秦建民

秦建民 ,海軍軍醫(yī)大學(xué)第三附屬醫(yī)院普外科 上海市 201805

0 引言

隨著生活水平的不斷改善以及診斷技術(shù)的提高,膽囊結(jié)石、息肉等疾病發(fā)病率逐漸增加,因膽囊良性疾病行膽囊切除手術(shù)亦隨之增加.腹腔鏡膽囊切除術(shù)(laparoscopic cholecystectomy,LC)具有微創(chuàng)、術(shù)后恢復(fù)快等優(yōu)點(diǎn),目前已經(jīng)成為膽囊良性疾病手術(shù)切除的首選方法,近年來LC技術(shù)已廣泛應(yīng)用臨床,術(shù)中或術(shù)后意外發(fā)現(xiàn)膽囊癌發(fā)生率逐漸增加.意外膽囊癌(unexpected gallbladder carcinoma,UGC)是指臨床上因膽囊良性疾病行膽囊切除,術(shù)中或術(shù)后偶然發(fā)現(xiàn)的膽囊癌.LC UGC的發(fā)生率為0.2%-2%,占膽囊癌總數(shù)50%[1,2].國內(nèi)LC術(shù)中和術(shù)后UGC發(fā)生率為0.17%-0.34%[3],低于國外0.22%-0.84%[4,5].70%膽囊癌發(fā)生與膽囊結(jié)石有關(guān),膽囊結(jié)石患者膽囊癌危險(xiǎn)度是無結(jié)石患者的13.7倍,由于膽囊癌多伴有膽囊結(jié)石或炎癥,缺乏特異性臨床表現(xiàn)和血腫瘤標(biāo)志物,導(dǎo)致30%膽囊癌在術(shù)中或術(shù)后診斷[6,7],術(shù)前膽囊癌確診率僅30%,膽囊癌惡性程度高,較早出現(xiàn)淋巴結(jié)轉(zhuǎn)移和侵犯臨近臟器,手術(shù)切除率低,5年生存率不足5%[8-10].由于UGC手術(shù)僅按膽囊良性疾病切除膽囊,未按惡性腫瘤原則處理,術(shù)后容易導(dǎo)致腫瘤種植、轉(zhuǎn)移淋巴結(jié)腫瘤殘留等問題,嚴(yán)重影響預(yù)后.因此早期發(fā)現(xiàn)膽囊癌,減少誤漏診發(fā)生,對(duì)UGC選擇合理的治療方法,是提高膽囊癌療效和改善預(yù)后的關(guān)鍵.

1 UGC的臨床特點(diǎn)與早期診斷

1.1 UGC誤漏診原因 膽囊癌發(fā)病隱匿,70%以上合并膽石癥,而膽石癥患者膽囊癌發(fā)生率為4.5%-14%,27%-41%膽囊癌患者是以UGC形式被發(fā)現(xiàn)[11,12].超過1%急性膽囊炎患者并發(fā)膽囊癌,非急性膽囊炎中膽囊癌發(fā)生率為0.4%,以急性膽囊炎為臨床表現(xiàn)患者中UGC的發(fā)生率高于非急性膽囊炎患者,急性炎癥臨床表現(xiàn)極易掩蓋膽囊癌的臨床表現(xiàn)和影像學(xué)表現(xiàn),導(dǎo)致術(shù)前UGC誤漏診[13,14].術(shù)前準(zhǔn)備時(shí)間短、檢查不夠充分,是UGC發(fā)生誤漏診的主要原因之一.膽囊結(jié)石或息肉合并膽囊炎癥時(shí)B超、計(jì)算機(jī)斷層掃描(computed tomography,CT) 和/或磁共振成像(magnetic resonance imaging,MRI)對(duì)膽囊壁內(nèi)微小病灶、膽囊壁厚度、膽囊壁與周圍組織的界限顯示欠清晰,易掩蓋膽囊癌早期的影像學(xué)特征.膽囊息肉樣病變分為腫瘤性(腺癌和腺瘤)和非腫瘤性(炎性息肉、膽固醇息肉、腺肌增生等),膽囊腺瘤癌變率為10%-19.3%[15].目前影像學(xué)和血液腫瘤標(biāo)志物等尚不能判斷膽囊息肉樣病變是否惡變,而且腹腔鏡手術(shù)中醫(yī)生對(duì)膽囊病變無觸覺感,尤其膽囊癌早期病變未侵犯漿膜層時(shí),術(shù)中更難以發(fā)現(xiàn)異常.若存在急性炎癥、充血、水腫、粘連等病理變化時(shí),術(shù)前、術(shù)中診斷更加困難、容易誤漏診.

