫瘤發(fā)生的重要標(biāo)志[14]。在HCC中，癌細(xì)胞可以產(chǎn)生組織蛋白酶H等蛋白酶降解細(xì)胞外基質(zhì)[15]。其次，腫瘤組織中E-鈣粘蛋白的過(guò)低表達(dá)降低了細(xì)胞間連接的穩(wěn)固性[16-18]，其他黏附分子的異常高表達(dá)可能進(jìn)一步促進(jìn)了上皮組織向間葉組織的化生過(guò)程[19, 20]。此外，通過(guò)將自己包裹在內(nèi)皮細(xì)胞內(nèi)，癌細(xì)胞團(tuán)塊逃避了機(jī)體正常的免疫應(yīng)答和凝血活化，從而使其能順利通過(guò)血流進(jìn)行播散[21]。HCC的新生血管生成和腫瘤轉(zhuǎn)移正是上述過(guò)程的共同結(jié)果。在HCC中，MVI可累及門靜脈分支，引起相應(yīng)的肝內(nèi)復(fù)發(fā)[22]；或累及肝靜脈分支，導(dǎo)致相應(yīng)的遠(yuǎn)處轉(zhuǎn)移[23]。

MVI的病理學(xué)評(píng)估

在病理學(xué)中，MVI定義為影像學(xué)或標(biāo)本解剖均未發(fā)現(xiàn)肉眼可見(jiàn)的血管內(nèi)癌栓，僅顯微鏡下于內(nèi)皮下查見(jiàn)部分或全部被覆內(nèi)皮細(xì)胞的癌細(xì)胞栓子或息肉，或于管腔中查見(jiàn)自由漂浮的、部分或全部被覆內(nèi)皮細(xì)胞的癌細(xì)胞栓子，需除外無(wú)內(nèi)皮細(xì)胞包裹、自由漂浮的小簇腫瘤細(xì)胞團(tuán)；累及血管可包括門靜脈分支、肝靜脈分支、腫瘤內(nèi)部血管、癌旁血管及腫瘤包膜血管，偶可見(jiàn)動(dòng)脈及淋巴管累及[6,24-29]。多項(xiàng)研究發(fā)現(xiàn)，HCC的腫瘤分化程度越低，MVI發(fā)生的可能性越大[30-32]。MVI與HCC的大體形態(tài)密切相關(guān)，根據(jù)Kanai等[33]提出的HCC形態(tài)學(xué)分類標(biāo)準(zhǔn)，單結(jié)節(jié)結(jié)外生長(zhǎng)型和連續(xù)多結(jié)節(jié)型HCC的MVI發(fā)生率顯著高于單結(jié)節(jié)型，是MVI的獨(dú)立預(yù)測(cè)因素[34-37]。

然而，術(shù)前HCC組織活檢取樣難度大、出血及腫瘤播散風(fēng)險(xiǎn)高、腫瘤異質(zhì)性導(dǎo)致針吸活檢難以避免取樣誤差等困境，目前MVI的臨床應(yīng)用主要局限于術(shù)后的組織病理學(xué)評(píng)估[38]。因此，進(jìn)一步提高M(jìn)VI術(shù)前活檢取樣準(zhǔn)確度、建立完善而標(biāo)準(zhǔn)的診斷及分級(jí)標(biāo)準(zhǔn)、探索新的免疫組織化學(xué)染色方式、明確術(shù)后組織病理學(xué)檢查所需的標(biāo)本數(shù)量及大小等，對(duì)于MVI的術(shù)前識(shí)別、提高M(jìn)VI診斷的準(zhǔn)確度具有重要意義。

MVI血清學(xué)評(píng)估

MVI是HCC患者預(yù)后不良的重要危險(xiǎn)因素，與多種物質(zhì)的血清水平密切相關(guān)。維生素K 缺乏或拮抗劑Ⅱ誘導(dǎo)的蛋白質(zhì)(protein induced by vitamin K absence/antagonism Ⅱ,PIVKA-Ⅱ)，也稱脫-γ-羧基凝血酶原( Des-γ-carboxy-prothrombin，DCP)，是一種高特異性的HCC相關(guān)血清標(biāo)志物，其γ-羧基谷氨酸結(jié)構(gòu)中1 個(gè)或多個(gè)谷氨酸殘基不完全羧化為γ-羧基谷氨酸，導(dǎo)致其失去正常凝血功能[39-41]。相關(guān)研究發(fā)現(xiàn)，血清PIVKA-Ⅱ的異常增高可用于預(yù)測(cè)MVI的發(fā)生，但對(duì)于PIVKA-Ⅱ血清水平的最佳臨界值，目前仍有較多爭(zhēng)議[37,42-44]。Poté等[42]及Kaibori[43]等提出，血清PIVKA-Ⅱ≥200 mAU/ml是MVI的獨(dú)立預(yù)測(cè)因素；而其他研究則認(rèn)為，血清PIVKA-Ⅱ>100 mAU/mL是預(yù)測(cè)MVI的最佳界值[37,44]。

