晏益核，黃玉斌　綜述　蔡小勇　審校

（廣西醫(yī)科大學(xué)微創(chuàng)外科中心/第二附屬醫(yī)院 普通外科，廣西 南寧 530007）

膽管癌（cholangiocarcinoma）指來(lái)源于膽管上皮細(xì)胞的惡性腫瘤，其發(fā)生率占全部惡性腫瘤的比例低于1%[1]，占原發(fā)性肝膽惡性腫瘤比例的10%[2]，按照發(fā)生的解剖部位不同分為肝內(nèi)、肝門(mén)部及遠(yuǎn)端膽管癌，其中肝門(mén)部膽管癌（hilarcholangiocarcinoma，HC）約占50%～70%[2]，由Klatskin在1965年首次報(bào)道，又被稱(chēng)為Klatskin腫瘤，外科手術(shù)是唯一治愈手段；半個(gè)多世紀(jì)以來(lái)，隨著醫(yī)學(xué)進(jìn)步，對(duì)HC疾病進(jìn)程、病理生理及腫瘤生物學(xué)的認(rèn)識(shí)也不斷提高，但是，仍然只有25%的初診患者有手術(shù)切除機(jī)會(huì)，術(shù)后5年生存率僅11%～42%[3-5]。本文將從術(shù)前準(zhǔn)備（腫瘤分期、術(shù)前治療）及外科手術(shù)（切除范圍、血管切除與重建、淋巴結(jié)清掃數(shù)目及范圍、腹腔鏡技術(shù)、肝移植應(yīng)用）對(duì)HC的外科治療現(xiàn)狀進(jìn)行闡述。

1　目前國(guó)際應(yīng)用的HC分期

Bismuth和Corlette在上世紀(jì)70年代提出Bismuth-Corlette分型，其中I型腫瘤位于肝總管、左右肝管匯合部以下，II型腫瘤侵犯匯合部但未侵及左右肝管，III型侵犯右肝管（IIIa）或左肝管（IIIb），IV型同時(shí)侵犯左右肝管[6]，該分型按照膽管受侵犯范圍分類(lèi)，簡(jiǎn)單實(shí)用，能夠指導(dǎo)手術(shù)方式選擇，目前仍然廣泛應(yīng)用于臨床，但并未提供其他信息，例如有無(wú)血管侵犯、淋巴結(jié)轉(zhuǎn)移、遠(yuǎn)處轉(zhuǎn)移、肝葉萎縮等，因此，無(wú)法準(zhǔn)確評(píng)估患者預(yù)后；之后，紀(jì)念Sloan-Kettering癌癥中心（MSKCC）的Jarnagin等[7]提出根據(jù)膽管受侵犯位置及范圍、門(mén)靜脈有無(wú)受侵犯以及有無(wú)肝葉萎縮這三個(gè)因素將HC分為T(mén)1、T2及T3期，在225例HC術(shù)前評(píng)估準(zhǔn)確率達(dá)到86%，但該分期較復(fù)雜，也未評(píng)估淋巴結(jié)及遠(yuǎn)處轉(zhuǎn)移或動(dòng)脈受侵犯；美國(guó)癌癥分期聯(lián)合委員會(huì)（American Joint Commission on Cancer，AJCC）制訂了HC的TNM分期[8]，這是一個(gè)基于術(shù)后病理結(jié)果的TNM分期，能夠評(píng)估預(yù)后，但有研究[9]顯示其判定預(yù)后的價(jià)值不及MSKCC中的T分期，也無(wú)法指導(dǎo)術(shù)前可切除性評(píng)估及手術(shù)方式選擇；為了在全球范圍內(nèi)收集病例、統(tǒng)一評(píng)估HC的可切除性及預(yù)后，Deoliveira等[10]提出了綜合包括腫瘤侵犯膽管范圍（B）、門(mén)靜脈侵犯（PV）、肝動(dòng)脈侵犯（HA）、殘余肝體積（V）、淋巴結(jié)轉(zhuǎn)移（N）、遠(yuǎn)處轉(zhuǎn)移（M）、以及腫瘤大小（T）、病理類(lèi)型（F）、肝臟基礎(chǔ)疾?。―）等因素的分期方法，但最近研究[11]顯示該方法需要收集大量信息而限制其應(yīng)用；Boudjema等[12]提出了根據(jù)左外葉膽管匯合部是否受侵犯來(lái)判斷切除可能性的分型，該分型依據(jù)：⑴ 肝門(mén)部的解剖特點(diǎn)，左右肝管匯合部及肝總管位于肝十二指腸韌帶右側(cè)并緊鄰肝動(dòng)脈右支，左肝管比右肝管長(zhǎng)，左肝動(dòng)脈位于肝十二指腸韌帶左側(cè)或肝胃韌帶、距離左右肝管匯合部較遠(yuǎn)；⑵ 左外葉是術(shù)后殘余肝體積的最低要求；⑶ 左外葉肝管匯合部受侵犯時(shí)腫瘤通常已經(jīng)范圍較廣并侵犯血管，切除可能性較小，即使通過(guò)擴(kuò)大半肝聯(lián)合血管切除及重建完成手術(shù)，但預(yù)后在大多數(shù)報(bào)道中并未改善。該分型與Bismuth分型的預(yù)測(cè)性較一致，對(duì)于可切除性判斷的準(zhǔn)確率較高，但是忽略了血管重建技術(shù)在門(mén)靜脈或肝動(dòng)脈受侵犯病例中的重要作用，因此特異性較低。一些無(wú)法切除病例通過(guò)血管重建技術(shù)能夠根治，雖然有研究[13-15]證實(shí)血管切除重建后患者并未獲得滿(mǎn)意療效，但仍然有支持患者獲益的研究報(bào)道[16-18]，對(duì)此，將在后文中進(jìn)一步闡述。

