修回日期: 2011-11-15
接受日期: 2011-12-23
在线出版日期: 2012-01-08
食管癌是我国最常见的恶性肿瘤之一, 其预后与疾病检出时的分期密切相关, 早期食管癌预后很好, 然而进展期食管癌预后却不容乐观. 因此, 疾病的早期发现至关重要. 近年来, 内镜技术得到了飞速发展, 涌现了荧光内镜、共聚焦显微内镜、光学相干层析技术和电子染色成像技术诸如内镜窄带成像技术、智能电子分光比色技术、I-Scan技术等多种诊断方法. 然而, 在未来的几年里这些技术的临床应用价值尚待确定. 本文就早期食管癌的内镜诊断进展作一综述.
引文著录: 王丹丹, 刘冰熔. 早期食管癌内镜诊断新进展. 世界华人消化杂志 2012; 20(1): 34-40
Revised: November 15, 2011
Accepted: December 23, 2011
Published online: January 8, 2012
Esophageal cancer is one of the most common malignancies in China. The prognosis of esophageal carcinoma is closely related to the stage of the disease at the time of detection. Patients with early lesions have an excellent prognosis, whereas those with more advanced stages of the disease usually have a poor prognosis. Therefore, the early detection of these lesions is of the greatest importance for treatment. Recently, many endoscopic methods have been developed, such as fluorescence endoscopy, confocal endoscopy, optical coherence tomography (OCT), and electronic staining imaging technology which includes narrow band imaging (NBI), Fujinon intelligent chromoendoscopy (FICE) and I-Scan. However, the clinical value of these techniques needs to be ascertained in the coming years. This paper reviews the progress of endoscopic diagnosis of early esophageal cancer.
- Citation: Wang DD, Liu BR. Advances in endoscopic diagnosis of early esophageal cancer. Shijie Huaren Xiaohua Zazhi 2012; 20(1): 34-40
- URL: https://www.wjgnet.com/1009-3079/full/v20/i1/34.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v20.i1.34
早期食管癌是指癌组织局限于食管黏膜层或黏膜下层而未达到肌层者[1]. 因早期食管癌症状常不典型, 大多数患者就诊时已发展至中、晚期, 综合治疗5年生存率低于10%, 而早期食管癌患者5年生存率高达90%以上[2]. 可见, 早诊断早治疗对降低死亡率, 提高患者生存质量至关重要. 近年来, 随着内镜技术的不断提高, 食管癌的内镜诊断技术亦取得了长足发展, 本文就近年早期食管癌内镜诊断进展综述如下.
早期食管癌黏膜呈3种特征性改变: (1)黏膜颜色改变: 有红区和白区2种表现. 红区呈边界清楚的红色区域, 黏膜稍粗糙浑浊, 少数呈边界不清的大片红色区域; 白区即黏膜白斑, 呈散在分布、边界清楚、大小不等、较粗糙、无光泽、稍隆起状; (2)黏膜增厚和血管结构变化: 正常食管黏膜上皮呈半透明状, 黏膜下血管网清晰可见, 黏膜上皮癌变时, 血管网不能透见; (3)黏膜形态学改变: 包括糜烂、斑块、粗糙和结节等, 多呈混合性改变. 上述3种改变均会使食管黏膜失去正常的结构和光泽, 质地脆, 易出血. 然而, 常规内镜检查不能清楚地观察到食管黏膜的细微结构, 活检及染色技术等对早期食管癌的诊断必不可少.
色素内镜是指通过口服、注射、直接喷洒等途径将色素(染料)导入内镜下要观察的黏膜, 使病灶与正常黏膜颜色对比更加明显, 从而有助于病变的辨认及目标性活检, 提高早期食管癌检出率. 近年来, 色素内镜广泛应用于早期食管癌的诊断, 大量早期食管癌病例被发现, 很多早期食管癌患者获得了及早治疗.
