Endoscopic submucosal dissection for early gastric adenocarcinoma: a review of the literature
Review Article

内镜黏膜下剥离术治疗早期胃腺癌：文献回顾

Katherine D. Gray, Maureen D. Moore, Adham Elmously, Rasa Zarnegar

Department of Surgery, New York Presbyterian Hospital, Weill Cornell Medicine, New York, NY, USA

Contributions: (I) Conception and design: KD Gray, R Zarnegar; (II) Administrative support: R Zarnegar; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: KD Gray; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

Correspondence to: Rasa Zarnegar. Department of Surgery, New York Presbyterian Hospital, Weill Cornell Medical College, 1300 York Ave, Suite A1027, New York, NY 10065, USA. Email: raz2002@med.cornell.edu.

摘要：内镜黏膜下剥离术（Endoscopic submucosal dissection，ESD）是大型临床中心治疗早期胃癌（即病灶局限于黏膜及黏膜下层的T1期肿瘤）的有效技术。ESD依赖于准确的术前分级以对无淋巴结侵犯的局限性病灶进行识别；在患者选择方面，相关指南界定了行ESD的绝对与扩大标准。对于接受整块切除的患者，其总体生存率与无疾病生存率和外科手术切除是相当的。局部复发与异时性复发的发生率约为1%和5%，因此术后需要接受长期内镜随访监测。ESD的术后并发症包括出血（5%）和穿孔（1%～9%），其发生率与肿瘤特征及操作者等因素具有相关性。对于ESD切除病灶的最终病理结果不符合切除标准的患者，需要接受进一步行外科手术治疗。本文回顾了ESD治疗早期胃癌的患者选择、内镜操作技术与并发症及术后结果的相关文献。

关键词：早期胃癌；内镜黏膜下剥离术（ESD）

Received: 19 December 2016; Accepted: 17 January 2017; Published: 11 February 2017.

doi: 10.21037/ales.2017.01.07

引言

胃癌（gastric cancer）是全球第5大最常见的癌症，2012年新发病例数为952 000[1]。胃癌患病率最高的区域为西太平洋地区，尤其是中国、韩国和日本。这些国家许多已经开展了早期胃癌的筛查，以期降低该疾病的高致病率与死亡率。日本和韩国开展了全国性的早期胃癌筛查计划，即所有年龄>40岁的公民，每2年接受1次上消化道内镜检查或钡餐吞服检查。文献报道表明该计划使胃癌早期诊断率获得提升[2,3]。在日本，约50%的胃癌在确诊时仍为局限于黏膜或黏膜下层的早期胃癌[4]。

既往治疗早期胃癌的主流方法是手术切除，而即使利用现代技术，手术切除仍可能导致较高的围术期和远期并发症[5]。这一难题也促进了内镜切除早期胃癌的技术创新与发展。内镜下黏膜切除（endoscopic mucosal resection，EMR）于20世纪80年代在日本到应用，该技术的目的是完整切除局限于胃黏膜层的小病灶，这些病灶淋巴结转移和远处转移的风险低，因此采用内镜下切除可获得根治性治疗效果[6]。随后，这项技术被扩展为内镜黏膜下剥离术（endoscopic submucosal dissection，ESD），该技术可实现对更深层病灶更精确的剥离，对更大的病灶也可实现更高的整块切除率和完整切除率。随着手术流程与技术的改进，特制的手术器械也随之问世，ESD如今也成功应用于更加复杂的早期胃癌病灶的治疗。

诊断

上消化道内镜检查是早期胃癌的主要诊断模式。对恶性肿瘤病灶进行完整评价的方法包括评价其组织病理学类型、病灶大小、侵袭深度，以及是否存在溃疡性病灶[8]。在一项随机对照研究中，使用日本奥林巴斯的“三重模式”内镜（Olympus Medical System，Tokyo，Japan），即将高分辨率白光（white light imaging，WLI）与窄带光成像（narrow band imaging，NBI）和自体荧光成像（autofluorescent imaging，AFI）两种增强放大成像模式相结合的检查模式。这种增强光学成像技术可针对浅表性胃癌病灶表面的微血管病灶进行分析[9]，与其他传统内镜诊断方法相比可获得最高的敏感性（89%）与特异性（100%），并提高早期胃癌的诊断率[10]。其他辅助方法，如染色内镜，通常使用靛蓝胭脂红染色剂（可添加或不添加乙酸），因其在恶性肿瘤病灶表面的洗脱速度更快而被广泛用于识别恶性肿瘤病灶的边界与表面结构[11]。内镜下还可使用活检钳对病灶进行活检，以获取病灶的病理学与组织学诊断。

