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溃疡性结肠炎相关结直肠癌手术治疗现况

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  摘要:溃疡性结肠炎(UC)是一种慢性特发性肠道疾病,病程慢性迁延,可出现UC相关结直肠癌(UC-CRC)。近年来,UC在亚洲地区的发病率呈上升趋势,随着UC病程延长,UC-CRC的发病率也在增加,但UC-CRC的疾病特点与散发性CRC有所不同,疾病的治疗更加复杂,延误手术时机或不规范外科处理均会带来不良的后果。为此,本文针对UC-CRC的个体化治疗策略,就UC-CRC手术治疗进展进行综述,旨在为临床治疗UC-CRC提供参考。
  关键词:溃疡性结肠炎;结直肠癌;癌变
  Abstract:Ulcerative colitis (UC) is a chronic idiopathic intestinal disease with chronic disease progression and UC-related colorectal cancer (UC-CRC). In recent years, the incidence of UC in Asia has been on the rise. As the course of UC is prolonged, the incidence of UC-CRC is also increasing, but the disease characteristics of UC-CRC are different from sporadic CRC, and the treatment of the disease is more complicated,delayed operation timing or non-standard surgical treatment will bring undesirable consequences. To this end, this article reviews the progress of UC-CRC surgical treatment for the individualized treatment strategy of UC-CRC, and aims to provide a reference for clinical treatment of UC-CRC.
  潰疡性结肠炎(ulcerative colitis,UC)是一种好发于青壮年、持续或反复发作的慢性特发性肠道疾病,可出现中毒性巨结肠、肠穿孔、下消化道大出血以及癌变等严重并发症。根据UC患者的严重程度、累及范围和治疗目标个体化地选择美沙拉嗪、糖皮质激素、免疫抑制制、生物制剂等药物,以及内镜和手术手术治疗。近年来,UC相关结直肠癌(UC-associated colorectal cancer,UC-CRC)的发病率呈上升趋势,其外科治疗较散发性结直肠癌更加复杂。本文就UC-CRC的流行病学、危险因素、内镜监测及治疗、外科手术的时机及方式等进行综述,为UC-CRC的外科治疗提供一定的参考依据。
  1流行病学及危险因素
  UC在欧美以北欧为最高发地区,UC发病率和患病率分别达24.3/10万、505/10万[1,2]。亚洲地区中,韩国近30年来UC上升趋势,UC发病率为5.82/10万,是1986年的20倍,男女比例1.2:1[3]。在中国,UC发病率为(1.64~2.05)/10万[4,5],Zhai H等[6]研究发现,2014年住院炎症性肠病患者占全部胃肠道疾病住院患者的3.27%,比2002年增加2.07倍,其中85.19%为UC患者。Fumery M等[7]的队列研究发现,671例大肠中存在轻度不典型增生的UC患者,进展为重度不典型增生的年合并发病率为1.8%,而进展为CRC的年合并发病率达到0.8%;这其中约9.7%的低级别异型增生可能在1年内进展为高级别异形增生[8]。Kishikawa J等[9]对289例日本UC患者回顾性分析发现其20年的结直肠癌的累积风险为3.2%。张琴等[10]对3561例UC 患者的回顾性分析发现我国UC患者的总体癌变率为0.81%,低于西方国家报道的3.7%。