Lugol碘是一种价钱便宜且使用广泛的染色剂, 常用浓度为1.0%-3.0%碘液, 正常食管鳞状上皮细胞糖原含量丰富, Lugol碘对糖原有亲和力从而使非角化的鳞状上皮染成深棕色. 内镜下Lugol碘染色可用于筛查有鳞癌高发风险的患者, 诸如颅脑肿瘤和颈部肿瘤的患者, 酗酒者或嗜烟者, 并可提高对这些人患早期食管鳞癌及不典型增生的检出[3-6]. 陈楚流等[7]将内镜下可疑食管病变的患者随机分为染色组和对照组各110例. 染色组进行食管黏膜Lugol液染色检查, 并分别对不染色区和浅染色区进行病理活检; 对照组不染色, 仅根据临床经验进行病理活检. 结果示内镜下碘染色能降低食管黏膜活检误差, 提高食管癌及其癌前病变的检出. Lugol碘溶液可以引起胸骨后疼痛或烧灼感, 也可引起食管痉挛, 当吸入支气管树时可能发生危险, 因此不应用于有碘过敏史或甲亢的患者[8].
甲苯胺蓝是一种嗜酸性的异性染液, 其临床应用不如Lugol碘液广泛, 因其对存在于癌细胞及癌前细胞的DNA和RNA的亲和力, 故可用于检测癌前病变和癌变[8]. 甲苯胺蓝主要用于口咽部鳞癌的检测, 但也可提高食管鳞癌的检出.
亚甲蓝又称美蓝, 是一种吸收性染料, 正常食管鳞状上皮细胞不吸收亚甲蓝而不染色, 但可被肠化细胞和柱状细胞吸收而染成蓝色. 亚甲蓝染色主要用于食管腺癌的早期诊断. Gossner等[9]对86个Barrett's食管已明确组织学诊断为高度上皮内瘤变和早期癌的患者分别进行常规内镜下随机活检和亚甲蓝指导的内镜下活检, 结果发现亚甲蓝染色指导活检具有活检阳性率高和活检组织块数少的优点. Ormeci等[10]通过随机对照实验证实亚甲蓝染色指导的内镜下活检检出Barrett's食管上皮和食管癌的敏感性高于不染色的常规内镜下活检. Ngamruengphong等[11]研究指出亚甲蓝指导的内镜下目标活检对于Barrett's食管的特殊类型肠化和任何程度的不典型增生的诊断与常规内镜下四象限随机活检相比无统计学差异, 不推荐临床上应用亚甲蓝染色法. 此外, 有研究表明亚甲蓝可能促进组织的DNA损伤[12,13], 且亚甲蓝染色耗时较长, 对操作者的技术水平要求较高, 因此不推荐临床使用.
醋酸可使细胞内的胞质蛋白产生可逆性变性, 常用的醋酸浓度是1.5%-3.0%, 喷洒2-3 min后食管鳞状上皮黏膜仍维持白色, 而柱状上皮则转为红色. Guelrud等[14]首次提出醋酸应用于Barrett's食管上皮的检出, 他们用醋酸染色以识别内镜下治疗后的Barrett's食管残存的柱状上皮, 结果在ll例患者显示出染色前未发现的小柱状上皮岛, 检出率为52%. Hoffman等[15]通过一个随机的交叉对照试验将常规内镜下四象限随机活检与醋酸染色结合放大内镜指导目标活检进行比较, 结果证实对Barrett's食管上皮的检出后者优于前者. Longcroft-Wheaton等[16]将醋酸染色指导活检与白光内镜下的随机活检进行对比, 指出醋酸染色辅助活检对检出Barrett's食管瘤变要优于白光内镜下的随机活检. 可见, 醋酸可改善Barrett's食管的黏膜显像, 特别是与放大内镜结合, 然而目前尚缺乏此法检出早期癌的研究资料, 故此法诊断早期食管癌有待更深入的研究.
由于染色剂浓度配比不一、喷洒方法不当及染色剂本身的局限等因素, 可出现病变处染色深浅、定位不准确或病变遗漏等, 单一染色法呈现了一定的局限性, 从而使双重染色法的优势得以体现. 目前用于早期食管癌诊断的双重染色法主要有: 美蓝-Lugol液染色法和甲苯胺蓝-Lugol液染色法. 彭贵勇等[17]将内镜下美蓝-Lugol液双重染色法与单用Lugol液对可疑食管表浅癌患者检查进行对比, 结果示内镜下美蓝-Lugol液双重染色法较单用Lugol液染色更有助于早期食管癌及癌前病变的检出. 甲苯胺蓝-Lugol液双重染色法, 对评估病变的浸润深度有一定意义, 病变浸润越深, 染色越深[18].