2　術(shù)前治療

目前，HC術(shù)前膽道引流（pre-operative biliary drainage，PBD）仍存爭(zhēng)議，原因之一是缺乏證據(jù)支持PBD能夠減少術(shù)后病死率及提高生存率[19-21]；另一方面，經(jīng)皮肝穿刺膽道引流（percutaneous transhepatic biliary drainage，PTBD）存在1.7%～5.2%的穿刺隧道癌細(xì)胞種植率[22]，而內(nèi)鏡下鼻膽管引流（endoscopic nasobiliary drainage，ENBD）既能夠避免癌細(xì)胞種植，又較內(nèi)鏡下膽道支架（endoscopic biliary stenting，EBS）內(nèi)引流的感染率降低，似乎是最佳的PBD方式，但仍有相當(dāng)比例的ENBD引流效果不佳而需要再次行PTBD引流[8,23-25]，同時(shí)，ENBD達(dá)到減黃預(yù)期的時(shí)間比PTBD更長(zhǎng)[8,23]。盡管PBD存在爭(zhēng)議，并且引流持續(xù)時(shí)間及適合手術(shù)的最佳膽紅素水平仍未達(dá)成共識(shí)，但是，對(duì)于膽管炎，擬行術(shù)前抗腫瘤治療，高膽紅素血癥引發(fā)的營(yíng)養(yǎng)不良、肝腎功能不全以及行門(mén)靜脈栓塞（portal vein embolization，PVE）的患者，術(shù)前PBD仍是最佳選擇[8,26]。

