胃癌復(fù)發(fā)、轉(zhuǎn)移的研究進展

黃倩倩，陳 晶

哈爾濱醫(yī)科大學(xué)附屬第二醫(yī)院消化內(nèi)科，黑龍江 哈爾濱 150081

專題·胃癌

胃癌復(fù)發(fā)、轉(zhuǎn)移的研究進展

黃倩倩，陳 晶

哈爾濱醫(yī)科大學(xué)附屬第二醫(yī)院消化內(nèi)科，黑龍江 哈爾濱 150081

胃癌早期診斷、早期治療的理念已經(jīng)深入人心，胃鏡檢查已經(jīng)成為普通人群必不可少的體檢項目。但胃癌的復(fù)發(fā)率和病死率仍居高不下，胃癌復(fù)發(fā)、轉(zhuǎn)移成為威脅胃癌患者生命的首要因素。所以,對胃癌復(fù)發(fā)、轉(zhuǎn)移的研究也越來越引起人們的關(guān)注。本文就胃癌復(fù)發(fā)、轉(zhuǎn)移的研究進展作一概述。

胃癌；復(fù)發(fā)；轉(zhuǎn)移；監(jiān)測；預(yù)防；危險因素

胃癌復(fù)發(fā)、轉(zhuǎn)移是胃癌患者預(yù)后差、病死率高的主要原因。胃癌不但復(fù)發(fā)率高，復(fù)發(fā)后再手術(shù)的生存率也很低。相關(guān)研究[1]表明，局部進展期胃癌術(shù)后復(fù)發(fā)率為40%～70%，2次術(shù)后的5年生存率不足25%[2]。因此，如何評估、監(jiān)測和預(yù)防胃癌復(fù)發(fā)就變得尤為重要。

1 胃癌復(fù)發(fā)、轉(zhuǎn)移的分型

胃癌因復(fù)發(fā)部位的不同分為手術(shù)區(qū)域的局部復(fù)發(fā)、腹膜復(fù)發(fā)、肝轉(zhuǎn)移、肝臟以外血行轉(zhuǎn)移、非手術(shù)區(qū)域的遠處淋巴結(jié)轉(zhuǎn)移、復(fù)發(fā)性轉(zhuǎn)移，根據(jù)復(fù)發(fā)的時間分為早期復(fù)發(fā)和晚期復(fù)發(fā)[3]。

2 胃癌復(fù)發(fā)、轉(zhuǎn)移的危險因素

2.1 癌組織因素

2.1.1 淋巴管、血管侵犯：淋巴管或血管轉(zhuǎn)移是胃癌常見的轉(zhuǎn)移途徑，淋巴管和血管受侵犯的患者極易發(fā)生胃癌復(fù)發(fā)、轉(zhuǎn)移。Saito等[4]表示，淋巴結(jié)陰性的2、3期胃癌患者，淋巴管和血管的侵犯是胃癌復(fù)發(fā)、轉(zhuǎn)移的高危因素。

2.1.2 癌組織分期：胃癌的復(fù)發(fā)、轉(zhuǎn)移風(fēng)險與癌組織分期密切相關(guān)。有研究[5]表明，無淋巴結(jié)侵犯的胃腺癌，T3或更高級別的腫瘤術(shù)后復(fù)發(fā)的時間明顯縮短。Fukuchi等[6]對34例不能進行腫瘤完全切除而行保守治療的胃癌患者進行研究，發(fā)現(xiàn)82%的患者在2年內(nèi)復(fù)發(fā)，并且通過對患者年齡、性別、腫瘤位置、大體分型、組織分型等25個因素進行觀察發(fā)現(xiàn)，臨床T4b期是與胃癌復(fù)發(fā)最相關(guān)的獨立危險因素。相關(guān)研究[7]也發(fā)現(xiàn)，pT4是術(shù)后5年以上無病生存患者發(fā)生遲發(fā)性復(fù)發(fā)的危險因素。