1.2 重視術(shù)前影像學(xué)和腫瘤標(biāo)志物檢查在早期膽囊癌診斷中的作用 超聲簡便易行、敏感性高,是診斷膽囊疾病的首選檢查方法,準(zhǔn)確率與檢查設(shè)備、操作醫(yī)生技術(shù)和臨床經(jīng)驗(yàn)密切相關(guān).增強(qiáng)CT與MRI、磁共振胰膽管成像(magnetic resonance cholangiopancreatography,MRCP)檢查能客觀反映膽囊與膽管影像全貌和臨近臟器關(guān)系,對(duì)臨床治療方案的制定具有重要參考價(jià)值.膽囊癌早期檢出率僅為8.3%,超聲、CT、MRI診斷準(zhǔn)確率分別為63.8%、58.3%、72.2%,超聲、CT和MRI聯(lián)合診斷準(zhǔn)確率為86.1%.超聲及MRI對(duì)膽囊腔內(nèi)病變顯示優(yōu)于CT.CT、MRI對(duì)合并周圍臟器浸潤的顯示較超聲清晰,MRI能夠更加敏感分辨血管及腫大淋巴結(jié)[16].早期膽囊癌尤其合并結(jié)石者,B超診斷的敏感性下降,僅為53%,彩色多普勒超聲對(duì)小結(jié)節(jié)型膽囊癌,以最大血流速度Vmax≥0.2 m/s作為判斷惡性病變的指標(biāo),敏感性為81.8%,特異性為98.5%,準(zhǔn)確性為96%; 若以阻力指數(shù)RI>0.6作為判斷惡性病變的指標(biāo),其敏感性為72.7%,特異性為98.5%,準(zhǔn)確性為94.7%[17,18].超聲造影(contrast-enhanced ultrasonography,CEUS)診斷膽囊癌符合率為92.31%,優(yōu)于彩色多普勒超聲,CEUS對(duì)于腫瘤性壁增厚的膽囊癌診斷敏感性、特異性、準(zhǔn)確率分別為84.6%、100%、98.4%[19,20].諧波對(duì)比增強(qiáng)超聲內(nèi)鏡(contrast-enhanced harmonic endoscopic ultrasonography,CEH-EUS)對(duì)壁厚型膽囊癌診斷的敏感性、特異性、準(zhǔn)確率分別為89.6%、98%和94.4%,敏感性高于超聲內(nèi)鏡(endoscopic ultrasonography,EUS); CEH-EUS對(duì)膽囊惡性結(jié)節(jié)樣病變?cè)\斷的敏感性、特異性、準(zhǔn)確率分別為100.0%、94.4%和95.8%,表明CEH-EUS對(duì)于區(qū)分膽囊良惡性病變具有重要的臨床應(yīng)用價(jià)值[21,22].CEH-EUS對(duì)直徑大于1 cm息肉樣膽囊癌診斷的敏感性和特異性分別為93.5%和93.2%優(yōu)于EUS(90%、91.1%)[23].增強(qiáng)CT對(duì)膽囊癌診斷符合率為84.35%,與超聲相比,CT在膽囊癌和慢性膽囊炎、膽囊息肉的鑒別診斷以及臨床分期和可切除性判斷等方面具有更強(qiáng)的優(yōu)勢(shì),對(duì)膽囊癌的總體確診率高于超聲[24].MRI對(duì)膽囊癌術(shù)前診斷符合率為91.57%,肝臟直接浸潤診斷符合率為70.45%,淋巴結(jié)轉(zhuǎn)移敏感性為64.51%,MRI彌散加權(quán)膽囊癌的診斷敏感性和特異性分別為83.3%和100%[25,26].MRI結(jié)合MRCP更能敏感地顯示膽囊癌及其與鄰近臟器受累情況,清晰地顯示肝內(nèi)外膽管受累所致膽道梗阻征象,有利于準(zhǔn)確評(píng)估腫瘤局部浸潤范圍.MRI在區(qū)分膽囊癌T1期(腫瘤局限于黏膜層)和T2期(腫瘤局限于黏膜肌層)敏感性(84.9%)優(yōu)于CT(83.9%)和EUS(79.5%)[27,28].正電子發(fā)射斷層掃描(positron emission tomography,PET)-CT作為一種功能及解剖顯像,膽囊癌診斷準(zhǔn)確率為95.9%,淋巴結(jié)轉(zhuǎn)移為85.7%,遠(yuǎn)處轉(zhuǎn)移為95.9%,術(shù)后局部殘余癌診斷敏感性和特異性分別為78%和80%,表明PET-CT對(duì)膽囊癌診斷、淋巴結(jié)、遠(yuǎn)處轉(zhuǎn)移和療效評(píng)估具有重要價(jià)值[29,30].浸潤型膽囊癌誤漏診率最多,為63.16%,與病灶較小、侵及肌層,影像學(xué)檢查早期難以清晰發(fā)現(xiàn)有關(guān); 結(jié)節(jié)型膽囊癌易將病灶誤認(rèn)為是結(jié)石、息肉,腫塊型膽囊癌易誤診為膽汁分層改變[31].