甲胎蛋白(Alpha fetoprotein,AFP)是目前診斷和評(píng)估HCC最重要的血清標(biāo)志物，但對(duì)于AFP在術(shù)前預(yù)測(cè)MVI的能力，目前仍有較多爭(zhēng)議。Zhao等[45]發(fā)現(xiàn)，血清AFP水平高于400 ug/L是MVI的獨(dú)立預(yù)測(cè)因素(OR= 3.732,P=0.016)。然而，其他相關(guān)研究卻發(fā)現(xiàn)，AFP與MVI的發(fā)生無(wú)明顯關(guān)聯(lián)，而PIVKA-Ⅱ是預(yù)測(cè)MVI更好的血清標(biāo)志物[42,43]。此外，Zhao[45]等也發(fā)現(xiàn)，血清谷氨酰轉(zhuǎn)肽酶(gammaglutamyltransferase,GGT)水平的異常升高也可以用于預(yù)測(cè)MVI。然而，盡管使用血清標(biāo)志物于術(shù)前預(yù)測(cè)MVI具有操作簡(jiǎn)便、快捷、經(jīng)濟(jì)等優(yōu)點(diǎn)，但目前仍需更多大樣本、多中心的高質(zhì)量研究來(lái)證實(shí)和進(jìn)一步評(píng)估上述血清學(xué)標(biāo)志物在預(yù)測(cè)MVI中的作用。

MVI的影像學(xué)評(píng)估

目前，HCC術(shù)前常規(guī)的影像學(xué)檢查手段難以直接顯示MVI，但CT、MRI、正電子發(fā)射斷層顯像-計(jì)算機(jī)斷層顯像(positron emission tomography-computed tomography,PET-CT)等無(wú)創(chuàng)影像檢查手段的部分征象可以為術(shù)前預(yù)測(cè)MVI提供有力的間接證據(jù)。

HCC的腫瘤邊緣是腫瘤組織與周圍正常肝組織的分界面，其形態(tài)特征與腫瘤血管生成密切相關(guān)。多項(xiàng)研究發(fā)現(xiàn)，CT或MRI圖像中HCC腫瘤邊緣不清與MVI的發(fā)生密切相關(guān)[5,8,9]。Chou等[9]發(fā)現(xiàn)，CT顯示腫瘤邊緣不清是MVI發(fā)生的獨(dú)立預(yù)測(cè)因素(OR=28.828，95%CI：7.718～107.680,P<0.001)。上述研究結(jié)果表明，對(duì)于影像學(xué)檢查表現(xiàn)出腫瘤邊緣不清的HCC患者，應(yīng)該考慮使用如大范圍手術(shù)切除、輔助化療等更積極的治療措施。

HCC的腫瘤大小可影響MVI的發(fā)生[46-48]。Kim等[49]發(fā)現(xiàn)，MRI顯示MVI陽(yáng)性的HCC患者的腫瘤直徑[(4.09±2.43 ) cm]顯著大于MVI陰性的HCC患者[(3.00±1.58) cm，P=0.030)。Chou等[8]也發(fā)現(xiàn)，CT顯示MVI陽(yáng)性的HCC患者腫瘤直徑[(4.6±2.6) cm]顯著大于MVI陰性的患者[(3.6±2.1) cm，P=0.036]。Ahn等[50]回顧性納入了51例HCC患者，發(fā)現(xiàn)腫瘤直徑>5 cm與MVI的發(fā)生密切相關(guān) (OR=12.091,P=0.001)。Eguchi等[7]也在其連續(xù)納入了229例接受了根治性LR的HCC患者的回顧性研究中發(fā)現(xiàn)，腫瘤直徑>5 cm是MVI的高危因素(OR=1.678，P<0.01)。

HCC癌組織周圍強(qiáng)化是MVI的又一重要預(yù)測(cè)因素[5,49,51,52]。Renzulli等[5]回顧性納入了125例HCC患者，由兩位放射科醫(yī)生根據(jù)患者的術(shù)前CT和MRI圖像獨(dú)立評(píng)估MVI發(fā)生情況，基于兩位閱片者，癌周組織強(qiáng)化分別出現(xiàn)在58.9%和65.6%的MVI陽(yáng)性的HCC患者中，而僅出現(xiàn)在10.0%和14.0%的MVI陰性的患者中(P<0.001)。對(duì)此可能的解釋是，當(dāng)HCC累及區(qū)域的門靜脈分支被癌栓阻塞后，上述門靜脈分支供給區(qū)域的門靜脈血流灌注減少，這種血流動(dòng)力學(xué)變化會(huì)引起相應(yīng)區(qū)域的代償性動(dòng)脈灌注增加，在影像學(xué)上就表現(xiàn)為癌組織周圍強(qiáng)化[53]。