正常肝臟可耐受最大切除量為20%的剩余肝體積（future liver remnant，F(xiàn)LR），而慢性肝炎或肝硬化則是40%的FLR，F(xiàn)LR不足將加大術(shù)后肝功能衰竭風(fēng)險(xiǎn)。Makuuchi等[27]首次報(bào)道在大范圍肝切除術(shù)治療膽管癌的患者術(shù)前應(yīng)用PVE能夠增加FLR，之后，大量研究[17,28-30]證實(shí)術(shù)前PVE通過(guò)增加FLR減少術(shù)后并發(fā)癥率及病死率；但是，并未見(jiàn)PVE能夠增加HC患者R0切除率或增加生存率的相關(guān)報(bào)道。除此之外，聯(lián)合肝臟離斷和門(mén)靜脈結(jié)扎的兩步肝切除術(shù)（associating liver partition and portal vein ligation for staged hepatectomy，ALPPS）也用于因FLR不足而無(wú)法手術(shù)切除的HC患者。相較于PVE能夠在4～8周內(nèi)增加11.9%的FLR，ALPPS則在一期術(shù)后9 d內(nèi)使FLR增加74%，但33%～64%的并發(fā)癥率遠(yuǎn)高于16%的PVE并發(fā)癥率，因此，該項(xiàng)技術(shù)還需要進(jìn)一步評(píng)估[28,31]。

3　手術(shù)切除范圍

R0切除是影響HC預(yù)后的重要因素之一[4-5,17]，因此，能否達(dá)到R0切除決定了外科手術(shù)切除范圍。通過(guò)對(duì)切除組織的病理學(xué)檢查發(fā)現(xiàn)浸潤(rùn)癌在膽管近切緣沿縱軸的粘膜下浸潤(rùn)達(dá)到0.6～18.8 mm，非浸潤(rùn)癌的表淺侵犯長(zhǎng)度達(dá)到（54±19）mm[32]；此外，術(shù)中膽管切緣的冷凍切片檢查準(zhǔn)確率、敏感性及特異性分別是56.5%、75.0%、46.7%[33]，近期1篇報(bào)道[34]也證實(shí)膽管切緣的冷凍檢查存在敏感性較低、假陰性結(jié)果的高風(fēng)險(xiǎn)以及陰性切緣的二次獲得率低的缺點(diǎn)，因此，臨床價(jià)值有限；基于此，在膽腸吻合技術(shù)可行及減少潛在并發(fā)癥的前提下，盡可能多地獲得膽管近端切緣長(zhǎng)度才能夠保證高的R0切除率。另一方面，肝門(mén)部膽管癌因?yàn)槟懝鼙谳^薄以及特殊的解剖位置而較容易侵犯膽管周?chē)Y(jié)構(gòu)以及向肝實(shí)質(zhì)侵犯，聯(lián)合大范圍肝切的肝外膽管切除能夠提高R0切除率[4,17,35-36]。

對(duì)于Bismuth I/II型腫瘤，有研究[36-37]認(rèn)為對(duì)乳頭型的T1及Tis期腫瘤行肝外膽管切除加或不加部分肝切除即可，但是，外科醫(yī)師無(wú)法在術(shù)前及術(shù)中準(zhǔn)確判斷腫瘤TNM分期，而乳頭型只占HC病理組織分型的5%～10%，其余是＞70%的硬化型以及20%的結(jié)節(jié)型[8]，因此，聯(lián)合大范圍肝切除術(shù)逐漸成為主流，其中，尾狀葉（I段）因?yàn)榫o貼肝門(mén)而受腫瘤沿膽管浸潤(rùn)或是直接侵犯肝實(shí)質(zhì)的幾率極大，因此，大范圍肝切除術(shù)需要聯(lián)合I段切除[17,20,36]。然而，考慮到大范圍肝切除術(shù)后肝功能衰竭發(fā)生率增加，有報(bào)道[36,38-39]對(duì)于Bismuth I/II型、T1及T2期的III型,甚至IV型腫瘤，應(yīng)用小范圍中央?yún)^(qū)肝切除，包括I段切除，I段和IV（IVb）段切除，I段、IV（IVb）段和Ⅴ段切除，以及包括I段、IV（IVb）段、Ⅴ段和VIII段的肝中葉切除，雖然對(duì)于這一手術(shù)方式仍存有爭(zhēng)議，其R0切除率及預(yù)后仍需多中心研究支持，但是該術(shù)式對(duì)于降低術(shù)前PBD率、術(shù)后并發(fā)癥率及病死率方面的作用是值得肯定的。