目前膽囊癌缺乏一種特異性公認(rèn)的血清學(xué)腫瘤標(biāo)志物,雖然現(xiàn)有的一些血清學(xué)腫瘤標(biāo)志物對(duì)膽囊癌早期診斷缺乏特異性,但這些腫瘤標(biāo)志物表達(dá)水平的異常對(duì)早期膽囊癌的診斷具有一定參考價(jià)值.CA242對(duì)膽道惡性腫瘤的敏感性優(yōu)于CA19-9、CEA,其敏感性、特異性分別為84%、98.7%,是目前已知的膽道腫瘤最敏感腫瘤標(biāo)志物[32,33].CA19-9對(duì)膽囊癌診斷陽性率為32%,CEA對(duì)膽囊癌診斷陽性率為26%,二者聯(lián)合檢測(cè)陽性率為64%[34].術(shù)前CEA、CAl9-9雙陰性組、單獨(dú)CAl9-9陽性組、單獨(dú)CEA陽性組和CEA、CAl9-9雙陽性組的膽囊癌患者R0切除率分別為86.1%、73.1%、71.4%、45.1%,術(shù)后5年生存率分別為36.7%、5.6%、9.5%、0,其中CEA、CAl9-9雙陰性組患者R0切除率較高、預(yù)后最好,建議積極行根治性手術(shù)治療,而CEA、CAl9-9雙陽性組患者R0切除率偏低、預(yù)后較差,且常合并有臨近臟器和淋巴結(jié)轉(zhuǎn)移,是否需要行擴(kuò)大性手術(shù)切除范圍需要綜合評(píng)估,謹(jǐn)慎選擇[35].四個(gè)標(biāo)志物聯(lián)合檢測(cè)有助于膽囊癌早期診斷、治療效果和預(yù)后評(píng)估[36].超聲聯(lián)合血清CA19-9、CEA診斷膽囊癌敏感性為90%,特異性92%,高于單純B超或血清CA19-9、CEA檢查[37].術(shù)前血清CA125和CA19-9水平高的膽囊癌患者中位生存時(shí)間明顯短于低水平者(P<0.05),但術(shù)前血清CEA水平與總體生存時(shí)間無關(guān)(P>0.05),術(shù)前血清CA1 9-9及CA125可以作為膽囊癌診斷及預(yù)后判斷指標(biāo)[33,38].影像學(xué)聯(lián)合血清學(xué)腫瘤標(biāo)志物檢查,對(duì)于提高膽囊癌早期檢出率,降低UGC發(fā)生率,具有重要的臨床應(yīng)用價(jià)值.

2 術(shù)中仔細(xì)探查和快速病理檢查是降低UGC誤漏診的重要措施

對(duì)于高危的膽囊癌患者,尤其術(shù)前影像學(xué)和/或血清腫瘤標(biāo)志物異常,高度懷疑膽囊癌的患者實(shí)施膽囊切除術(shù),應(yīng)仔細(xì)操作,盡可能避免術(shù)中膽囊破裂、膽汁外溢情況發(fā)生,如果局部炎癥粘連嚴(yán)重,LC操作切除困難,及時(shí)中轉(zhuǎn)開腹,保證膽囊切除的完整性,術(shù)中對(duì)肝臟結(jié)節(jié)或腫大淋巴結(jié)獲取組織病理檢查.UGC的診斷主要依賴于手術(shù)中病理檢查.術(shù)中發(fā)現(xiàn)膽囊內(nèi)有腫塊或膽囊壁有浸潤性或增厚性改變時(shí)應(yīng)快速冰凍病理檢查,術(shù)中快速病理檢查診斷膽囊癌的特異度和靈敏度分別為100%和65%,對(duì)于膽囊原位癌診斷率為42%[39,40].因此術(shù)中發(fā)現(xiàn)膽囊異常,膽囊切除后標(biāo)本均應(yīng)常規(guī)剖開檢查,仔細(xì)觀察和觸摸膽囊壁有無異常腫塊、硬結(jié)以及局限增厚情況,膽囊黏膜是否規(guī)則、完整,有無潰瘍、中斷、增厚突起、皺縮變硬,膽囊黏膜有無灰白色顏色改變,和乳頭狀物附著等.病變處或可疑病變處組織多點(diǎn)全層取材,尤其病變與膽囊粘膜交匯處組織,減少漏診率,提高快速病理準(zhǔn)確率.

