[202105综述]结直肠锯齿状病变的癌变机制及内镜诊断研究进展
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[引用本文]
宋曜如,宋顺喆,宫爱霞.结直肠锯齿状病变的癌变机制及内镜诊断研究进展[J].中华消化内镜杂志,38(5):412-415.
DOI:10.3760/cma.j.cn321463-20200420-00093
Advancement in the study of carcinogenesis mechanism and endoscopic diagnosis of colorectal serrated lesions
宋曜如 宋顺喆 宫爱霞
大连医科大学附属第一医院消化内镜中心
通信作者：宫爱霞，
Email：doctorgax@sina.com
【提要】结直肠锯齿状病变以往被认为是一种良性病变，近10年的研究表明其具有恶性潜能，锯齿状途径被认为是除腺瘤—癌、炎症—异型增生—癌变、de novo癌途径外新的结直肠癌癌变途径。据最新的世界卫生组织分类标准，锯齿状病变分为增生性息肉、无蒂锯齿状病变和传统锯齿状腺瘤3种类型。由于锯齿状病变具有相对特异的癌变途径及内镜下特点，本文对其恶变机制及内镜下诊治方面作一综述。
【关键词】结直肠肿瘤；内窥镜检查；锯齿状病变；癌变机制；内镜治疗
基金项目：国家自然科学基金（81603424）
结肠癌(colorectal cancer，CRC)是常见的消化道恶性肿瘤，其发病率在各种癌症中位居第三，占恶性肿瘤的10.2%，死亡率在恶性肿瘤中位列第四，每年超过185万新发病例[1]。结直肠锯齿状病变可通过锯齿状途径进展为结直肠癌，占结直肠癌发生率的15%~30%[2]，目前被公认为除腺瘤—癌、炎症—异型增生—癌变、de novo癌途径外新的结直肠癌变途径。锯齿状病变在人群中发病率20%~40%，根据2019年世界卫生组织（World Health Organization，WHO）指南，锯齿状病变分类为：（1）增生性息肉（hyperplastic polyps，HP），（2）无蒂锯齿状病变（sessile serrated lesions，SSL）及伴有细胞异型的无蒂锯齿状病变（sessile serrated lesions with dysplasia，SSL-D），（3）传统锯齿状腺瘤（traditional serrated adenomas，TSA），其中约75%为HP，约25%为SSL，TSA的发病率不足1%[3]。当前研究认为，SSL和TSA具有恶性潜能，是结直肠癌的前期病变[4]。由于SSL内镜下边界模糊、表面苍白，表面常被覆黏液，与背景黏膜不易区分，因而易导致漏诊和不完全切除等不良事件的发生[5]。伴随内镜技术的发展，对锯齿状病变的早期诊断及治疗可以有效预防结直肠癌的发生[6-7]。因此提高内镜医师对锯齿状病变的认识，对于预防结直肠癌的发生及改善患者预后具有重要意义。
一、锯齿状病变的恶变机制及分子特征
有研究表明，SSL及TSA具有恶性潜能，可通过锯齿状途径发展为结直肠癌，该途径涉及一系列基因水平及表观遗传学的改变，主要的分子机制包括BRAF突变、KRAS突变、CpG岛甲基化以及微卫星不稳定性[4,8-9]。
1.HP：HP可进一步细分为微泡型增生性息肉（microvesicular hyperplastic polyp，MVHP）以及富杯状细胞型增生性息肉（goblet cell–rich hyperplastic polyp，GCHP）。MVHP是HP中最常见的类型， O'Brien等[10]研究发现MVHP与SSL的分子特征具有一致性，所以推测MVHP为SSL的前期病变。Rosty等[11]认为GCHP是由于正常黏膜发生KRAS基因突变后异常增殖所产生的，并可以进一步进展为TSA，但具体机制尚不明确。
2.SSL：SSL的癌变途径主要包括BRAF突变、CpG岛甲基化以及微卫星不稳定性[4]。BRAF突变可以进一步激活MAPK通路，进而抑制细胞凋亡，促进细胞增殖，导致肿瘤的发生[12]。CpG岛是位于DNA上富含CpG双核苷酸的DNA片段，位于启动子区域并以非甲基化形式存在；甲基化改变可以导致下游基因表达下降或缺失，导致某些错配修复基因表达缺失，进而引发包括肿瘤在内的多种疾病[13-14]。微卫星不稳定性常发生在SSL-D中，是锯齿状途径的终末阶段，也是向结直肠癌进展的关键[4,15]。Yozu等[16]研究表明，MLH1是参与介导微卫星不稳定性的主要基因，并可以作为鉴别SSL是否伴有细胞异型的潜在分子标志物。
3.TSA：TSA由于发病率较低，当前研究尚不明确。恶变途径主要包括KRAS突变、BRAF突变、CpG岛甲基化以及WNT通路激活[4,17]。Bettington等[17]研究表明KRAS突变及BRAF突变都可发生在TSA中，进一步介导细胞增殖，促进肿瘤的发生。Whitehall等[18]研究表明TSA中的微卫星不稳定性主要由于MGMT基因的甲基化导致，与SSL中由MLH1介导的不一致。当前研究表明，TSA中WNT通路可由PTPRK-RSPO3复合体突变激活，进而促进其向结直肠癌发展[19-20]。
二、锯齿状病变内镜下诊断特点
内镜技术在锯齿状病变的诊断中起到重要作用，部分新技术的发展使锯齿状病变的内镜下诊断更加准确，减少了锯齿状病变的漏诊率。