2.1.3 癌組織位置：癌組織的原發(fā)部位不同，也會對其復(fù)發(fā)、轉(zhuǎn)移產(chǎn)生影響。研究[8]表明，早期胃癌患者邊界切除不完全、操作時間長、安全界緣窄均是胃癌內(nèi)鏡黏膜下剝離術(shù)(endoscopic submucosal dissection,ESD)術(shù)后復(fù)發(fā)的危險因素，但腫瘤的部位和肉眼邊界是諸多因素中更為重要的，病變位于胃上1/3的患者比病變位于胃下1/3的患者復(fù)發(fā)率高。除以上因素外，還有研究[5，9-10]表明，胃癌復(fù)發(fā)與腫瘤的大小、分化程度、浸潤深度及組織病理分型密切相關(guān)。

2.2 非癌組織因素

2.2.1 體質(zhì)量丟失：胃癌的預(yù)后因素與患者營養(yǎng)失調(diào)也有一定關(guān)系[11]。Yu等[12]報道外科手術(shù)后6～12個月，體質(zhì)量丟失是不良預(yù)后的一個獨立危險因素。Lee等[13]也發(fā)現(xiàn)，外科手術(shù)6個月內(nèi)體質(zhì)量丟失超過30%與胃癌的復(fù)發(fā)明顯相關(guān)。Kubo等[14]通過大量的研究證明，胃癌術(shù)后體質(zhì)量丟失過多會促進胃癌復(fù)發(fā)。

2.2.2 感染：Hayashi等[15]對502例行胃癌切除術(shù)的患者進行研究發(fā)現(xiàn)，術(shù)后感染的患者比無術(shù)后感染的患者5年無復(fù)發(fā)生存率明顯降低。術(shù)后并發(fā)感染是胃癌術(shù)后復(fù)發(fā)的獨立危險因素。

2.2.3 其他：相關(guān)研究[16]表明，圍手術(shù)期的同種異體輸血與胃癌術(shù)后無復(fù)發(fā)生存率及總生存率降低有關(guān)。診斷胃癌時的年齡大小也是早期胃癌復(fù)發(fā)的獨立危險因素[10]。

3 胃癌復(fù)發(fā)、轉(zhuǎn)移的隨訪和監(jiān)測

3.1 隨訪胃癌復(fù)發(fā)、轉(zhuǎn)移是威脅患者生命的主要原因，如何推遲和防止胃癌的復(fù)發(fā)、轉(zhuǎn)移十分重要。研究[17]表明，多數(shù)胃癌患者在術(shù)后3年復(fù)發(fā)，無淋巴結(jié)轉(zhuǎn)移的患者通常術(shù)后5年以上發(fā)病，這一時限超過了一般胃癌患者的隨訪期。因此，對于有遲發(fā)性復(fù)發(fā)風(fēng)險者，應(yīng)采取包括放、化療的多模式治療和個體化的隨訪。Tavares等[18]發(fā)現(xiàn)，臨床和病理檢查淋巴結(jié)轉(zhuǎn)移陰性的胃癌患者仍有很高的復(fù)發(fā)率，可能存在假陰性的情況，特別是在淋巴結(jié)觀察<15個的情況。因而，為了減少淋巴結(jié)假陰性率，從而減少復(fù)發(fā)，對淋巴結(jié)活檢陰性的患者也要定期隨訪。

3.2 監(jiān)測

3.2.1 內(nèi)鏡監(jiān)測：內(nèi)鏡檢查是胃癌早診斷、早治療及術(shù)后定期監(jiān)測復(fù)發(fā)的有效手段。Min等[19]對ESD術(shù)后5年內(nèi)的早期胃癌患者進行觀察，發(fā)現(xiàn)異時性胃癌的復(fù)發(fā)持續(xù)存在，并且胃外復(fù)發(fā)也會出現(xiàn)，甚至毫無征兆。所以，Min建議，術(shù)后5年內(nèi)，每年1次或2次復(fù)查胃十二指腸鏡及腹部CT。還有研究[7]表明，2.8%的患者會發(fā)生胃癌術(shù)后的遲發(fā)性復(fù)發(fā)，發(fā)生時間多在術(shù)后5～8年，因此，胃癌術(shù)后患者應(yīng)長期監(jiān)測，甚至監(jiān)測5年以上。Na等[20]對3 037例患者進行研究發(fā)現(xiàn)，對于腫瘤完整切除或高分化的早期胃癌，隨訪過程中，對于黏膜扁平、瘢痕部位不伴充血的病例沒有必要活檢。