3 UGC治療方法的選擇

3.1 術(shù)中或術(shù)后病理分期是選擇UGC治療方法的重要依據(jù) 由于膽囊壁生理解剖結(jié)構(gòu)特殊,僅有黏膜層與肌層直接相連,而無黏膜下組織,且肌層薄弱,使膽囊癌易侵犯肌層而突出漿膜外,造成周圍局部組織器官受[41,42].15%-20%膽囊癌是在術(shù)中探查或術(shù)后病理檢查發(fā)現(xiàn),而在膽囊癌得到確診時(shí),僅有20%患者病變局限于膽囊壁內(nèi),80%已侵犯臨近組織或出現(xiàn)遠(yuǎn)處轉(zhuǎn)移[43].膽囊癌患者預(yù)后與腫瘤是否R0切除、淋巴結(jié)轉(zhuǎn)移、病理T分期、血管侵犯等因素密切相關(guān),由于初次手術(shù)僅行單純膽囊切除缺乏淋巴結(jié)、臨近臟器是否有轉(zhuǎn)移等資料,無法完成TNM分期準(zhǔn)確評(píng)估,因此將病理T分期作為UGC危險(xiǎn)因素評(píng)估和治療方法選擇的重要依據(jù)[44-46].TNM分期中原發(fā)腫瘤T分期[47]:(1)Tis為黏膜原位癌; (2)T1為腫瘤侵犯黏膜固有層(Tla)或肌層(Tlb); (3)T2為腫瘤穿透肌層,但未侵犯漿膜或肝臟; (4)T3為腫瘤穿透漿膜層,或直接侵犯肝臟和(或)一個(gè)鄰近器官; (5)T4為腫瘤侵犯門靜脈主干或肝動(dòng)脈,或直接侵犯兩個(gè)或以上肝外器官.UGC中T2期腫瘤最常見,占47%,T3期與T1期分別位25.1%、23%,T4期與Tis期較少見,分別為4.2%、2.4%[47].由于術(shù)中冰凍病理檢查取材范圍局限性,不可能涉及整個(gè)膽囊壁,而且冰凍病理檢查難以區(qū)分黏膜不典型增生與膽囊局灶癌變,導(dǎo)致術(shù)中冰凍病理檢出癌細(xì)胞靈敏度為64%-84.2%,靈敏度隨腫瘤浸潤深度增加而增加.術(shù)中冰凍病理檢查評(píng)估Tis期靈敏度為40%,T2及T3期腫瘤靈敏度為83%,術(shù)中冰凍病理檢查對(duì)癌細(xì)胞侵犯深度的評(píng)估準(zhǔn)確性為70%-85.7%,對(duì)膽管切緣陽性診斷誤差率為25%[48-50].膽囊癌淋巴結(jié)轉(zhuǎn)移與腫瘤浸潤深度(T分期)密切相關(guān),淋巴結(jié)轉(zhuǎn)移和淋巴管侵犯在Tlb期中分別為15.7%、18.4%,T2、T3、T4期淋巴結(jié)轉(zhuǎn)移陽性率隨T分期逐漸增加,分別為46%-48%、72%和80%,淋巴結(jié)轉(zhuǎn)移程度與患者預(yù)后明顯相關(guān),pN0、pN1、pN2及pN3期膽囊癌患者5年生存率分別為60.3%、30%、16.8%及5.9%; Tla期、T1b期、T2期、T3期患者5年累積生存率分別為95.7%、90%、75%、40%,隨T分期和淋巴結(jié)轉(zhuǎn)移增加膽囊癌生存率逐漸降低[51,52].UGC行LC后腫瘤復(fù)發(fā)和腹膜種植發(fā)生率為10%-29%,膽漏發(fā)生率為22%,癌細(xì)胞可能會(huì)通過漏出的膽汁種植于腹膜、大網(wǎng)膜、皮膚切口或其他器官表面,造成腹腔種植轉(zhuǎn)移或切口轉(zhuǎn)移,膽囊破潰膽汁漏出是切口及腹膜轉(zhuǎn)移的主要原因,是影響Tis及T1期UGC預(yù)后的重要因素[53-57].病理T分期、有無淋巴結(jié)轉(zhuǎn)移、術(shù)中膽囊破裂是影響UGC患者預(yù)后的獨(dú)立危險(xiǎn)因素[52],因此術(shù)中或術(shù)后病理分期是評(píng)估UGC嚴(yán)重程度和制定治療方案的客觀依據(jù).