对病灶侵袭深度的评估可采用白光内镜成像对病灶表面的特点加以判断。表面光滑的外凸型或凹陷型病灶、病灶边缘轻度抬高，以及皱襞光滑变细等特点常提示黏膜性疾病，而表面不光滑、边缘抬高明显、皱襞聚集融合、走形不规则等特点则常提示存在黏膜下层浸润[12]。超声内镜（endoscopic ultrasound，EUS）在鉴别早期胃癌黏膜层与黏膜下层侵袭中的作用目前尚存争议。近期一篇荟萃分析报道EUS评估黏膜层侵袭的敏感性与特异性分别为76%和72%，而评估黏膜下层侵袭的敏感性与特异性分别为62%和78%[13]。另一项研究表明传统内镜相比EUS的诊断效能更高，单纯内镜检查组的诊断准确性为73.7%，EUS组为67.4%（n=955，P<0.001）[14]。在一篇EUS对早期胃癌分级的Cochrane系统综述中，EUS诊断区域性淋巴结转移的敏感性与特异性亦较为局限，分别为83%和67%[15]。是否使用EUS检查最终取决于内镜医生的个人偏好。

切除标准

并非所有早期胃癌均可通过ESD切除。日本消化内镜学会（Japan Gastroenterological Endoscopy Society，JGES）与日本胃癌学会（Japan Gastric Cancer Association，JGCA）于2016年对ESD的诊疗指南发表了一项联合声明[8]，欧洲胃肠内镜学会（European Society of Gastrointestinal Endoscopy，ESGE）于2015年也发表了类似的声明[15]。这些指南旨在对淋巴结转移风险可忽略不计的病灶进行识别。两项声明均建议将病灶位于黏膜内、分化型、非溃疡性病灶、直径小于2 cm的腺癌作为ESD的绝对适应证，而某些方面的微小差异可作为扩大适应证（图1）。

图1
图1 ESD的应用标准[8,15]。ESD，内镜黏膜下剥离术。

ESD技术

ESD可在全麻或静脉镇静下进行，使用接入能量源的治疗用内镜，注入二氧化碳（相比空气充气患者耐受度更高）[17]，按照标准操作步骤进行（图2）[18]。首先，使用电灼器械环形标记待切除病灶的周围，以确定切除范围。然后将靛蓝胭脂红或亚甲基蓝注射于黏膜下层以抬举病灶，以更好地辨别切除平面。随后，使用尖端绝缘的特制手术电刀[如IT刀（Olympus America, Center Valley, USA）]先行环形切除，再深入黏膜下层完整切除病灶。如操作中发生出血，可用电凝或止血夹进行止血。

图2
图2 ESD技术。（A）使用电灼环形标记病灶周围；（B）黏膜下层注射含靛蓝胭脂红染色剂的胶体液，抬举病灶；（C）使用连接能量源的特制内镜电刀环形切除病灶；（D）切除深度达黏膜下层，整块切除病灶。 ESD，内镜黏膜下剥离术。

ESD技术应该需要事先进行特定的培训，以便术者更好地掌握手术操作，确保充分切除的同时减少并发症。日本的一家培训中心表明，对于位置较好的胃远端病灶须有30例成功切除经验才能掌握熟练的操作技术，而对于更复杂的远端病灶或中部至近端胃体的病灶，则需要额外进行进一步训练[19]。ESD的术前培训可使用离体猪或活体猪等模拟训练模型[20,21]。在西方国家，由于早期胃癌较为少见，因此使用这些非人体训练模型是尤其重要的。

结果

ESD与EMR效果对比

许多中心仍然会对<2 cm和分化良好的病灶采用EMR治疗。在一个纳入177名早期胃癌的队列研究中，这些患者同时符合EMR和ESD的切除标准，结果显示对于>5 mm的病灶，ESD的整体切除率、完整切除率及局部复发率结果均占优[22]，且并发症发生率未见显著升高。2014年发表的一项荟萃分析纳入了先前的研究和9项额外的回顾性研究，该分析进一步比较了EMR和ESD的上述指标差异，结果表明尽管ESD组穿孔率明显更高（OR 4.67，2.77-7.87），但其余指标差异与前文结论一致[7]。EMR确实仍可用于特定病灶的治疗，但ESD对于更大、更复杂病灶的切除仍是业内主流，而且可获得更精确的切除效果。