3.2.2 影像學(xué)監(jiān)測：臨床上常用影像學(xué)監(jiān)測方法包括CT、磁共振成像(magnetic resonance imaging，MRI)及正電子發(fā)射計算機斷層顯像(PET)[21]。江曉鴻等[22]對47例胃癌患者行CT檢查，發(fā)現(xiàn)其對局部復(fù)發(fā)、腹腔淋巴結(jié)轉(zhuǎn)移、腹壁、盆腔的轉(zhuǎn)移均有較好診斷，但診斷為局部復(fù)發(fā)的15例患者中有5例經(jīng)病理證實為炎性水腫，即存在一定的假陽性率。MRI能夠很好地顯示殘胃壁及吻合口胃壁的厚度，準確地判斷腫瘤浸潤的深度、侵襲范圍及與周圍組織的毗鄰關(guān)系，是否有淋巴結(jié)及腹腔內(nèi)臟轉(zhuǎn)移等，對指導(dǎo)復(fù)發(fā)的治療有重要臨床意義[23]。近年來，PET對胃癌復(fù)發(fā)的監(jiān)測越來越受到人們的關(guān)注。相關(guān)研究[24]發(fā)現(xiàn)，18F-FDG吸收率高的患者比吸收率低的患者遠處轉(zhuǎn)移的發(fā)生率明顯升高，對于原發(fā)腫瘤18F-FDG吸收率高的患者，使用PET監(jiān)測18F-FDG吸收率可以早期探查腫瘤，并精確探測遠期復(fù)發(fā)。18F-FDG PET/CT除腹膜外，對其他部位的復(fù)發(fā)轉(zhuǎn)移病灶敏感度高且能夠全身顯像，對胃癌復(fù)發(fā)的診斷價值較其他影像學(xué)手段高，并可有效指導(dǎo)臨床決策[25]。

3.2.3 血清學(xué)監(jiān)測：CA19-9、CA153和CA125等腫瘤標志物，血管內(nèi)皮生長因子(vascular endothelial growth factor，VEGF)、缺氧誘導(dǎo)因子1α(hypoxia inducible factor-1α，HIF-1α)、血清可溶性上皮型鈣黏附蛋白(soluble epithelial cadherin，sE-cad)和骨橋蛋白(osteopontin，OPN)均對胃癌術(shù)后復(fù)發(fā)和轉(zhuǎn)移的監(jiān)測有重要意義。近年來關(guān)于Angiopoietin-like Protein 2(ANGPTL2)的研究也越來越受到人們的關(guān)注，Shimura等[26]發(fā)現(xiàn)，表達ANGPTL2的胃癌患者，腫瘤進展和轉(zhuǎn)移的可能性大，預(yù)示著預(yù)后不良，有可能成為監(jiān)測胃癌患者術(shù)后復(fù)發(fā)的有效指標。還有研究[27]報道，ANGPTL2與淋巴結(jié)及遠處器官轉(zhuǎn)移，淋巴管、血管侵犯密切相關(guān)，作為監(jiān)測胃癌復(fù)發(fā)和判斷患者預(yù)后的工具，比CEA和TNM更敏感。

