術(shù)前預(yù)測肝細胞癌并微血管侵犯的研究進展

陳潔 綜述　黎樂群 審校

（廣西醫(yī)科大學(xué)附屬腫瘤醫(yī)院 肝膽外科，廣西 南寧 530021）

肝細胞癌（HCC）是世界上最常見的惡性腫瘤之一，特別是我國廣西地區(qū)，腫瘤致死率高居第三位[1]，該腫瘤具有侵襲肝內(nèi)血管的傾向，導(dǎo)致肝內(nèi)和肝外轉(zhuǎn)移[2]。外科手術(shù)治療和肝移植（LT）是目前最主要的HCC治療手段[3]，然而，手術(shù)切除和肝移植的預(yù)后仍無法達到預(yù)期效果，其中最需要克服的難題就是術(shù)后復(fù)發(fā)[4]。手術(shù)切除后、肝移植后5年復(fù)發(fā)率分別高達70%、35%[5]。大血管侵犯和微血管侵犯（microvascular invasion，MVI）均與腫瘤分期和疾病進展有關(guān)。通常大血管腫瘤侵犯可通過影像學(xué)檢查確診[6]。MVI是HCC發(fā)生發(fā)展過程中出現(xiàn)的一種病理征象，是腫瘤早期轉(zhuǎn)移的標志[7]。但MVI的臨床意義常被低估，認為MVI是一種較為溫和的腫瘤侵襲形式，隨著對MVI的研究認識和其對預(yù)后的不良影響，MVI已經(jīng)成為HCC研究的熱門話題，而目前僅能通過術(shù)后標本的組織病理學(xué)檢查診斷[8]，這對于術(shù)前治療方案的制定具有滯后性。因此，術(shù)前合理預(yù)測MVI對HCC患者個體化治療方案的制定及其遠期預(yù)后的評估具有重要意義[9]。本文綜合近年來對HCC術(shù)前預(yù)測MVI的文獻報道，予以綜述。

1　MVI

MVI的診斷標準尚未統(tǒng)一。Sumie等[10]指出只要在門靜脈或肝靜脈系統(tǒng)發(fā)現(xiàn)腫瘤細胞即可診斷為MVI。不過，他們沒有考慮到膽管和淋巴管侵犯以及血管侵犯到腫瘤邊緣的距離。目前，較多學(xué)者[11]對MVI定義為顯微鏡下于內(nèi)皮細胞襯覆的血管腔內(nèi)見到癌細胞巢團的觀點表示認可。MVI是一種由多因素參與導(dǎo)致的復(fù)雜的生物過程，包括HCC與微環(huán)境的相互作用，以及與宿主狀態(tài)（免疫、內(nèi)分泌和代謝等）[12]。目前機制尚未明確。

2　術(shù)前預(yù)測MVI的重要性

大量研究[13]表明MVI可反映HCC早期轉(zhuǎn)移能力和侵襲程度，并且可作為HCC預(yù)后的獨立危險因素。在HCC合并MVI時，患者總生存率及3年無復(fù)發(fā)率都將縮短[3,14]。近年來對MVI的研究越來越具體化，主要集中在MVI多發(fā)位置、對微血管侵犯程度以及微血管數(shù)目等[15-17]；Parfitt等[18]研究甚至將淋巴管侵犯也歸納為MVI。隨著對MVI研究范圍的擴展，目前報道的HCC的MVI發(fā)生率明顯升高。Lim等[19]通過對225例HCC切除術(shù)患者的調(diào)查研究發(fā)現(xiàn)，MVI陽性組中位復(fù)發(fā)時間（12.0個月）顯著低于MVI陰性組（42.2個月）；Hou等[20]研究結(jié)果表明，MVI不僅是限制首次術(shù)后生存的危險因素（HR=2.62，95% CI為2.15～3.19），再次手術(shù)也具有同樣重要作用（2次術(shù)前MVI均陽性：HR=4.79，95% CI=2.54～9.53；首次術(shù)前MVI陰性、再次復(fù)發(fā)術(shù)前MVI陽性：HR=4.02，95% CI=2.27～7.13）。＜2 cm早期小HCC通常認為手術(shù)切除的預(yù)后效果較好[21]，但Yamashita等[22]研究149例＜2 cm早期小HCC中發(fā)現(xiàn)43例合并MVI的患者接受HCC切除后，1年復(fù)發(fā)率為23.3%，顯著大于不伴有MVI的復(fù)發(fā)率（7.5%）。Roayaie等[23]研究證實擴大手術(shù)切緣（＞1 cm）可以減少HCC伴有MVI患者的腫瘤復(fù)發(fā)。Zhou等[24]研究也表明肝解剖切除可見降低HCC并MVI患者的術(shù)后復(fù)發(fā)率。因此，如果術(shù)前可以確定MVI的風險，可以術(shù)前做出解剖切除或非解剖切除以及手術(shù)切緣的寬度的合理選擇，在術(shù)中更具針對性的外科治療策略，對提高生存時間具有重要價值[25-26]。

