免疫组化筛查林奇综合征的缺陷和应对策略

Defects of screening Lynch syndrome by immunohistochemistry and corresponding solution

林奇综合征(LS)是由于错配修复基因(MLH1、MSH2、MSH6、PMS2)的胚系突变引起的,是最常见的遗传性结直肠癌综合征,约占所有结直肠癌的3%。目前,多个权威国际组织建议对所有初诊的结直肠癌患者进行LS的普查。LS的普查方法包括免疫组化(IHC)检测错配修复蛋白缺陷(dMMR)和微卫星不稳定性(MSI)检测两种。IHC由于具有检测费用低、对检测设备的要求低、便于基层医院开展、可以提示突变基因等优点,成为LS筛查的首选。但是,由于组织固定、抗体质量、IHC染色技术问题以及不寻常的染色模式,IHC结果容易出现各种误读。干扰IHC结果解读的因素包括:肿瘤细胞的胞浆染色、内对照细胞染色弱、肿瘤细胞的异质性、特殊的病理形态表现(如:淋巴细胞浸润肿瘤上皮,印戒细胞癌)、新辅助放化疗等。注意避免IHC结果解读的各种陷阱,对于准确识别LS至关重要,有助于节省患者和亲属的监测费用,并避免不必要的焦虑。同时,由于采用IHC进行LS的普查本身还存在一些固有缺陷,所以不能将IHC作为LS的唯一筛查手段,应综合应用各种筛查标准、IHC、MSI、BRAF V600E突变、MLH1启动子甲基化和基因的胚系突变检测,以便对LS做出准确的诊断。

Lynch syndrome(LS), which is caused by germline mutations in mismatch repair genes(MLH1, MSH2, MSH6, PMS2), is the most common hereditary colorectal cancer syndrome, accounting for approximately 3% of all colorectal cancers. Recently, several authoritative international organizations recommend universal screening of LS for all newly diagnosed colorectal cancers. Universal screening of LS can be performed by immunohistochemistry(IHC) to identify deficient mismatch repair(dMMR) or by microsatellite instability(MSI) test. IHC has become the first choice for LS screening, due to its low detection cost, low requirements for testing equipment, availability in primary hospitals, and indication of potential mutant genes. However, due to the interference of impropriate tissue fixation, poor antibody quality, unskilled IHC staining techniques and unusual staining patterns, sometimes it is difficult to make a correct interpretation of IHC results. Influencing factors of interpreting IHC results include: cytoplasmic staining of tumor cell, weak staining of internal control cells, heterogeneity of tumor cells, special pathological manifestations(such as lymphocytic infiltration of tumor epithelium, signet ring cell carcinoma) and neoadjuvant chemoradiation. Avoiding the defects of IHC interpretation is critical to identify LS accurately, to reduce monitoring costs of the LS patients and their family members, and to avoid unnecessary anxiety for sporadic colorectal cancer patients. At the same time, due to its inherent defects in LS screening, IHC should not be used as the only method for LS screening. All currently available methods, including various screening standards, IHC, MSI, BRAF V600 E mutation, MLH1 promoter methylation and germline gene mutation detection, should be comprehensively applied to make an accurate diagnosis of LS.