肝細胞癌微血管侵犯的術前診斷與評估

蔣涵羽， 陳婕， 張晗媚， 劉曦嬌， 黃子星， 宋彬

肝細胞癌(hepatocellular carcinoma，HCC)是世界范圍內最常見的惡性腫瘤之一，其發病率在所有惡性腫瘤中位居全球第五，腫瘤相關死因更高居全球第三[1]。外科手術肝切除(liver resection,LR)和肝移植(liver transplantation,LT)是HCC根治性治療的主要手段。然而，腫瘤高復發率嚴重影響了HCC患者的預后及遠期療效[2,3]。目前，腫瘤大小、數目、血管侵犯等被認為是影響HCC復發和總生存期(overall survival,OS)的主要危險因素[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無創影像學檢查或術后病理檢查能夠用肉眼辨識的血管侵犯，主要累及大到中等大小血管、二級或二級以上肝靜脈或門靜脈。MVI為僅在顯微鏡下可見的血管侵犯，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等常規的術前影像技術目前難以直接準確識別和評估MVI[1,12,13]。然而，HCC患者一旦發生大血管轉移，則基本喪失了根治性治療的可能。因此，早期識別MVI可以為HCC的診斷、分期和預后判斷提供極為重要的信息；而針對MVI的及時處理也能顯著延長HCC患者的術后生存期，降低患者復發和轉移風險。同時，隨著分子生物學、核醫學以及功能MRI等的發展與進步，越來越多的研究發現，部分血清學和影像學征象可間接提示MVI的存在。本文總結了近年來HCC相關MVI的診斷與評估研究進展，并探討了未來可能的發展方向。

MVI的病理生理學基礎

新生血管生成是腫瘤發生的重要標志[14]。在HCC中，癌細胞可以產生組織蛋白酶H等蛋白酶降解細胞外基質[15]。其次，腫瘤組織中E-鈣粘蛋白的過低表達降低了細胞間連接的穩固性[16-18]，其他黏附分子的異常高表達可能進一步促進了上皮組織向間葉組織的化生過程[19, 20]。此外，通過將自己包裹在內皮細胞內，癌細胞團塊逃避了機體正常的免疫應答和凝血活化，從而使其能順利通過血流進行播散[21]。HCC的新生血管生成和腫瘤轉移正是上述過程的共同結果。在HCC中，MVI可累及門靜脈分支，引起相應的肝內復發[22]；或累及肝靜脈分支，導致相應的遠處轉移[23]。

MVI的病理學評估

在病理學中，MVI定義為影像學或標本解剖均未發現肉眼可見的血管內癌栓，僅顯微鏡下于內皮下查見部分或全部被覆內皮細胞的癌細胞栓子或息肉，或于管腔中查見自由漂浮的、部分或全部被覆內皮細胞的癌細胞栓子，需除外無內皮細胞包裹、自由漂浮的小簇腫瘤細胞團；累及血管可包括門靜脈分支、肝靜脈分支、腫瘤內部血管、癌旁血管及腫瘤包膜血管，偶可見動脈及淋巴管累及[6,24-29]。多項研究發現，HCC的腫瘤分化程度越低，MVI發生的可能性越大[30-32]。MVI與HCC的大體形態密切相關，根據Kanai等[33]提出的HCC形態學分類標準，單結節結外生長型和連續多結節型HCC的MVI發生率顯著高于單結節型，是MVI的獨立預測因素[34-37]。

然而，術前HCC組織活檢取樣難度大、出血及腫瘤播散風險高、腫瘤異質性導致針吸活檢難以避免取樣誤差等困境，目前MVI的臨床應用主要局限于術后的組織病理學評估[38]。因此，進一步提高MVI術前活檢取樣準確度、建立完善而標準的診斷及分級標準、探索新的免疫組織化學染色方式、明確術后組織病理學檢查所需的標本數量及大小等，對于MVI的術前識別、提高MVI診斷的準確度具有重要意義。

MVI血清學評估

MVI是HCC患者預后不良的重要危險因素，與多種物質的血清水平密切相關。維生素K 缺乏或拮抗劑Ⅱ誘導的蛋白質(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相關血清標志物，其γ-羧基谷氨酸結構中1 個或多個谷氨酸殘基不完全羧化為γ-羧基谷氨酸，導致其失去正常凝血功能[39-41]。相關研究發現，血清PIVKA-Ⅱ的異常增高可用于預測MVI的發生，但對于PIVKA-Ⅱ血清水平的最佳臨界值，目前仍有較多爭議[37,42-44]。Poté等[42]及Kaibori[43]等提出，血清PIVKA-Ⅱ≥200 mAU/ml是MVI的獨立預測因素；而其他研究則認為，血清PIVKA-Ⅱ>100 mAU/mL是預測MVI的最佳界值[37,44]。

甲胎蛋白(Alpha fetoprotein,AFP)是目前診斷和評估HCC最重要的血清標志物，但對于AFP在術前預測MVI的能力，目前仍有較多爭議。Zhao等[45]發現，血清AFP水平高于400 ug/L是MVI的獨立預測因素(OR= 3.732,P=0.016)。然而，其他相關研究卻發現，AFP與MVI的發生無明顯關聯，而PIVKA-Ⅱ是預測MVI更好的血清標志物[42,43]。此外，Zhao[45]等也發現，血清谷氨酰轉肽酶(gammaglutamyltransferase,GGT)水平的異常升高也可以用于預測MVI。然而，盡管使用血清標志物于術前預測MVI具有操作簡便、快捷、經濟等優點，但目前仍需更多大樣本、多中心的高質量研究來證實和進一步評估上述血清學標志物在預測MVI中的作用。