3.2.4 其他：意大利胃癌研究組織(GIRCG)的預(yù)測評分系統(tǒng)[28]、CD44單核苷酸的多態(tài)性和同種型轉(zhuǎn)換[29]、血漿纖維蛋白原[30]均對胃癌的復(fù)發(fā)有預(yù)測作用。miR21-5P可以作為腫瘤內(nèi)基質(zhì)含量高的年輕胃癌患者復(fù)發(fā)的預(yù)測指標[31]。腫瘤浸潤分型對胃癌的復(fù)發(fā)也有一定預(yù)測作用。浸潤型胃癌與腹膜復(fù)發(fā)密切相關(guān)，擴張型和中間型與肝癌復(fù)發(fā)密切相關(guān)[32]。

4 胃癌復(fù)發(fā)、轉(zhuǎn)移的預(yù)防

4.1 早癌根治性切除近年來，由于不能準確地判斷早期胃癌的病變范圍，ESD術(shù)后的早期胃癌患者復(fù)發(fā)率也有所增加，且腫瘤越大，ESD手術(shù)遺漏的病損面積越大，復(fù)發(fā)率越高，因而，建議對于腫瘤>2 cm，或ESD術(shù)后切緣陽性長度>6 mm者，應(yīng)行外科手術(shù)或二次內(nèi)鏡下治療[33]。

4.2 根除H.pyloriBang等[34]通過大量的研究發(fā)現(xiàn)，早期胃癌內(nèi)鏡切除后，根除H.pylori可以有效預(yù)防異時性胃癌復(fù)發(fā)。

4.3 化療治療胃癌的有效方法仍是手術(shù)，但對于晚期患者，常因不能徹底清除病灶而發(fā)生復(fù)發(fā)和轉(zhuǎn)移。為減少該類事件的發(fā)生，常順伍[35]通過研究發(fā)現(xiàn)，術(shù)后應(yīng)用化療加強治療可有效地徹底清除病灶，降低胃癌術(shù)后復(fù)發(fā)及轉(zhuǎn)移的發(fā)生率，有利于提高患者遠期生存率。仇愛峰等[36]研究也證實，胃癌術(shù)中區(qū)域性植入氟尿嘧啶患者與僅用蒸餾水沖洗腹腔相比，前者吻合口的復(fù)發(fā)率和鄰近臟器復(fù)發(fā)率均較后者低。因此，對有復(fù)發(fā)風(fēng)險的患者，有選擇地進行術(shù)中及術(shù)后化療可能會降低患者的復(fù)發(fā)和轉(zhuǎn)移。

胃癌的復(fù)發(fā)、轉(zhuǎn)移是導(dǎo)致患者預(yù)后不良的主要原因，腫瘤大小，浸潤深度，組織低分化，淋巴管、血管侵犯均是胃癌復(fù)發(fā)的獨立因素，根治性癌組織切除和綜合性治療是防止胃癌復(fù)發(fā)的有效方法，定期隨訪、監(jiān)測有利于早期發(fā)現(xiàn)胃癌的復(fù)發(fā)和轉(zhuǎn)移，為患者的生存贏得更多機會。

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(責(zé)任編輯：馬 軍)

Progress of recurrence and metastasis of gastric cancer

HUANG Qianqian, CHEN Jing

Department of Gastroenterology, the Second Affiliated Hospital of Harbin Medical University, Harbin 150081, China

Although the idea that early diagnosis and treatment of gastric cancer have already deeply rooted in the hearts of people. Regular endoscopic examination has become essential physical examination method. The recurrence rate and mortality do not descend, recurrence and metastasis of gastric cancer become the most important factors of the patients’ death. As a result, studies on recurrence and metastasis of gastric cancer gradually draw the medical scientists’ attention. The progress of recurrence and metastasis of gastric cancer was reviewed in this article.

Gastric cancer; Recurrence; Metastasis; Surveillance; Preventation; Risk factors

黃倩倩,在讀碩士，研究方向：炎癥性腸病的基礎(chǔ)與臨床研究。E-mail:1057237951@qq.com

陳晶,博士，副主任醫(yī)師。研究方向：肝癌的發(fā)生機制及治療進展。E-mail：chenjing7@medmail.com.cn

10.3969/j.issn.1006-5709.2017.03.001

R735.2

A 文章編號：1006-5709(2017)03-0241-04

2016-12-19