ESD与手术效果对比

ESD和手术切除的长期肿瘤学结果是相似的。与手术切除效果相关的最长随访数据来自韩国的一个单中心研究，该研究将611对符合ESD或手术绝对与相对适应证的术后患者进行倾向性得分匹配，完成了长达10年的随访[23]。结果表明，手术组与ESD组的总体10年生存率分别为94.9%和96.7%（P=0.120）。并发症发生率在不同队列中存在差异，但ESD组总体相对更低[24,25]。其他大型研究表明，内镜治疗术后早期并发症发生率相对更高，而手术治疗的并发症发生时间通常更晚[23]。相比手术切除，ESD在各研究中的术后住院天数均更短，ESD组平均术后住院天数为5～7天，而手术组术后住院天数为11～13天[23,26]。

绝对标准与扩大标准效果对比

ESD对符合绝对标准与扩大标准患者的治疗结果是相近的。日本的两项大型研究（纳入超过1000名患者）表明，无论采用何种纳入标准，术后5年总体生存率均>90%[27,28]。另外，多项大型回顾性研究也报道了相似的结果，且无病生存率[28,29]或局部复发率[29,30]均未见差异。多数研究表明，相比扩大标准（汇总结果为64.5%～88.4%），采用绝对标准纳入患者的完整切除率更高（汇总结果为91.1%～95.9%），而日本的一项多中心研究的两组间完整切除率是相似的（93.4% vs 96.4%，P=0.736），整体切除率均>97%（组间P=0.867）[28-31]。局部复发率与异时性复发率在这些研究中均未见明显差异。部分研究表明采用扩大标准进行ESD治疗的穿孔率（6.6% vs 2.4%，P<0.001）与出血率（6.36% vs 3.31%，P=0.020）更高[28,31]。扩大标准所纳入的病灶在技术上可能更难以切除，而这些病灶如能实现完整切除，则其肿瘤学指标相比绝对标准所纳入的病灶是相近的。

淋巴结转移

早期胃癌出现淋巴结转移提示显著更差的生存期[32]，因此内镜切除治疗所假定的前提是淋巴结转移的风险是可忽略不计的。一项针对接受胃切除术的T1a或T1b期胃癌患者的荟萃分析表明，对于黏膜层病灶，总体淋巴结转移率为3.2%，而黏膜下层病灶总体淋巴结转移率为19.2%[33]。Gotoda等在2000和2001年的开创性研究[34,35]表明，淋巴血管侵犯、肿瘤病灶>30 mm、溃疡性病灶及组织学未分化是早期胃癌淋巴结转移的独立危险因素。在一项纳入超过5 000例患者的研究中，当上述危险因素不存在，且肿瘤局限于黏膜层或黏膜下浅层（<500 μm）时，淋巴结转移的风险为0。这也构成了被广泛采用的前文所述绝对切除标准与扩大切除标准的基础。

后续研究进一步回顾性分析了既往接受胃切除+标准淋巴结清扫的早期胃癌患者，并证实了上述结果，而这些患者均符合如今行ESD的切除标准。尽管这些病例淋巴结转移的风险不是0，但也是极低的。韩国的一项纳入3,951名患者的研究表明，符合绝对ESD切除标准的患者淋巴结转移风险为0.3%，而符合扩大ESD切除标准的患者淋巴结转移风险为0.4%[32]。另一项纳入超过1 000名患者的回顾性研究纳入淋巴结转移患者18例（1.8%），而未分化型病灶淋巴结侵犯的风险比为6.104（95%置信区间：1.1317-28.284）[36]。为更准确地鉴别局灶性肿瘤，相关学术组织正致力于进行切除标准的更新。

术后复发

ESD治疗后可能出现局部复发与异时性复发。韩国的一项倾向性得分匹配队列研究表明，ESD切除后的局部复发率为1.6%（5/288），而胃切除术后局部复发率为0.6%（1/173），但无统计学差异[37]。ESD切除后发生异时性复发的风险体现为内镜下切除与手术切除之间主要的肿瘤学差异，前者发生异时性复发的风险为5.3%～6.2%，而后者的风险低至几乎可忽略不计[23,26,38]。即便如此，异时性复发病灶也可通过再次内镜下剥离成功治疗，而不会导致生存期的减少[26,39]。