HCC的纖維包膜主要由厚層的膠原纖維和薄層的血管結(jié)構(gòu)組成，其完整程度也能反映腫瘤的微血管侵犯情況。Lim[54]等發(fā)現(xiàn)，CT顯示包膜完整的HCC患者腫瘤周圍肝實(shí)質(zhì)發(fā)生門靜脈分支或肝靜脈MVI的概率明顯小于包膜不完整的HCC患者(P<0.001)。然而，也有研究表明，MVI的存在與否與HCC腫瘤包膜的完整程度無(wú)關(guān)[4,8]，這可能與實(shí)驗(yàn)設(shè)計(jì)、納入患者人群、掃描方案等因素的差異有關(guān)，但仍需進(jìn)一步研究證實(shí)腫瘤包膜完整程度與MVI的關(guān)系。

此外，灌注CT、核醫(yī)學(xué)、放射組學(xué)以及功能MR等的快速發(fā)展也為更好地預(yù)測(cè)和評(píng)估MVI提供了重要幫助。Wu[55]等發(fā)現(xiàn)，使用灌注CT評(píng)估HCC患者的腫瘤門靜脈血流(PVFtumor)、腫瘤與肝組織門靜脈血流差值(ΔPVF)以及ΔPVF與肝組織門靜脈血流比(rPVF)，可以定量預(yù)測(cè)MVI的發(fā)生。Segal等[10]用放射組學(xué)的方法，發(fā)現(xiàn)腫瘤內(nèi)部動(dòng)脈、低密度環(huán)與MVI的發(fā)生有關(guān)，上述研究得到了Renzulli等[5]的證實(shí)。Banerjee[56]等發(fā)現(xiàn)，使用由腫瘤內(nèi)部動(dòng)脈、低密度環(huán)和肝組織-腫瘤差異這三個(gè)獨(dú)立的影像學(xué)特征組成的影像基因相關(guān)的靜脈侵犯(Radiogenomic venous invasion, RVI)這一放射組學(xué)標(biāo)志，能夠很好地預(yù)測(cè)HCC患者M(jìn)VI發(fā)生(準(zhǔn)確度89%，敏感度76%，特異度94%)、腫瘤復(fù)發(fā)以及整體預(yù)后。此外，多項(xiàng)研究表明，使用PET-CT評(píng)估HCC，腫瘤氟代脫氧葡萄糖(18F-fluorodeoxyglucose,18F-FDG)高攝取能夠有效預(yù)測(cè)MVI的發(fā)生[50,57,58]。

釓塞酸二鈉(gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid,Gd-EOB-DTPA)是一種肝細(xì)胞特異性MRI對(duì)比劑，能夠特異性顯示肝細(xì)胞功能和組織微血管的形成情況。相關(guān)研究發(fā)現(xiàn)，HCC患者肝膽期癌周Gd-EOB-DTPA攝取降低[59,60]和腫瘤邊緣不清[49,61]與MVI的發(fā)生密切相關(guān)。此外，使用肝臟網(wǎng)狀內(nèi)皮系統(tǒng)特異性對(duì)比劑超順磁性氧化鐵(superparamagnetic iron oxid,SPIO)的增強(qiáng)MRI也能用于預(yù)測(cè)MVI[51]。不僅如此，磁共振擴(kuò)散加權(quán)成像(diffusion weighted imaging,DWI)中HCC的表觀擴(kuò)散系數(shù)(apparent diffusion coefficient,ADC)值降低也與MVI的發(fā)生有關(guān)[62]。

目前的影像學(xué)檢查手段雖難以在術(shù)前直接顯示HCC腫瘤微血管的侵犯情況，但HCC腫瘤大小、數(shù)目、形態(tài)，腫瘤邊緣不清與否，腫瘤包膜是否完整，癌組織周圍強(qiáng)化情況，腫瘤內(nèi)部是否存在動(dòng)脈和低密度空洞等影像學(xué)征象可以為MVI的術(shù)前評(píng)估提供重要信息。

HCC是全球范圍內(nèi)最常見(jiàn)的惡性腫瘤之一，具有病死率高、易復(fù)發(fā)轉(zhuǎn)移的特點(diǎn)[63]。目前，外科綜合治療是HCC最有效的根治性治療手段。MVI是HCC患者術(shù)后復(fù)發(fā)的主要危險(xiǎn)因素之一，其早期識(shí)別和評(píng)估對(duì)HCC的準(zhǔn)確診斷、分期、治療以及預(yù)后判斷意義重大。MVI的診斷主要依賴于術(shù)后組織病理學(xué)檢查，但近期的研究進(jìn)展表明血清AFP、PIVKA-Ⅱ水平以及腫瘤邊緣、大小、癌周組織強(qiáng)化、包膜完整程度等影像學(xué)征象可以為MVI的術(shù)前預(yù)測(cè)提供重要幫助。然而，目前仍需更多多中心、大樣本的高質(zhì)量研究來(lái)進(jìn)一步驗(yàn)證上述指標(biāo)或影像學(xué)征象在MVI的術(shù)前預(yù)測(cè)與評(píng)估中的作用。同時(shí)，建立涵蓋多項(xiàng)MVI預(yù)測(cè)因素的綜合評(píng)估系統(tǒng)能克服依靠單一因素進(jìn)行評(píng)估的不足，提供更為全面、準(zhǔn)確、可靠的MVI臨床預(yù)測(cè)與診斷信息。

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