超声内镜是一种头端具有微型超声探头的内镜, 在内镜观察胃肠道各种异常改变的同时, 可于距病灶最近的位置对病灶进行超声扫描[19-23]. 虽然对于EUS判断食管肿瘤的浸润深度及淋巴结转移的精确度的研究数据在不断的波动, 超声内镜在判断食管肿瘤的浸润深度及淋巴结转移方面仍有较高的准确性. 其对有无相邻器官侵犯也可进行较准确的判断, 在临床上应用广泛.
即通过对胃肠道黏膜显像进行特殊光学处理, 从而实现电子染色, 比普通内镜能更清楚地显示黏膜表面结构, 同时弥补了色素内镜对血管分布观察不足的缺点. 其中比较有代表性的有Olympus公司的窄带成像技术、Fujinon公司的智能电子分光比色技术以及PENTAX公司的I-Scan技术.
窄带成像技术(narrow band imaging, NBI)利用滤光器过滤掉内镜光源所发出的宽带光谱, 仅留下窄带光谱用于诊断胃肠道病变, NBI依靠光谱组合来显现血管和黏膜表面的细微变化, 实现了内镜下"光染色". 因操作简单, 且不存在色素内镜染色剂的不良反应[8], 因此NBI有着广阔的临床应用前景. 迄今为止, NBI结合放大内镜检查已应用于Barrett's食管[24], 早期食管腺癌[25,26], 早期食管鳞癌[27]的诊断. NBI对Barrett's食管、早期食管腺癌的诊断已得到普遍认可, 但其用于早期食管鳞癌的诊断目前尚有争议[28]. Chang等[29]的研究指出, 即使使用放大NBI内镜, 要想得到显著优于传统内镜的诊断准确率, 一定时间的练习及经验的积累仍是必不可少的.
智能电子分光比色内镜系统(Fujinon intelligent chromoendoscopy, FICE)后又被称为计算机虚拟的色素内镜(computed virtual chromoendoscopy, CVC), 他和NBI都是以一定波长光谱的选择为基础, 但NBI是利用光学滤波器缩窄光谱的带宽, 而FICE则将传统白光图像分解成诸多单一波长的分光图像, 然后从中提取合适波长的图像并加以合成, 最终产生一幅实时FICE重建图像[8]. FICE能够清楚地显示食管病变黏膜上皮乳头内毛细血管(intrapapillary capillary loops, IPCL)的变化, 从而很好地确定食管浅表性病变的性质, 对食管肿瘤性病变的诊断具有重要的应用价值[30]. Pohl等[31]研究了CVC用于胃肠道疾病诊断的可行性, 并指出CVC有潜力用于胃肠道早癌的诊断. 然而, 这一新的成像技术的临床应用价值以及如何设置以挑选出最佳波长组合尚待研究.
日本Pentax公司开发的I-Scan技术是一项新的先进的增强成像内镜技术, 他包含对比增强、表面增强和色调增强3种强调模式, 最大的特色在于色调增强功能, 针对胃肠道不同部位黏膜的特性, 通过主机软件系统针对性设计染色功能, 从而使不同部位病变显示出最佳光染色效果, I-Scan可达到与普通白光内镜相同的光亮度, 其3种模式可以瞬间完成转换, 使操作简单、快速, I-Scan还可降低频繁的色素染色和活检, 基于以上优势, 我们有理由相信这项技术将会提高内镜下诊断和治疗的质量[32].