3.2 堅(jiān)持循證醫(yī)學(xué)原則,合理選擇UGC治療方法 術(shù)中或術(shù)后發(fā)現(xiàn)UGC,依據(jù)術(shù)中探查情況、淋巴結(jié)和腫瘤組織病理檢查結(jié)果,需要術(shù)中及時(shí)中轉(zhuǎn)開腹或腹腔鏡膽囊癌根治切除術(shù),以及術(shù)后再次行膽囊癌根治性手術(shù).Tis期、T1a期膽囊癌腫瘤未侵及肌層,淋巴結(jié)轉(zhuǎn)移率為2.5%,84%UGC患者行單純膽囊切除術(shù),其中46%采用LC,單純膽囊切除術(shù)后腫瘤復(fù)發(fā)率為1.1%-3.7%,5年生存率為90%-100%[57,58-60].術(shù)中膽囊完整切除,無破潰及膽汁溢出,單純切除膽囊即達(dá)到根治效果,無需常規(guī)行膽囊床肝臟楔形切除和肝十二指腸韌帶淋巴結(jié)清掃,術(shù)后1、3、5年累計(jì)生存率分別為100%、96.2%、96.2%[61-63].T1b期UGC侵及膽囊肌層,膽囊床側(cè)膽囊沒有漿膜層,癌細(xì)胞通過膽囊靜脈回流入肝臟致肝床微轉(zhuǎn)移,腫瘤肝床微轉(zhuǎn)移距離不超過1.6 cm,需行距膽囊床2 cm以上肝組織切除,獲得腫瘤根治性切除.淋巴結(jié)轉(zhuǎn)移首先累及膽囊三角淋巴結(jié)及沿膽總管分布的淋巴結(jié),淋巴結(jié)轉(zhuǎn)移率15.7%,淋巴管浸潤率為18%.術(shù)中常規(guī)行13a淋巴結(jié)活檢,若13a淋巴結(jié)活檢陰性,行12組和8組淋巴結(jié)清掃; 若13a淋巴結(jié)活檢陽性,則行擴(kuò)大淋巴結(jié)清掃,包括12組、8組、13組和9組淋巴結(jié)[64,65].Tlb期UGC患者術(shù)后1、3、5年累積生存率分別為100%、89.7%和82.8%.T1b期膽囊癌根治術(shù)后淋巴結(jié)轉(zhuǎn)移率僅為1.4%,擴(kuò)大切除并未增加T1b期膽囊癌的長期生存率,根治切除術(shù)后5年生存率為83.3%,與開腹膽囊切除、LC術(shù)后5年生存率84.4%、68.8%相比,無顯著性差異(P>0.05)[59,66-69].但多數(shù)研究發(fā)現(xiàn)Tlb期UGC出現(xiàn)淋巴管、神經(jīng)侵犯發(fā)生率分別為12%、2.5%,遠(yuǎn)高于Tla期的2.5%、0.4%.Tlb期UGC行單純膽囊切除術(shù)后腫瘤殘留發(fā)生率為10%,膽囊癌根治手術(shù)使Tlb期膽囊癌5年生存率由42%增加為79%,腫瘤復(fù)發(fā)率由24.5%降低為8.6%,差異具有顯著性(P<0.05)[59,67].因此基于T1b期UGC病理和生物學(xué)行為特點(diǎn),筆者認(rèn)為對(duì)于T1b期UGC行膽囊癌根治性切除術(shù)是合理的選擇.

T2期UGC侵犯膽囊肌層及周圍結(jié)締組織,但未突破漿膜層或未侵及肝臟,膽囊癌細(xì)胞經(jīng)膽囊靜脈回流入肝臟,回流肝臟范圍距膽囊床2-5 cm,且至少有1個(gè)方向范圍>4 cm.31% T2期膽囊癌患者合并肝轉(zhuǎn)移,因此對(duì)于T2期UGC患者常規(guī)行肝臟Ⅳb和Ⅴ段切除[65,70].T2期UGC中將膽囊腹腔游離側(cè)腫瘤分為T2a期,肝臟側(cè)分為T2b期,T2a期淋巴結(jié)轉(zhuǎn)移、神經(jīng)侵犯和血管侵犯概率遠(yuǎn)低于T2b期膽囊癌.T2a期UGC患者接受根治性切除術(shù)5年生存率(70.5%),與未行肝切除的患者(54.8%)無顯著性差異,而T2b期UGC患者行根治性切除術(shù)后5年生存率為80.3%,明顯高于未行肝切除30%; T2a期膽囊癌術(shù)后3年、5年存活率(73.7%、64.7%)顯著高于T2b期(52.1%、42.6%),T2a期膽囊癌預(yù)后優(yōu)于T2b期膽囊癌[71,72].T2期膽囊癌中神經(jīng)浸潤發(fā)生率為25%-35%,淋巴結(jié)轉(zhuǎn)移率為19%-62%,術(shù)中先行16組淋巴結(jié)病理檢查,若為陽性表明已有遠(yuǎn)處轉(zhuǎn)移,僅行姑息治療; 若l6組淋巴結(jié)陰性,再行13a組淋巴結(jié)活檢,13a組淋巴結(jié)活檢陽性者,則行8組、12組、13a組、9組淋巴結(jié)和神經(jīng)纖維組織清掃; 13a組淋巴結(jié)活檢陰性者,需要清掃8組、l2組淋巴結(jié)和神經(jīng)纖維組織; T2期膽囊癌患者術(shù)中行淋巴結(jié)清掃和未清掃術(shù)后5年生存率分別為50%、10%,有顯著性差異(P<0.05)[65,73,74].由于T2期UGC行單純膽囊切除術(shù)后腫瘤殘留率為40%,單純膽囊切除術(shù)后5年生存率顯著低于膽囊癌根治術(shù)(38%vs78%),膽囊癌根治性切除術(shù)顯著提高T2期UGC患者生存率[75-77],T3期UGC神經(jīng)浸潤發(fā)生率為25%-35%,36.4%患者出現(xiàn)肝臟轉(zhuǎn)移,淋巴結(jié)轉(zhuǎn)移發(fā)生率為45%-70%,腫瘤殘留發(fā)生率為36%,單純膽囊切除術(shù)后5年存活率(8%-19%)顯著低于膽囊癌根治術(shù)(34%-40%)[74,78,79]; 因此T3期膽囊癌需行膽囊癌擴(kuò)大根治術(shù),包括膽囊腫瘤切除、受累部分肝臟切除、臨近臟器組織聯(lián)合切除及淋巴結(jié)清掃,達(dá)到R0切除的T3期膽囊癌患者術(shù)后5年生存率可達(dá)到60.6%[80,81].由于T4期膽囊癌腫瘤累及臨近或遠(yuǎn)處多個(gè)臟器組織,淋巴結(jié)轉(zhuǎn)移率高達(dá)67%-80%,預(yù)后差,但對(duì)于部分患者可行擴(kuò)大性根治性手術(shù),包括受累肝臟的半肝以上切除、聯(lián)合臨近受累臟器、動(dòng)脈或靜脈切除、擴(kuò)大淋巴結(jié)范圍清掃,可改善其預(yù)后[80,82].對(duì)于UGC是否需要肝外膽管切除,與腫瘤部位、膽囊管切緣是否受侵有關(guān),如果術(shù)中發(fā)現(xiàn)腫瘤累及膽囊管或病理檢查膽囊管殘端腫瘤殘留,則需要肝外膽管切除.對(duì)于膽囊頸部或膽囊管癌患者,膽囊管癌易經(jīng)肝十二指腸韌帶侵犯至胰頭、主動(dòng)脈旁淋巴組織及肝臟Glission鞘,膽囊管癌對(duì)周圍神經(jīng)、淋巴結(jié)/管、血管的侵犯比例明顯高于膽囊底、體部癌,膽囊管癌3、5年生存率明顯低于膽囊底、體部癌,膽囊管癌要比同期的其它部位膽囊癌手術(shù)范圍更大,無論任何分期均需要行聯(lián)合肝外膽管切除的膽囊癌根治術(shù),降低術(shù)后復(fù)發(fā)率,改善預(yù)后[83,84].