MVI的影像學評估

目前，HCC術前常規的影像學檢查手段難以直接顯示MVI，但CT、MRI、正電子發射斷層顯像-計算機斷層顯像(positron emission tomography-computed tomography,PET-CT)等無創影像檢查手段的部分征象可以為術前預測MVI提供有力的間接證據。

HCC的腫瘤邊緣是腫瘤組織與周圍正常肝組織的分界面，其形態特征與腫瘤血管生成密切相關。多項研究發現，CT或MRI圖像中HCC腫瘤邊緣不清與MVI的發生密切相關[5,8,9]。Chou等[9]發現，CT顯示腫瘤邊緣不清是MVI發生的獨立預測因素(OR=28.828，95%CI：7.718～107.680,P<0.001)。上述研究結果表明，對于影像學檢查表現出腫瘤邊緣不清的HCC患者，應該考慮使用如大范圍手術切除、輔助化療等更積極的治療措施。

HCC的腫瘤大小可影響MVI的發生[46-48]。Kim等[49]發現，MRI顯示MVI陽性的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]也發現，CT顯示MVI陽性的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，發現腫瘤直徑>5 cm與MVI的發生密切相關 (OR=12.091,P=0.001)。Eguchi等[7]也在其連續納入了229例接受了根治性LR的HCC患者的回顧性研究中發現，腫瘤直徑>5 cm是MVI的高危因素(OR=1.678，P<0.01)。

HCC癌組織周圍強化是MVI的又一重要預測因素[5,49,51,52]。Renzulli等[5]回顧性納入了125例HCC患者，由兩位放射科醫生根據患者的術前CT和MRI圖像獨立評估MVI發生情況，基于兩位閱片者，癌周組織強化分別出現在58.9%和65.6%的MVI陽性的HCC患者中，而僅出現在10.0%和14.0%的MVI陰性的患者中(P<0.001)。對此可能的解釋是，當HCC累及區域的門靜脈分支被癌栓阻塞后，上述門靜脈分支供給區域的門靜脈血流灌注減少，這種血流動力學變化會引起相應區域的代償性動脈灌注增加，在影像學上就表現為癌組織周圍強化[53]。

HCC的纖維包膜主要由厚層的膠原纖維和薄層的血管結構組成，其完整程度也能反映腫瘤的微血管侵犯情況。Lim[54]等發現，CT顯示包膜完整的HCC患者腫瘤周圍肝實質發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關[4,8]，這可能與實驗設計、納入患者人群、掃描方案等因素的差異有關，但仍需進一步研究證實腫瘤包膜完整程度與MVI的關系。

此外，灌注CT、核醫學、放射組學以及功能MR等的快速發展也為更好地預測和評估MVI提供了重要幫助。Wu[55]等發現，使用灌注CT評估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)，可以定量預測MVI的發生。Segal等[10]用放射組學的方法，發現腫瘤內部動脈、低密度環與MVI的發生有關，上述研究得到了Renzulli等[5]的證實。Banerjee[56]等發現，使用由腫瘤內部動脈、低密度環和肝組織-腫瘤差異這三個獨立的影像學特征組成的影像基因相關的靜脈侵犯(Radiogenomic venous invasion, RVI)這一放射組學標志，能夠很好地預測HCC患者MVI發生(準確度89%，敏感度76%，特異度94%)、腫瘤復發以及整體預后。此外，多項研究表明，使用PET-CT評估HCC，腫瘤氟代脫氧葡萄糖(18F-fluorodeoxyglucose,18F-FDG)高攝取能夠有效預測MVI的發生[50,57,58]。

釓塞酸二鈉(gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid,Gd-EOB-DTPA)是一種肝細胞特異性MRI對比劑，能夠特異性顯示肝細胞功能和組織微血管的形成情況。相關研究發現，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的發生密切相關。此外，使用肝臟網狀內皮系統特異性對比劑超順磁性氧化鐵(superparamagnetic iron oxid,SPIO)的增強MRI也能用于預測MVI[51]。不僅如此，磁共振擴散加權成像(diffusion weighted imaging,DWI)中HCC的表觀擴散系數(apparent diffusion coefficient,ADC)值降低也與MVI的發生有關[62]。

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

HCC是全球范圍內最常見的惡性腫瘤之一，具有病死率高、易復發轉移的特點[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患者術后復發的主要危險因素之一，其早期識別和評估對HCC的準確診斷、分期、治療以及預后判斷意義重大。MVI的診斷主要依賴于術后組織病理學檢查，但近期的研究進展表明血清AFP、PIVKA-Ⅱ水平以及腫瘤邊緣、大小、癌周組織強化、包膜完整程度等影像學征象可以為MVI的術前預測提供重要幫助。然而，目前仍需更多多中心、大樣本的高質量研究來進一步驗證上述指標或影像學征象在MVI的術前預測與評估中的作用。同時，建立涵蓋多項MVI預測因素的綜合評估系統能克服依靠單一因素進行評估的不足，提供更為全面、準確、可靠的MVI臨床預測與診斷信息。

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