荧光内镜是以氮-镉激光、氪激光为激发光源, 有的以光敏剂辅助加强肿瘤色带, 用高敏摄像机摄取人体组织红、绿色谱, 取得谱区荧光, 利用成像颜色的差异辨别良、恶性病变, 近年来越来越多的学者研究了荧光内镜在早期食管癌诊断方面的应用价值. Mayinger等[33]用该法检测13例食管癌(9例鳞癌, 4例腺癌), 结果示检出的敏感度为97%, 特异度为95%. Kara等[34]先后用荧光内镜和常规内镜检查60例Barrett's食管患者, 共检出早期癌或重度不典型增生20例, 其中由荧光内镜单独检出6例, 常规内镜和荧光内镜均发现明显异常后经活检病理检查证实为早期食管癌和重度不典型增生14例. 该研究虽取得了较为满意的结果, 但未采用盲法而未能避免主观因素的影响, 使荧光内镜检查法假阳性率较高. 此后, Kara等[35]将自体荧光内镜与窄带成像技术相结合以发现Barrett's食管的异型增生和早癌病灶. 应用自体荧光内镜共发现47处可疑病灶, 经病理检查证实28处为重度异型增生, 诊断准确率为60%. 用窄带成像技术观察这些可疑病灶, 其中25处黏膜小凹形态明显紊乱, 3处轻微不规则, 19处假阳性病灶中, 14处窄带成像下黏膜小凹形态基本正常, 从而使诊断的假阳性率由40%降至10%, 提高了诊断的准确率. Suzuki等[36]分别用白光内镜和自体荧光内镜检查食管鳞癌癌灶, 结果示自体荧光内镜对早期食管鳞癌的诊断率高于白光内镜. 自体荧光内镜诊断早癌是一种方便、快速、无创的方法, 但该技术的可靠性和临床应用价值尚需进一步研究, 相信随着影像系统的飞速发展, 自体荧光内镜成像技术有望在临床上普遍应用.
将激光共聚焦显微镜结合于标准电子内镜, 在内镜检查的过程中对体内组织实时显微成像, 并将图像放大1 000倍, 使患者在接受内镜检查的同时完成类似组织病理学的诊断. 进行共聚焦内镜检查时, 为了增强对比度, 往往需使用荧光对比剂, 目前应用较广泛的主要是静脉注射剂荧光素钠和局部应用的盐酸吖啶黄. 共聚焦激光显微内镜在食管疾病研究中应用最广的是Barrett's食管. 因杯状细胞的存在, Barrett's食管及由其衍生的早期食管腺癌组织的共聚焦图像具有独特的形态[37]. Kiesslich等[38]对63例长期胃食管反流和已知Barrett's食管的患者进行共聚焦内镜检查, 并对可疑病灶进行病理活检, 结果示: 共聚焦内镜对Barrett's食管及Barrett's食管相关瘤变诊断的敏感性分别是98.1%和92.9%, 特异性分别是94.1%和98.4%, 准确性分别是96.8%和97.4%, 且不同内镜医师具有较好的诊断一致性. 因此, 共聚焦内镜对Barrett's食管及其相关腺癌的早期诊断具有重要价值. 随着共聚焦内镜临床应用范围的不断扩大, 其对于早期食管鳞癌的诊断亦初见成效, 共聚焦内镜能够直接观察食管黏膜的超微结构, 可将食管上皮细胞分成2类, 即正常鳞状上皮细胞和瘤变的鳞状细胞. 瘤变的细胞内镜表现如下[39]: 上皮细胞排列不规则、表面毛细血管环直径增大、表面毛细血管环形态不规则以及伴有弯曲的血管和长分支血管. Deinert等[40]通过共聚焦显微内镜检测到食管细胞和血管结构的改变, 诊断了1位63岁的早期食管鳞癌患者. Pech等[41]对21例早期食管鳞癌患者进行共聚焦显微内镜检查, 结果显示, 共聚焦显微内镜发现了21位患者的43处病变, 其诊断准确率高达95%, 敏感性和特异性分别为100%和87%. 共聚焦内镜作为一项新型诊断工具, 有望在很多方面代替传统病理学, 对内镜诊断技术具有划时代意义.
细胞内镜是在超高倍放大内镜的基础上发展而来的, 目前使用的细胞内镜由日本Olympus公司生产, 直径3.2 mm, 可插入到普通治疗性胃镜的工作孔道中, 操作时, 先用浓度为0.5%-1.0%的亚甲蓝对检查部位进行染色, 在普通胃镜头端安装透明帽, 以吸引局部黏膜组织, 使细胞内镜与黏膜充分接触从而对细胞的细微结构进行观察. Pohl等[42]用细胞内镜对Barrett's食管患者进行食管癌的筛查, 用组织病理学检查来评价其结果, 发现细胞内镜诊断食管癌和异型增生的敏感性为43%, 特异性为85%. Eberl等[43]的试验结果更优于前者, 其敏感性和特异性分别可达91%, 100%. Inoue等[44]用细胞内镜对食管组织异型性进行了初步研究, 他们以细胞及细胞核的形态和大小为基础将异型增生分为5级, 细胞内镜的这种分级诊断结果与组织病理学(Vienna分级)诊断相比较, 细胞内镜区分癌变组织与非癌变组织诊断的准确率可达82%. 细胞内镜可对食管组织细胞进行实时观察, 并指导目标活检, 随着科技的不断发展, 细胞内镜指导早癌的内镜治疗必将成为现实. 然而, 目前的系统还不能观察到上皮下的结构, 故不能对病变浸润深度进行判断[8]. 如能进一步改进细胞内镜的技术性能, 并进行大样本的临床试验, 细胞内镜将会有更广阔的发展空间.