術(shù)后發(fā)現(xiàn)UGC需要再次手術(shù)的膽囊癌患者,再次手術(shù)的時(shí)機(jī)一直是臨床醫(yī)生關(guān)注的問題.腫瘤的轉(zhuǎn)移發(fā)生在第1次手術(shù)后30 d內(nèi),建議再次手術(shù)間隔時(shí)間為第1次手術(shù)后6 wk內(nèi)[64,85].雖然Butte等[86]研究發(fā)現(xiàn)UGC首次行膽囊切除術(shù)與二次切除的時(shí)間間隔長短對(duì)預(yù)后無明顯影響,首次手術(shù)方式(LC、開腹膽囊切除、LC+中轉(zhuǎn)開腹、剖腹探查等)對(duì)再次根治性切除患者生存率無顯著影響,但大多數(shù)研究認(rèn)為再次手術(shù)應(yīng)在初次手術(shù)后1-4 wk內(nèi)實(shí)施為宜[87,88].Du等[89]分析UGC術(shù)后2 wk內(nèi)、2 wk-1 mo和超過1 mo再次行根治性手術(shù),結(jié)果發(fā)現(xiàn)2 wk內(nèi)再次手術(shù)術(shù)后1、3、5年累積生存率分別為94.6%、69.6%和 41.4%(P<0.01),但2 wk-1 mo和超過1 mo再次行根治性手術(shù)后生存期之間無顯著性差異(P>0.01),2 wk內(nèi)再次手術(shù)術(shù)后生存期優(yōu)于2 wk后手術(shù),建議UGC再次手術(shù)時(shí)間宜在2 wk內(nèi)進(jìn)行,延遲手術(shù)可使腫瘤播散,失去根治性手術(shù)機(jī)會(huì).孟強(qiáng)勞等[90]研究發(fā)現(xiàn)UGC術(shù)后生存期與初次手術(shù)T分期、病理分化程度、有無病灶殘留、二次術(shù)后N分期及切緣有關(guān),而與性別、年齡及二次手術(shù)時(shí)間無關(guān),初次手術(shù)有無病灶殘留和二次術(shù)后手術(shù)切緣是影響UGC預(yù)后重要因素.無病灶殘留UGC患者預(yù)后與二次手術(shù)時(shí)間無關(guān),但對(duì)有病灶殘留的UGC患者,手術(shù)時(shí)間越早,患者預(yù)后越好,二次手術(shù)力求達(dá)到R0切除.術(shù)后依據(jù)病理分期決定是否需要化療和/或局部放療,對(duì)于無法根治性切除的患者術(shù)后依據(jù)腫瘤生物學(xué)行為和基因檢測(cè)結(jié)果,針對(duì)高腫瘤負(fù)荷、高微衛(wèi)星不穩(wěn)定性、DNA錯(cuò)配修復(fù)的UGC患者,聯(lián)合化療、分子靶向藥物、pembrolizumab單抗、放療等綜合性治療,延長患者生存期.