ESD发生局部复发的危险因素也得到了更好的认识。仅有的几项研究表明，即使切缘为阴性，分块切除肿瘤可导致局部复发风险提高[40,41]。然而，即使是整块切除后，仍可能出现局部复发。与局部复发相关的因素包括肿瘤边界不清、切缘距肿瘤距离近（<1 mm）及病灶位于胃体上1/3处。肿瘤体积>3 cm、淋巴血管侵犯、黏膜下层浸润深度>500 μm也与水平切缘阳性及局部复发相关[42,43]。组织学分化程度与同时性及异时性病灶的发生率升高相关[44]。

西方研究结果

西方国家关于ESD的文献数据十分有限。仅有的一项直接比较ESD与胃癌切除术的研究来自加拿大，该小型研究（ESD组n=30，手术组n=37）表明两组间术后2年生存期无统计学差异；然而，由于本研究样本量较小，且ESD组同时纳入了异型增生性病灶（30%），研究结果的证据效力较为有限[45]。德国的一项纳入91名患者的研究表明在西方人群中对早期胃癌及腺瘤进行ESD是可行的，但失败率较高，且整块切除率较低[41]。这可能与西方有相关疾病的患者数量少、培训机会减少相关。

非治愈性切除/适应证外病灶

内镜切除的可行性是基于术前评估加以判断的。最近的一项研究表明ESD术前与术后病理特征存在显著差异，在经ESD切除的所有病灶中，15.9%（120/756）的最终病理结果不符合适应证，30.2%（29/96）初始分级为扩大适应证的病灶最终证实为超适应证[46]。这些最终病理发现为超适应证的患者通常须接受外科手术治疗。

许多学者都在致力于确定接受非治愈性切除术后发生肿瘤复发或淋巴结转移的特定危险因素，以更好地指导后续治疗。目前最大的多中心回顾性研究来自日本，该研究纳入了1 969名接受非治愈性ESD治疗后采取手术治疗或仅观察随访的患者，发现两组间的3年总体生存期存在显著差异（96.7% vs 84.0%，P<0.001）；无病生存率差异虽更小，但也具有统计学意义（99.4% vs 98.7%，P=0.012）[47,48]。对总体生存期的解读应更加谨慎，因为采取观察随访的患者年龄更大，合并症也更多。对于那些超适应证但无淋巴血管侵犯或切缘阳性的病灶，淋巴结转移或局部复发的风险并未升高，提示对于经仔细筛选的特定患者，仅采用随访也可能是合适的方案[47,49]。

疾病监测

ESD术后的常规监测对发现局部复发与异时性复发是十分重要的。治愈性切除后的上消化道内镜检查通常在初始治疗后3～6个月进行，随后每6～12个月复查1次[8,16]。回顾性研究表明，即使是符合绝对适应证的病灶，接受初始切除5年后，发生异时性复发的概率仍稳定于每年约3.5%，提示长期监测可能是必要的[50,51]。常规CT复查一般不是必须的，因为该检查发现胃外转移的概率极低，但仍有部分中心常规开具术后CT检查；一项纳入2 182例患者的研究表明ESD切除5年后每年行CT检查仅发现了2例胃外复发[52]。

并发症

ESD术后并发症包括出血（5%）、穿孔（1%～9%）与狭窄（1%～2%）。出血既可发生于术后早期（＜48 h），也可为迟发性出血（≥48 h）。出血的危险因素包括患者及肿瘤与操作的相关特点。一项荟萃分析表明，慢性肾病、肿瘤>2 cm、切除标本>3 cm、操作时间>60 min这些因素导致出血风险的风险比均>2.0[53]。肿瘤位于胃体下1/3也是出血的危险因素之一[54]。一些研究者报道了局部喷涂纤维蛋白胶成功预防迟发性出血的经验；一项研究表明使用该方法后，出血率从对照组的5.98%降低至0（P=0.03）[55]。抗血小板与抗凝药物通常在大多数患者的围术期应停用，但持续服用低剂量阿司匹林似乎并未增加出血风险[56]。肝素替代治疗与恢复抗血小板治疗是造成迟发性出血风险显著升高的危险因素[57,58]。降低出血风险的方案，包括围术期应用质子泵抑制药（proton pump inhibitor, PPI）[59]或二次内镜检查并未获得一致的获益结果[60]。然而，已有研究发表了使用PPI，尤其是与黏膜促愈剂（如瑞巴派特，已在日本、韩国和中国获批）合用成功治疗因ESD所致医源性溃疡的成功经验[61,62]。