1.锯齿状病变在传统白光内镜下的特点：HP的镜下特点多为扁平或锯齿状、颜色苍白、边界颜色略深（图1A），常分布于直肠及乙状结肠，大小一般小于5 mm[21-22]。SSL与HP 在传统白光内镜下部分特点相似，区分困难，SSL通常大于5 mm，常分布于右半结肠[23]。Murakami等[24]研究发现大部分SSL与SSL-D都可伴有黏液帽（图1B），并以此特征与HP进行鉴别，若黏液帽清洗之后，则不易区分。Murakami等[24]进一步研究发现SSL-D常伴有亚蒂形态、双峰样外观、中央凹陷以及颜色发红等特点（图1C），并用以镜下鉴别SSL与SSL-D，具有以上特点之一对于SSL-D诊断的灵敏度为91.7%，特异度为85.3%。TSA白光下特点与SSL相似，通常为亮红色的不规则病变（图1D）[22]，鉴别相对困难。Ishigooka等[25]研究发现TSA通常位于左半结肠，与HP相比体积较大，常大于5 mm，常伴有蒂。
图1 锯齿状病变白光内镜下特点（图片均来自大连医科大学附属第一医院内镜中心）1A：增生性息肉，表面苍白，边界颜色略深；1B：无蒂锯齿状病变，表面可见黏液帽覆盖；1C：伴有异型增生的无蒂锯齿状病变，病变局部可见结节状隆起，颜色略发红；1D：传统锯齿状腺瘤，病变不规则呈分叶状，表面不均匀红色
2.窄带光成像技术对锯齿状病变的诊断：内镜下电子染色技术如窄带光成像对锯齿状病变的诊断有更好的提示效果[26-27]。Tadepalli等[28]研究表明，窄带光成像下SSL的黏液帽会呈红色，与传统白光相比更加突出。Hazewinkel等[29]研究发现，SSL在窄带光成像下通常可观察到棕褐色的黑点，其本质为SSL扩大的隐窝，可以辅助内镜医师做出诊断。
3.放大内镜下锯齿状病变的形态学特点：放大内镜联合靛胭脂或结晶紫染色可以更好地突出腺管结构，进而区分病变性质，预测肿瘤浸润深度。Kimura等[30]研究表明，Ⅱ-O型腺管可作为区分SSL及HP的指标，放大内镜下Ⅱ-O型腺管比普通Ⅱ型腺管更加宽大，与窄带光成像下观察到的黑点一样，本质都是SSL扩大的隐窝，以此诊断SSL的敏感度为66%，特异度为97%。Murakami等[24]研究发现，Ⅱ-O型腺管可以辅助诊断SSL-D，当Ⅱ型腺管与ⅢL、Ⅳ、ⅤI或ⅤN腺管同时存在，则高度提示异型增生或癌变。
三、锯齿状病变的内镜治疗研究进展
锯齿状病变的早期内镜下切除可以有效预防结直肠癌的发生。考虑到直径<5 mm的锯齿状病变更倾向于HP，因此当前指南建议除直肠及乙状结肠直径<5 mm的锯齿状病变外，所有的锯齿状病变均需要切除[31-32]。但因为近年来研究发现HP有向SSL和TSA方向转化的可能，而且长期随访直径5 mm以下的锯齿状病变，大大占用了医疗资源，也有学者建议对其进行内镜下冷切除。锯齿状病变的内镜下切除方法主要包括冷圈套器息肉切除术(cold snare polypectomy，CSP)、内镜黏膜切除术(endoscopic mucosal resection，EMR)、内镜黏膜分片切除术(endoscopic piecemeal mucosal resection，EPMR)以及内镜黏膜下剥离术(endoscopic submucosal dissection，ESD)。术式的选择主要取决于病变的大小及病理级别。冷切技术对于直径<10 mm且不伴有上皮内瘤变的锯齿状病变具有良好的有效性及安全性[33-35]。但Pohl等[36]研究发现，冷切除锯齿状病变的不完全切除率是腺瘤的3.7倍，因此选择冷切技术对SSL的切除应格外注意[37]。EMR适用于直径>10 mm的锯齿状病变，对于伴有上皮内瘤变的病变依然适用。Rao等[38]通过251例SSL的研究表明，EMR对于直径>10 mm的锯齿状病变具有很好的安全性，经过近2年的随访，术后复发率仅为3.6%。EPMR可以应用于较大病变的切除，但EPMR术后病理诊断困难并且原位复发率较高[39-40]。与EPMR相比，ESD可以保证病变的完整性，便于术后病理诊断，且具有更高的治愈率[41-42]。Terasaki等[43]通过对269例分别接受ESD（56例）和EPMR（213例）的患者术后复发率统计分析，56例ESD术后均未见复发，而EPMR术后复发率为12.1%。因此对于较大病变，ESD具有更高的根治率。
四、锯齿状病变的术后随访方案
目前锯齿状病变的随访尚存在争议[44]。根据美国多协会工作组的指南[45]，SSL直径>10 mm，SSL伴有上皮内瘤变或TSA均应3年内复查肠镜，SSL直径<10 mm且不伴有上皮内瘤变应5年内复查，直径<10 mm的HP应10年内复查。日本消化协会当前建议息肉切除术后3年内应复查结肠镜；针对直径≥10 mm的SSL、伴有上皮内瘤变的SSL及TSA等高危锯齿状病变，建议1年内复查[46]。
五、总结
锯齿状病变由于内镜下缺乏特异性表现，漏诊率较高。内镜医师应该提高认识，保证充足的退镜时间，灵活应用窄带光成像、放大内镜等内镜新技术，进一步提高锯齿状病变的诊断水平，选择有效的治疗手段，以到达预防结直肠癌发生的目的。
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（收稿日期：2020-04-20）
（本文编辑：朱悦）