4 心理支持在UGC患者康復(fù)中具有不可忽視的重要作用

LC或開腹膽囊切除術(shù)后發(fā)現(xiàn)UGC,患者在術(shù)后短期內(nèi)需要接受第二次手術(shù),短期內(nèi)再次手術(shù)作為一種強(qiáng)烈的心理應(yīng)激源,導(dǎo)致患者緊張、恐懼、焦慮和悲觀等不良心理反應(yīng),嚴(yán)重者出現(xiàn)失眠、食欲減退、失去生活信心等負(fù)面情緒,這種心理狀態(tài)直接影響患者術(shù)后康復(fù)和治療效果,因此根據(jù)患者心理狀態(tài)評(píng)估,制定針對(duì)性心理干預(yù)計(jì)劃,通過耐心、細(xì)致的心理疏導(dǎo),解答患者提出的各種問題,消除內(nèi)心疑慮、恐懼和悲觀情緒,提高患者對(duì)疾病以及再次治療手術(shù)方式的了解,建立良好的支持性家庭社會(huì)關(guān)系,消除緊張、焦慮的負(fù)面情緒[91].有效的心理支持可消除患者的心理問題,通過音樂療法、心理暗示法、轉(zhuǎn)移注意力法等緩解患者負(fù)性情緒,必要時(shí)讓手術(shù)成功UGC患者面對(duì)面分享經(jīng)驗(yàn),幫助患者樹立治療信心,增強(qiáng)患者對(duì)抗疾病的信心[92].

5 重視膽囊癌的早期預(yù)防,降低UGC發(fā)生率

國內(nèi)膽囊癌伴發(fā)膽囊結(jié)石為20%-82.6%,國外膽囊癌伴發(fā)膽囊結(jié)石為54.3%-100%,膽囊結(jié)石患者發(fā)生膽囊癌危險(xiǎn)度是無膽囊結(jié)石的13.7倍,結(jié)石<1 cm患癌概率為1%,結(jié)石2-2.2 cm為2.4%,結(jié)石>3 cm為10%,膽囊結(jié)石反復(fù)機(jī)械刺激、合并細(xì)菌感染、膽汁中毒素刺激誘發(fā)膽囊癌發(fā)生[93-95].膽囊腺癌占膽囊息肉樣病變8.4%-16.4%,膽囊腺瘤的癌變率為19.3%-58.8%[96,97].膽囊息肉病變直徑>14.5 mm應(yīng)高度懷疑癌變,T1期膽囊癌病變平均直徑為20.5 mm±5.8 mm,超過27 mm則可能在T2期及以上,表明膽囊息肉樣病變大小與膽囊癌發(fā)生有一定的相關(guān)性[98].膽囊腺瘤直徑>1 cm腺瘤惡變幾率更高,膽囊腺肌病為癌前病變,具有癌變傾向[99,100].

圖1 意外膽囊癌臨床診治流程 .CEUS:超聲造影; CEH-EUS:諧波對(duì)比增強(qiáng)超聲內(nèi)鏡; CT:計(jì)算機(jī)斷層掃描; MRI:磁共振成像; PET:正電子發(fā)射斷層掃描.

膽囊癌發(fā)生的高危因素[101,102]:(1)年齡≥60歲,慢性膽囊炎、膽囊結(jié)石病史≥10年,疼痛反復(fù)發(fā)作; (2)膽囊充滿型結(jié)石或結(jié)石占據(jù)膽囊腔50%以上,結(jié)石直徑≥2 cm; (3)長期膽囊結(jié)石伴膽囊萎縮,或伴膽囊壁增厚、鈣化,尤其瓷化膽囊; (4)單個(gè)廣基、無蒂的息肉,直徑>1 cm,近期明顯增大; (5)膽囊結(jié)石合并膽囊息肉; (6)糖尿病合并膽囊結(jié)石,反復(fù)發(fā)作; (7)膽囊腺肌癥、膽囊黃色肉芽腫性膽囊炎、膽囊腺瘤.對(duì)于膽囊結(jié)石或/和膽囊息肉患者腹痛失去原有的誘因與規(guī)律性,疼痛時(shí)間明顯延長; 無癥狀的膽囊息肉、萎縮性膽囊炎近期出現(xiàn)明顯持續(xù)性疼痛; 明顯的飲食減少、乏力、體重下降而又排除胃腸道疾病等情況時(shí),應(yīng)警惕膽囊癌變發(fā)生[103].對(duì)有高危因素的膽囊良性疾病患者,應(yīng)做到術(shù)前結(jié)合B超、CEUS、CA19-9、CA125、CEA等進(jìn)行初步篩選,必要時(shí)行CT、MRI、CEH-EUS、PET-CT等影像學(xué)檢查進(jìn)行定位診斷,以實(shí)現(xiàn)早期診斷膽囊癌.對(duì)于結(jié)石性萎縮膽囊炎、瓷化膽囊或直徑1 cm以上的膽囊息肉、腺瘤、腺肌癥,以及膽囊結(jié)石合并膽囊息肉者,不管息肉大小或有無癥狀,因?yàn)槟懩医Y(jié)石反復(fù)刺激膽囊黏膜和息肉,雙重危險(xiǎn)因素會(huì)增加膽囊癌發(fā)生,均應(yīng)積極行預(yù)防性膽囊切除,降低膽囊癌的發(fā)生率.