ESD术后胃穿孔是另一个主要并发症，既可发生于内镜切除时，也可迟发于切除后数天。ESD总体穿孔发生率介于1.2%与9.5%之间[63-65]。危险因素包括肿瘤自身特征（如组织学分化较差、浸润深度较深、病灶位于近端胃、病灶纤维化等），以及患者年龄及操作时间等[63,65,66]。穿孔一般情况下可在内镜下使用标准止血夹或OTSC（over the scope clips，OTSC）吻合夹（Ovesco Endoscopy USA Inc.，Cary，USA）内镜下缝合和（或）仅观察出血情况[64,66]。更复杂的内镜下操作，如圈套器-内镜夹技术，已成功用于直径达2 cm穿孔的修补。这项技术首先使用圈套器夹持穿孔边缘的正常黏膜，随后收紧圈套器并固定，以使缺损边缘重新对合[67]。对于迟发性穿孔，如未并发腹膜炎或脓毒症，可尝试使用鼻胃管减压及抗生素等方法保守治疗[64]。如出现临床失代偿或存在腹膜炎，则应行大网膜修补或手术切除等方法治疗。

ESD术后狭窄是较为罕见的并发症。较大病灶的内镜下切除可导致近环形的溃疡，而位于贲门或胃窦部的病灶发生术后狭窄的风险最高[68,69]。患者可出现吞咽困难或胃流出道梗阻的相关症状。与狭窄相关的症状可通过球囊扩张进行治疗，但这也可能导致胃穿孔而需要进一步的内外科治疗[68,70]。其他治疗方法包括内镜下黏膜内切开以缓解ESD术区张力，或经病灶内或静脉使用类固醇药物以改善肉芽组织生长，并减轻组织纤维化[69,71]。

特殊人群

对于既往接受胃部手术或食管切除胃代食管而出现胃解剖结构改变的胃癌患者，ESD可能带来额外的风险。一些小样本研究也报道了这类患者接受ESD治疗的肿瘤学结果。一项研究表明，对于经胸胃代食管的患者，近半数需要在ESD进镜前对吻合口狭窄段行球囊扩张，但这些病例最终均成功完成操作[72]。值得注意的是，一项研究报道的穿孔率为18%，发生率相比正常解剖结构的患者明显更高，因为这些患者的操作难度更高[74]。

结论

ESD是治疗早期胃癌的一项重要技术，对于有经验的中心，可在成功切除病灶的前提下具有较低的并发症与较好的肿瘤控制效果。对于患者数量低的中心而言，可能存在较长的学习曲线，且治疗效果通常欠佳。最优切除标准与随访计划尚待后续研究进一步完善。

Conclusions

ESD is an important technique which allows for successful curative resection of early gastric cancer with low morbidity and excellent oncologic value in skilled centers. A substantial learning curve persists in low volume areas, and outcomes are worse in those areas. Further investigation is needed to establish optimal resection criteria and surveillance patterns.

Acknowledgments

Funding: None.

Footnote

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/ales.2017.01.07). RZ serves as an unpaid editorial board member of Annals of Laparoscopic and Endoscopic Surgery from Jul 2016 to Jun 2018. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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译者介绍
常易凡
长海医院泌尿外科。（更新时间：2021/8/12）
审校介绍
肖怀文
上海市浦东新区浦南医院普外科。从事普外科工作23年以来，先后在多所三甲医院及同济大学医学院不断学习普外科医疗及腹腔镜、内镜技术，师从上海多位高级专家，酷爱医学事业，熟练掌握普外医疗及科研技术。（更新时间：2021/8/12）

（本译文仅供学术交流，实际内容请以英文原文为准。）

doi: 10.21037/ales.2017.01.07
Cite this article as: Gray KD, Moore MD, Elmously A, Zarnegar R. Endoscopic submucosal dissection for early gastric adenocarcinoma: a review of the literature. Ann Laparosc Endosc Surg 2017;2:17.

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