  由于疾病的慢性迁延,UC诊断后5年的累积手术率约13.1%[11]。在接受外科手术的UC患者中,约12.5%~31.58%合并结直肠癌或者肠黏膜不典型增生[12-15]。Bopanna S等[16]研究发现,亚洲人群UC-CRC累积发病率在10、20、30年分别为0.02%、4.8l%、13.91%;而Gong W等[17]研究显示,我国UC患者UC-CRC累积发病率在10、20、30年分别1.15%、3.56%和14.36%,高于散发的结直肠癌患者[18],其发病率是正常人群的2~5倍[7]。
  与UC-CRC相关的危险因素主要有低龄起病、病程长、肠道病变范围广泛、如原发性硬化性胆管炎等伴随疾病、肠道黏膜持续炎症、大肠癌家族史、强烈免疫抑制剂使用等[18-22]。细胞因子、一氧化氮、环氧酶、Toll样受体4等各种促炎相关因子组成的肿瘤微环境,通过对肿瘤基因和抑癌基因的甲基化、调控基因异常表达等表观遗传学、NF-κB、丝裂酶原活化蛋白激酶等各种信号通路作用,以及遗传因素、肠道菌群紊乱等刺激导致的慢性炎症,经“炎症一异型增生一癌变”的途径发展[23-26]。
  2 UC-CRC的肠镜特点和手术治疗
  UC-CRC肠镜下癌灶可呈平坦、浸润或隆起型生长,表面多发的溃疡面,背景黏膜可存在结节样不平或黏膜无结构区,并可伴不同程度的肠腔狭窄[27]。放大内镜、色素内镜等技术可使UC-CRC诊断的敏感性和特异性达到72%以上,并可较好的进行病变范围的确定,提高病变阴性切除率[28]。规律内镜监测的UC-CRC患者,其肿瘤分期偏向更早并可提高术后整体生存率[29]。一般肠镜检查应在UC起病后6~10年开始,如合并原发性硬化性胆管炎,应在确诊后每年进行结肠镜检查。   内镜下黏膜切除术和内镜下黏膜剥离术是常用的内镜下治疗技术。Yuki S等[30]报道了一名50岁UC患者,直肠出现10 mm的平坦分化型管状腺瘤且无浸润性生长,经内镜下黏膜切除术达阴性切除的效果。Kinoshita S等[28]回顾性分析了25例缓解期UC合并结直肠不典型增生或肿瘤性病变患者,发现经内镜下黏膜剥离术治疗后其阴性切除率高达76%,术后出血及穿孔率极低,21周中位随访时间均未见原病灶处肿瘤复发;说明内镜下黏膜剥离术既有切除病变诊断作用,又能在一定程度上达到治疗目的。对于散发性腺瘤或隆起型肿块上出现异型增生而不伴有周围平坦黏膜上的异型增生时,可行肠镜下病变治疗,因炎症黏膜上出现息肉样腺瘤患者,其癌变风险提高4倍,故内镜治疗后仍需要密切内镜随访[31],并评估是否需要追加外科手术,当病变累及黏膜下层及以深或孤立病变周围存在异型增生时,宜行外科手术治疗[32]。
  需要说明的是,内镜下治疗UC相关早期癌变、重度不典型增生病变的远期疗效仍有待进一步研究,尤其是多灶性不典型增生、黏膜下纤维化严重、处于UC活动期等情况时,需要审慎开展内镜下治疗[33]。
  3外科治疗
  UC病变的靶器官为结直肠,通过外科手术切除全部结直肠可达到治愈效果。UC-CRC的治疗需要综合结直肠癌治疗原则,兼顾UC个体化手术治疗需要[32,34],结合加速康复外科理念,可更好提高患者生存质量[35]。癌变是UC外科手术的绝对适应症,在肿瘤治疗的基础上,UC的外科手术时机和方式需综合考虑患者的年龄、全身情况、对排粪便的要求、病变肠段范围和程度、肿瘤分期、肛管括约肌功能以及术者经验等[14]。
  3.1手术时机  UC急诊外科手术率在近30年来由10.4%下降至0.5%[36]。多数患者病情较危重,伴贫血、营养障碍、长期应用糖皮质激素等情况,手术风险和术后并发症发生率较高,应注意加强多学科协助[14,37]。UC-CRC患者结直肠存在慢性炎症的疾病特点,虽然急诊手术的并发症发生率及病死率均较高,但拖延手术时机会增加术后并发症[38]。最终约20%~30%的UC患者需要外科手术,因合并消化道自发性穿孔、肠道大出血、中毒性巨结肠而需要手术的约占UC手术患者2.8%~13.8%、2.8%~16.1%、13.9%等,此类UC-CRC患者应评估病情,行急诊手术治疗[39-42]。重症UC患者在静脉用足量激素治疗的转换时机从5 d更改为3 d(可结合病情,适当延长至7 d)[32]。Bernardo S等[43]总结112例重症UC患者治疗,发现42%的患者对静脉激素无效,28.6%接受了转换治疗,最终26.8%接受了外科手术。