膽囊具有儲(chǔ)存、濃縮膽汁和收縮功能,以及復(fù)雜的化學(xué)和免疫功能,膽汁進(jìn)入膽囊進(jìn)行存儲(chǔ)和濃縮(濃縮后的膽汁比肝膽汁濃縮30倍),膽囊具有重要的調(diào)節(jié)消化功能,膽囊切除術(shù)后膽汁持續(xù)排入腸道,因此膽汁返流性胃炎的機(jī)會(huì)增加,進(jìn)食時(shí)無足夠的膽汁,影響腸道消化降解及細(xì)菌調(diào)節(jié)功能,從而引起消化不良、腹脹、腹瀉等癥狀[104].另外膽囊切除術(shù)后膽鹽代謝異常和自主神經(jīng)功能紊亂,膽道壓力改變使膽管內(nèi)流體壓力失去了緩沖作用,導(dǎo)致膽總管內(nèi)壓力增高,引起膽總管代償性擴(kuò)張,膽汁容易在膽管內(nèi)形成渦流產(chǎn)生結(jié)石.膽汁壓力改變、渦流形成及膽汁返流引起膽管下端局部慢性炎癥水腫,導(dǎo)致Oddi括約肌狹窄和縮窄性 Vater乳頭炎,引起腹痛等癥狀[105].膽囊切除術(shù)膽管損傷發(fā)生率為0.6%-1.5%,因膽管損傷所致病死率為6%[106,107].膽囊切除術(shù)后結(jié)腸癌發(fā)生危險(xiǎn)性增加1.34倍,尤其右半結(jié)腸癌增加1.88倍,多發(fā)生于膽囊切除術(shù)后10-15年[108].由于膽囊切除術(shù)后這些因素的影響,近年來腹腔鏡保留膽囊取石、息肉摘除術(shù)作為治療膽囊結(jié)石、息肉等膽囊良性疾病的治療方法之一,具有創(chuàng)傷小、恢復(fù)快、并發(fā)癥少等特點(diǎn),在臨床上應(yīng)用逐漸增多,但UGC與結(jié)石、息肉術(shù)后再復(fù)發(fā)逐漸成為膽囊保留取石或息肉摘除手術(shù)后不可回避的問題,成為制約膽囊保留性手術(shù)發(fā)展的重要因素,保留膽囊息肉摘除后息肉復(fù)發(fā)率0.1%,膽囊結(jié)石復(fù)發(fā)率為3.9%,UGC發(fā)生率為0.53%[109].由于保膽手術(shù)中的膽囊切開、術(shù)中反復(fù)沖洗和擠壓膽囊、術(shù)中膽道鏡、腔內(nèi)超聲檢查等方法的運(yùn)用,將難以避免造成膽汁外溢,如果存在惡性腫瘤時(shí)有促進(jìn)腫瘤腹腔轉(zhuǎn)移的可能,惡變的膽囊息肉摘除術(shù)后可能存在基底部腫瘤殘留.

因此,對(duì)于有膽囊結(jié)石或/和息肉的患者有強(qiáng)烈保膽治療愿望時(shí),應(yīng)嚴(yán)格掌握保膽手術(shù)的指征,對(duì)于存在膽囊癌高危因素的膽囊良性疾病不宜采用保膽手術(shù)治療,不應(yīng)將患者主觀保膽愿望作為保膽治療的附加條件,嚴(yán)格掌握保膽手術(shù)的技術(shù)規(guī)范和適應(yīng)證,術(shù)前需要影像學(xué)和血腫瘤標(biāo)記物等嚴(yán)格篩查,加強(qiáng)術(shù)中對(duì)可疑膽囊壁病變或息肉快速病理檢查,降低UGC發(fā)生率.

6 結(jié)論

UGC是在膽囊切除術(shù)中或術(shù)后意外發(fā)現(xiàn)的,由于UGC臨床上常以膽囊結(jié)石、急慢性膽囊炎表現(xiàn)為主,早期缺乏特異性臨床表現(xiàn)、影像學(xué)特征和特異性血清腫瘤標(biāo)志物,導(dǎo)致早期確診困難,易誤診或漏診.隨著LC臨床廣泛應(yīng)用和手術(shù)指征不斷擴(kuò)大,UGC發(fā)生率逐漸增加,如何降低UGC發(fā)生率和處理好不同分期的UGC,是目前臨床醫(yī)生面臨的主要問題,只有加強(qiáng)規(guī)范化的臨床診治流程,才能有效降低UGC發(fā)生率,提高臨床療效(圖1).雖然現(xiàn)在的影像學(xué)檢查和血清腫瘤標(biāo)志物雖然缺乏特異性,但這些輔助檢查的異常表現(xiàn)能夠?yàn)榕R床膽囊癌早期診斷提供重要的參考價(jià)值,尤其對(duì)于存在膽囊癌高危因素的患者,臨床醫(yī)生要引起足夠的重視.與術(shù)前已確診的膽囊癌相比,因?yàn)閁GC僅行單純膽囊切除,未按惡性腫瘤原則實(shí)施手術(shù),而且不同病理分期臨床處理具有相對(duì)特殊性,因此需要采用個(gè)體化的治療方案,選擇合適的治療時(shí)機(jī)和方法,術(shù)后加強(qiáng)患者心理支持和其它輔助治療,才能提高UGC療效.

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