目前，MVI的診斷主要依靠手術(shù)標本的病理檢查。術(shù)前肝臟穿刺活檢診斷MVI準確性低，不確定因素多，且屬于有創(chuàng)檢查，患者接受度差。由此導(dǎo)致的結(jié)果就是，由于無法依據(jù)MVI信息制定擴大肝切緣的治療方案，具有明顯的滯后性，使患者失去延長生存期的機會[27]。同時，MVI常發(fā)生于晚期HCC患者，而在早期HCC中發(fā)生率相對較低，然而早期HCC才是接受根治性治療的最佳適應(yīng)指征，因此術(shù)前預(yù)測早期HCC MVI有著更大的臨床應(yīng)用價值。隨著診療設(shè)備及醫(yī)學(xué)理論的發(fā)展，MVI的術(shù)前預(yù)測也得到巨大進步，目前比較公認的檢測方法主要為影像學(xué)、血清學(xué)及信號通路檢查。

3　用術(shù)前影像學(xué)特征預(yù)測MVI

3.1　CT預(yù)測MVI

CT是最早用于預(yù)測HCCMVI的影像學(xué)方法之一。Eguch等[28]研究表明，HCC瘤灶單節(jié)結(jié)型較之于其他分型HCC（多節(jié)結(jié)型或單結(jié)節(jié)結(jié)外生長型）發(fā)生MVI的風險率更低。張俊等[29]研究進一步指出，HCC的常見CT征象（腫瘤最大直徑、癌組織邊緣強化程度、腫瘤包膜及腫瘤形態(tài)）中，只有腫瘤形態(tài)對預(yù)測MVI有意義，其診斷的靈敏度、特異度、準確率分別為76.7%、75.0%、76.0%。此外，李文柱團隊[30]還驗證了能譜CT對預(yù)測微血管侵犯的可行性，該研究指出動脈期標準碘基值（NIC-a）與HCC微血管密度（MVD）呈中度相關(guān)（r=0.507，P＜0.05）。楊創(chuàng)勃等[31]也發(fā)現(xiàn)能譜CT掃描對評估微血管侵犯具有重要價值，進一步證實能譜CT碘基值與微血管侵犯的相關(guān)性。Banerjee等[5]研究更是將CT對MVI的預(yù)測延生到分子影像學(xué)層面，該實驗通過CT靶向性MVI高危基因（91-gene）來評估靜脈侵潤程度（RVI），并利用RVI診斷MVI的準確率、靈敏度、特異度分別為89%、76%、94%，RVI陰性組3年HCC切除術(shù)后無復(fù)發(fā)率為62%，較之RVI陽性組（無復(fù)發(fā)率27%）高出1倍以上。可見，CT對HCC形態(tài)學(xué)的判斷以及MVI分子標記物的示蹤，為MVI的預(yù)測提供了一個新的思路，在臨床醫(yī)師制定HCC治療策略時應(yīng)該特別注意。