聯(lián)合大范圍肝切除術(shù)對(duì)于Bismuth III/IV型腫瘤的手術(shù)方式通常在IIIa及IV型（病變以右肝為主）中選擇右半肝或擴(kuò)大右半肝切除，在IIIb及IV型（病變以左肝為主）中選擇左半肝或擴(kuò)大左半肝切除，但是，右半肝及擴(kuò)大右半肝切除術(shù)后病死率比較左半肝及擴(kuò)大左半肝切除增高，同時(shí)，有報(bào)道對(duì)于病變左肝為主的病例擴(kuò)大左半肝切除也能獲得高的R0切除率[40]，并且左半肝及擴(kuò)大左半肝切除對(duì)于IIIb型與右肝切除對(duì)于IIIa及IV型在R0切除率及生存率的比較無(wú)明顯差異，而術(shù)后病死率減低[41]，因此，手術(shù)方式的選擇應(yīng)該結(jié)合病變位置、預(yù)計(jì)殘余肝臟體積、肝臟基礎(chǔ)病變以及手術(shù)醫(yī)師經(jīng)驗(yàn)來(lái)共同決定。

4　聯(lián)合門(mén)靜脈、肝動(dòng)脈切除與重建

如前文所述，雖然不少研究[15,18]證實(shí)聯(lián)合門(mén)靜脈切除及重建沒(méi)有增加術(shù)后并發(fā)癥率及病死率，但是患者的生存率也未從中獲益[13-15]；然而，這些研究當(dāng)中也有闡述行門(mén)靜脈切除重建的病例往往腫瘤分期更晚，即腫瘤生物學(xué)行為更具有浸潤(rùn)性[15]，這些病例即使與沒(méi)有門(mén)靜脈切除重建病例的生存率相同，但該群患者仍然是獲益的，因此，門(mén)靜脈切除重建在經(jīng)驗(yàn)豐富的專(zhuān)業(yè)中心仍然被推崇，并且也有支持患者術(shù)后生存率獲益的研究報(bào)道[16-18,42-43]。而肝動(dòng)脈切除重建術(shù)后并發(fā)癥率，包括血栓形成、狹窄等血管特異性并發(fā)癥，其他非特異性并發(fā)癥率及病死率均較門(mén)靜脈切除重建增高[13,20,42-44]，因此，該技術(shù)在HC的手術(shù)切除中并不做常規(guī)推薦；但是，與門(mén)靜脈切除重建患者的腫瘤分期較晚相似，該群患者術(shù)后生存是否也能從中獲益仍需要更多論證，同時(shí)，該技術(shù)在專(zhuān)業(yè)中心開(kāi)展，隨著術(shù)者手術(shù)例數(shù)增加及選擇經(jīng)過(guò)嚴(yán)格評(píng)估后的合適病例，并發(fā)癥率及病死率逐漸在可控制范圍[42,44]。

