摘要
分化型甲状腺癌(DTC)呈惰性进展且预后良好,但其易在早期即出现颈部淋巴结转移(LNM),与术后复发及不良预后密切相关。高分辨率超声、CT扫描、细针穿刺针吸活检是术前判断是否存在颈部LNM及转移范围的常用手段,随着分子生物学技术的发展,DTC预后相关分子机制的研究取得了很大进步,有望为术前精准评估颈部LNM、个体化制定手术方案、减少不必要的淋巴结清扫提供新的无创且准确的评价方式。在此,笔者结合目前临床的研究总结并探讨分子标志物与DTC颈部LNM的关系及其在诊断和预后中的潜在价值。
甲状腺癌是内分泌系统,也是头颈部最常见的恶性肿瘤,据统
分子标志物检测是近年进展迅速的一种诊断方式,有望成为影像学和病理学鉴别DTC侵袭性疾病特征如LNM的有力辅助手段。本文旨在总结并探讨各分子标志物检测在DTC术前预测颈部LNM中的应用价值,以期指导DTC患者颈部淋巴结清扫范围选择,避免过度手术或手术不足导致的医疗资源浪费或不必要的手术创伤。
DTC通常沿颈部淋巴引流途径呈逐站转移,最常发生于靠近甲状腺腺体的中央区淋巴结(Ⅵ区),而后经气管旁淋巴结引流,向上转移至颈静脉链淋巴结(Ⅱ~Ⅳ区)及颈后三角区淋巴结(Ⅴ区),向下转移至上纵隔淋巴结(Ⅶ区),以多区转移为主(占81.4%),仅单区转移较少
甲状腺癌发病的分子机制主要与丝裂原活化蛋白激酶(mitogen-activated protein kinase,MAPK)和磷脂酰肌醇-3-激酶/蛋白激酶B(phosphatidylinositol-3-kinase/protein kinase B,PI3K/Akt)信号通路的失调有关,但其确切的进展机制仍未阐明(

图1 DTC相关信号转导通路图
Figure1 Signal pathways associated with DTC
BRA
约30%的FTC中存在RAS突变,其中NRAS突变较HRAS、KRAS突变更常见,RAS突变属于弱驱动突变,在良性甲状腺肿瘤,如14%~48%的滤泡型腺瘤(follicular adenoma,FA)中也很常见。迄今为止,很少有文献讨论RAS突变与LNM的关联,这可能与FTC较少发生LNM,而多通过血行转移有关。Medici
TERT启动子区域存在C228T和C250T两个突变热点,TERT C228T和C250T突变在PTC、FTC中的发生率分别为10% vs. 2%、30% vs. 5
TERT启动子突变与BRA
PTC与3种不同的跨膜酪氨酸激酶基因重排有关:RET、NTRK1和NTRK3,RET重排所得的嵌合基因被称为RET/PTC,NTRK重排所得的嵌合基因被称为TRK,其产生的嵌合蛋白具备非配体依赖性激活的酪氨酸激酶活性。早期的一些研究认为无法发现RET重排与PTC的任何临床病理特征包括LNM存在密切关联,相较之下RET/PTC3通常使PTC具备更有侵袭性的表型,但也与LNM无关,后来Zhou
MMP中MMP-9是肿瘤发生过程中基底膜降解、包膜外侵犯、侵袭性增强的关键性酶之一,Liu
Ki-67增殖指数是细胞增殖的标志物,被认为是甲状腺癌预后分类的可靠标志物。Zhou
血管内皮生长因子C(VEGF-C)引导肿瘤相关淋巴管生长并促进循淋巴系统传播,Šelemetjev研
DTC总体上来讲是高度可治愈的,但仍有相当一部分患者出现区域LNM,出现侵袭性肿瘤行为和高疾病复发率、病死率。目前,术前评估是否有区域LNM主要通过影像学手段,或对明显肿大的淋巴结进行粗针穿刺病理活检,分子检测无疑提供了一种无创、有可能会更加准确敏感的新思路,虽然临床研究数据目前仍存在矛盾和争议点,但联合应用几种分子标志物预测LNM情况、亚组分析等研究正在开展,以期为临床上DTC淋巴结清扫问题提供解决新思路。
作者贡献声明
赵小慧负责论文撰写、文献整理、文献阅读;安常明、李正江负责研究指导、研究设计与经费支持;魏明辉负责文献整理、经费支持。
利益冲突
所有作者均不存在利益冲突。
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