  3.2手术方式  UC-CRC术前诊断明确时,择期根据肿瘤分期手术行结直肠癌手术治疗切除癌变或疑癌肠段,并贴近血管根部离断和清扫淋巴结基础上,进行一期或分期全结肠直肠切除+回肠储袋肛管吻合术,为目前最常用的手术方式[44]。对于无法根治性切除者,则评估姑息手术、辅助放化疗[34]。在手术方式确立基础上,根据情况,进行传统的开腹手术、腹腔镜手术、手辅助腹腔镜手术、经自然腔道内镜手术、机器人辅助腹腔镜手术等外科手术模式的選择[45,46]。Wang YN等[47]回顾性分析25例UC-CRC的TNM分期,发现Ⅰ期、Ⅱ期、Ⅲ期、Ⅳ期患者占比分别为16.0%、40.0%、28.0%、16.0%,其中10例进行了全结肠切除,13例进行部分结肠切除,3例术后复发,1例发生远处转移。①肠襻修补/切除+造口术:急诊手术的目标是以快捷切除病变结肠,缓解患者急诊症状,抢救患者生命,并根据病情进行分期手术治疗[38]。对于患者全身情况差、腹腔内感染严重时,宜先行局部病变肠襻切除或穿孔修补+回肠末端造口术;但对于单纯肠穿孔修补,可能出现穿孔部位愈合困难,甚至出现肠瘘及腹腔感染加重[48]。UC-CRC合并肠梗阻时,多数患者营养状态欠佳,术前放置肠道支架,可降低术后并发症发生率[49]。②结直肠癌手术+结直肠切除术+回肠末端造口术/回肠储袋肛管吻合术:若结肠病变广泛且肿瘤未累及直肠,病情可耐受时行保留直肠的全结肠切除+回肠末端造口术;2期或3期再综合患者情况,并结合肿瘤分期,病情允许时行结合结直肠癌根治术所需要的对应肠系膜血管的离断和淋巴结清扫,并注意腹腔常规全面探查[34,50],行结肠次全切除+回肠末端造口术、全结肠直肠切除+回肠储袋肛管吻合术。UC-CRC肿瘤位于直肠患者,根据肿瘤TNM分期,Tis、T1、T2(N0M0)可行直肠癌根治术治疗,不需要辅助放化疗[34],此时可进行直肠癌根治术,联合全结肠直肠切除+回肠储袋肛管吻合术。但当直肠癌处于局部进展期时,因术后需要辅助放疗[34],回肠储袋对放疗的耐受性差,增加吻合口瘘、储袋炎等风险,全结肠直肠切除+永久性的回肠造口可能是更合理的选择,但Inoue Y等[51]报道了1例UC合并进展期直肠癌,术前先行放化疗,随后进行全结肠直肠切除+回肠储袋肛管吻合术,恢复良好,术后1年未见复发。总之,UC外科手术多种基本术式,目前以下两种术式应用较多:第一,全结肠直肠切除+回肠储袋肛管吻合术,为目前最常用的UC手术方式[52];第二,全结肠直肠切除+永久性回肠造口术,该术式适用于肛门括约肌功能障碍或直肠远端有癌变的患者[53]。此外,对结直肠癌患者术前也应排查溃疡性结肠炎,因术前忽视了UC的病史而仅常规行结直肠癌手术,术后并发症的发生率将增高[54]。如Koyama M等[12]发现术前肠镜检查无癌的UC患者中,有5例(4.5%)术中合并结直肠癌,提示术中应注意探查,尤其合并高危CRC因素的患者。
  3.3手术局限性  手术可以解决UC-CRC患者的一部分情况,但手术也带来一定的相关并发症:回肠储袋肛管吻合术后患者储袋炎患病率达28.5%~31.3%,可表现为排粪次数增多、排粪失禁、夜间渗液、里急后重、腹痛、盆腔疼痛和形成瘘管等[37,55],抗生素治疗为治疗急性储袋炎的一线药物,约4.2%~14%患者因严重储袋炎或储袋失功能无法耐受而切除回肠储袋行永久造口[56,57]。而吻合口瘘、 肠梗阻、缝合口狭窄等发生率分别为30%、20%、16%,另外还存在脱水、结直肠癌等相关并发症[14,37,57]。因UC严重的结肠炎症病变有时难以区分UC与克罗恩病,病情观察过程中约1.3%~28%UC术后患者修正诊断为克罗恩病,提醒注意术后评估,及时对疾病诊断重新修正[57]。   4總结
  UC-CRC发病率可随着病程迁延而升高,严格的内镜的监测对UC-CRC的发现及预后均有重要意义,未来联合粪便和血液生化相关生物标志物可更好提高癌变监测效能。内镜手术在部分UC-CRC中可起到一定的作用,但远期疗效仍有待观察,外科手术应综合患者的个体化情况,选择合适的手术时机和术式。由于目前UC-CRC多以病例报道为主,病例数相对较少,手术的预后情况、并发症的控制、术后生活质量等很多方面尚未完全明确,有待更多的研究对临床早期预防以及治疗的选择提供更多的理论依据。
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  收稿日期:2020-02-25;修回日期:2020-03-05
  编辑/成森
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