5　淋巴結(jié)清掃數(shù)目與范圍

大量研究[4-5,17,45-47]證實(shí)區(qū)域淋巴結(jié)轉(zhuǎn)移（N1）是與R0切除一樣影響HC手術(shù)切除預(yù)后的獨(dú)立危險(xiǎn)因素，淋巴結(jié)轉(zhuǎn)移的HC術(shù)后5年生存率低于25%[4,17,46]。Mao等[46]研究發(fā)現(xiàn)在N0的HC中淋巴結(jié)清掃數(shù)目＞13個(gè)預(yù)后會(huì)優(yōu)于清掃數(shù)目＜3個(gè)，而N1（膽囊管、膽總管、肝動(dòng)脈及門(mén)靜脈周?chē)馨徒Y(jié)陽(yáng)性）與N2（主動(dòng)脈旁、腔靜脈旁、腸系膜上動(dòng)脈和/或腹腔動(dòng)脈淋巴結(jié)陽(yáng)性）的預(yù)后沒(méi)有明顯差異，但多于3個(gè)陽(yáng)性淋巴結(jié)及陽(yáng)性率＞0.27的病例預(yù)后顯著差過(guò)＜3個(gè)及＜0.27，因此，清掃13個(gè)淋巴結(jié)應(yīng)該作為腫瘤準(zhǔn)確分期的要求，并且，預(yù)后應(yīng)由轉(zhuǎn)移淋巴結(jié)的數(shù)目及陽(yáng)性率而不是位置所決定。Kambakamba等[45]認(rèn)為清掃淋巴結(jié)數(shù)目應(yīng)該至少7個(gè)才能對(duì)預(yù)后準(zhǔn)確分期，而＞15個(gè)淋巴結(jié)也并不能提高陽(yáng)性發(fā)現(xiàn)率。Giuliante等[47]報(bào)道陽(yáng)性率超過(guò)0.2可作為影響預(yù)后的獨(dú)立因素，但陽(yáng)性率受清掃淋巴結(jié)總數(shù)影響，應(yīng)達(dá)到5個(gè)以上。大多數(shù)外科醫(yī)師推崇清掃范圍包括肝十二指腸韌帶、肝總動(dòng)脈旁及胰腺旁，不主張行腹主動(dòng)脈旁淋巴結(jié)清掃，因?yàn)檫@不能提高預(yù)后[4,42,46,48]。

6　腹腔鏡技術(shù)應(yīng)用

腹腔鏡技術(shù)在HC中的應(yīng)用始于腫瘤探查分期，14%～45%的病例通過(guò)腹腔鏡探查可發(fā)現(xiàn)肝臟或腹膜轉(zhuǎn)移，準(zhǔn)確率達(dá)32%～71%[20,49]。此外，腹腔鏡下門(mén)靜脈結(jié)扎能獲得與PVE相似的效果[49]，完全腹腔鏡或機(jī)器人輔助膽腸吻合也用于晚期梗阻患者的姑息治療，并發(fā)癥率低、生活質(zhì)量提高[50-51]。至于完全或輔助下的腹腔鏡根治性切除，盡管有相關(guān)病例報(bào)道[52-54]，但是否符合聯(lián)合尾狀葉切除及淋巴結(jié)清掃的原則，仍存有爭(zhēng)議，期待更多病例研究證實(shí)。然而，隨著腹腔鏡技術(shù)在肝膽胰外科應(yīng)用的發(fā)展，在嚴(yán)格挑選的HC病例中，遵循根治性原則的前提下應(yīng)用腹腔鏡切除術(shù)，也能夠達(dá)到理想的效果[55-56]。

7　肝移植在HC中應(yīng)用

聯(lián)合新輔助放化療的肝移植應(yīng)用于適應(yīng)證嚴(yán)格的HC患者，5年無(wú)瘤生存率達(dá)到59%～82%，并且在合并硬化性膽管炎的患者中預(yù)后好于單純手術(shù)切除[57-60]。適應(yīng)證包括無(wú)法切除的直徑≤3cm的病灶且沒(méi)有肝內(nèi)及肝外轉(zhuǎn)移，有區(qū)域淋巴結(jié)轉(zhuǎn)移的患者在移植前經(jīng)過(guò)腹腔鏡探查排除。目前，沒(méi)有明確證據(jù)支持可以手術(shù)切除的患者能夠從肝移植中獲益，而對(duì)于可能切除的患者，選擇手術(shù)切除還是肝移植仍然困難，有待更多臨床研究確定[59]。

8　展　望

HC外科治療在不斷發(fā)展，更加強(qiáng)調(diào)臨床證據(jù)來(lái)選擇治療方案，而在精準(zhǔn)醫(yī)學(xué)時(shí)代，證據(jù)來(lái)源應(yīng)該更多地依據(jù)腫瘤的生物學(xué)特征，憑借以無(wú)創(chuàng)或微創(chuàng)方式獲得的腫瘤細(xì)胞分子標(biāo)志來(lái)制定基因分型，更準(zhǔn)確地指導(dǎo)外科手術(shù)方案的選擇，從而讓更多HC患者獲益。

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