光学相干层析技术(opti cal coherence tomography, OCT)即通过红外光光波的后向散射, 形成切面深度为3 mm的横断面的高分辨率图像, 用途与超声内镜相似[1]. OCT的空间分辨率约为10 mm, 他的分辨率比超声内镜高10倍, 因而比超声内镜更能清晰地显示食管壁的各层结构[45]. OCT显示食道壁有5层结构: 鳞状上皮、黏膜固有层、黏膜肌层、黏膜下层和肌层, 其结果与组织病理学有很高的一致性[46,47]. Isenberg等[48]研究了OCT诊断Barrett's食管不典型增生的价值, 以组织病理学结果作为最终诊断标准. OCT诊断Barrett's食管不典型增生有以下2个标准: (1)光散射能力的下降; (2)组织结构的缺失. 研究证实OCT诊断Barrett's食管不典型增生的敏感度68%, 特异度82%, 精确度78%, 但指出此法还不能单独用来诊断Barrett's食管不典型增生. Hatta等[49]研究了OCT对表浅型食管鳞癌的术前分期, 研究共纳入62例患者, 以ESD或手术标本病理作为金标准, 将浸润深度分3类: 上皮或固有层、黏膜肌层和黏膜下层. 结果发现, OCT对侵及上皮或固有层的诊断精确度为94.9%, 对侵及黏膜肌层的诊断精确度为85.0 %, 对侵及黏膜下层的诊断精确度为90.9%, 总的诊断精确度为92.7%, 这说明OCT是术前对表浅型食管鳞癌浸润深度判断的良好方法. 然而, 目前尚没有统一的标准运用OCT对食管鳞癌进行分期, OCT对于食管腺癌的分期因其穿透深度有限而受到限制[8]. 将来可能会运用染料来增强OCT的穿透能力[50]. OCT对食管高度不典型增生及早期癌的诊断仍待进一步研究, 随着OCT的发展, 将来可能会出现超高分辨率OCT、光谱OCT、多普勒OCT和光学频域成像等, 从而提高OCT检出不典型增生的精确度并将应用于更广阔的领域[51-53].
食管癌患者症状出现常较晚, 导致预后欠佳. 随着新的内镜技术的不断发展, 分子水平的成像已成为可能, 早期食管癌、癌前病变的诊断率将不断提高. 相信越来越多的食管癌患者将得到及早诊治.
食管癌是我国最常见的恶性肿瘤之一, 其发病率和死亡率呈逐年上升的趋势, 而其预后取决于疾病检出时的分期. 近年来随着内镜技术的不断发展, 越来越多的食管早期癌患者获得诊断.
张小晋, 主任医师, 北京积水潭医院消化内科
本文主要研究早期食管癌的内镜诊断. 近年来, 荧光内镜、共聚焦显微内镜、光学相干层析技术和电子染色成像技术等相继出现, 食管癌的内镜诊断技术日趋完善, 但这些技术的临床应用价值尚待进一步研究.
本文不仅阐述了食管癌的常规内镜诊断技术, 还深入论述了目前国内外正在研究的较新较热的内镜技术.
本文参阅了近年来大量国内外文献, 对早期食管癌的内镜诊断研究新进展做了概括, 拓展了临床内镜诊疗思路.
I-Scan技术: 是日本PENTAX公司开发的集成于EPK-i处理机内的一项新功能, 目前他除了包含了传统的对比增强和表面增强两种基本强调模式, 最大的特色在于色调增强功能.
本文通过参阅近年相关文献报道, 综述了早期食管癌的内镜诊断新进展, 论文内容新颖, 文字流畅, 条理清晰. 对操作消化内镜的医生有一定的帮助和借鉴作用.
编辑:曹丽鸥 电编:何基才
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