3.2　MRI預(yù)測MVI

MRI因其較高的軟組織分辨率及功能成像的日漸成熟，該技術(shù)用于MVI的預(yù)測的研究也得到較大進展。Chandarna等認為[32]，HCC瘤灶形態(tài)的不規(guī)則是預(yù)測MVI得唯一指標，包括病理及AFP在內(nèi)的其他臨床特征都與MVI不相關(guān)。MRI對HCCMVI的預(yù)測除了依據(jù)瘤灶形態(tài)學(xué)指征外，MRI功能學(xué)成像同樣具有重要診斷價值。Xu等[33]利用磁共振擴散加權(quán)成像對HCC微血管侵犯的研究結(jié)果表明，以表觀彌散系數(shù)（ADC）＜1.227×10-3s/mm2作為最佳診斷閾值時，其靈敏度、特異度分別為66.7%、78.6%。Renzulli等[34]研究表明，同時存在HCC的3個危險征象（腫瘤邊緣不光整、邊緣強化以及靜脈侵潤）時，在不計腫瘤大小的情況下，其診斷陽性預(yù)測值可達95%。由此可知，MRI對HCCMVI的預(yù)測同樣具有重要價值。

4　血清蛋白標志物預(yù)測MVI

該方法主要是檢測血清中某種HCC特異性抗原表達量來預(yù)測MVI發(fā)生，現(xiàn)在研究較多的有異常凝血酶原（DCP）和AFP等。Poté等[35]發(fā)現(xiàn)HCC患者血清DCP＞90 mAU/mL可作為MVI的獨立預(yù)測因素（HR=3.5，95% CI=1.08～11.8），該診斷閾值對應(yīng)的靈敏度、特異度分別為70%、63%，若聯(lián)合組織DCP檢查，則靈敏度、特異度可提高到87%、90%。Dumitra等[36]研究發(fā)現(xiàn)AFP斜率對預(yù)測MVI及HCC的復(fù)發(fā)具有重要意義。Zhao等[37]以多結(jié)節(jié)HCC進行亞組分析，發(fā)現(xiàn)GGT＞130 U/L時，MVI陽性率比MVI陰性率高出1倍多。這種方案局限性是特異性不強，例如DCP和AFP在慢性肝炎和肝硬化等非HCC患者的血清同樣呈高表達[38]，容易造成診斷重疊。目前尚未發(fā)現(xiàn)對MVI特異的血清蛋白標志物。

5　用HCC信號通路蛋白、mRNA或基因預(yù)測MVI

這一思路的創(chuàng)新性在于著眼于HCC發(fā)生機制，通過對病理組織的樣本檢測，發(fā)現(xiàn)與HCC關(guān)系密切的信號通道基因或蛋白發(fā)生了改變，這其中的一些分子生物學(xué)指標被認為與MVI的存在有關(guān)[39]。Poté等[40]利用質(zhì)譜成像發(fā)現(xiàn)組蛋白4的修飾物（H4K16ac與H4K20me2）在MVI陽性組高表達，明顯不同于MVI陰性組。Yu等[41]發(fā)現(xiàn)抗血清熱休克蛋白70在MVI陰性患者中顯著高于MVI陽性患者，由此推測抗血清熱休克蛋白70可作為MVI陰性患者血清學(xué)標志物。Ding等[42]應(yīng)用Li-鈣黏蛋白（Li-cadherin）與其他黏附分子結(jié)合，預(yù)測HCC患者的MVI和預(yù)后。Mínguez等[43]發(fā)現(xiàn)了35個基因標記（14個基因高表達和21個基因低表達）與血管侵犯有關(guān)，對MVI預(yù)測的準確度為69%?？紤]到低特異性、技術(shù)復(fù)雜性和高成本，這些方法仍處于研究階段，在目前較短時間內(nèi)難以將基礎(chǔ)研究轉(zhuǎn)化為臨床應(yīng)用[44]。

6　結(jié)　語

綜上所述，MVI對HCC的治療方式及預(yù)后發(fā)展都有著重大作用，現(xiàn)有的MVI術(shù)前預(yù)測技術(shù)各有所長又各有短板，故而在臨床推廣應(yīng)用上應(yīng)該綜合考慮，使得建立一個整合多個預(yù)測因子的臨床預(yù)測模型逐漸成為現(xiàn)實，為減低HCC患者術(shù)后復(fù)發(fā)及轉(zhuǎn)移，改善患者預(yù)后等方面帶來福祉。

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