甲状腺乳头状癌高侵袭性亚型的分子演进 研究进展

Research Progress on the Molecular Evolution of Aggressive Subtypes of Papillary Thyroid Carcinoma

摘要: 甲状腺乳头状癌(papillary thyroid carcinoma, PTC)是甲状腺最常见的恶性肿瘤，多数患者分化良好、预后理想，但其内部仍存在一组具有更强侵袭性和较差临床结局的组织学亚型。现有文献关于这一主题大致沿两条路径展开：一条聚焦高侵袭性亚型的临床病理与分子特征，常涉及高细胞、鞋钉、柱状细胞等；另一条则聚焦PTC向低分化或未分化方向演进时获得的附加分子事件。将两者结合，可更好理解高侵袭性亚型并非单一基因异常的简单结果，而更可能是在MAPK通路起始驱动背景上，进一步叠加进展相关事件和协同网络重塑后形成的侵袭性表型。目前认为，BRAF、RAS突变及RET融合等MAPK通路异常激活构成PTC常见的起始驱动框架，而TERT启动子改变、TP53异常、EIF1AX异常以及PI3K/AKT通路相关改变等更常与侵袭性增强、去分化倾向及不良预后相关。本文围绕高侵袭性亚型的界定、共同分子背景、经典进展事件、候选协同改变及高通量测序推动下的认识转变等方面进行综述，以期为高危患者风险评估及分子分型优化提供参考。

Abstract: Papillary thyroid carcinoma (PTC) is the most common malignant tumor of the thyroid. Most patients have well-differentiated tumors and a favorable prognosis. However, a subset of histological variants shows more aggressive behavior and is associated with poorer clinical outcomes. Current studies on this topic mainly follow two lines of research. One focuses on the clinicopathological and molecular features of aggressive histological variants, especially the tall cell, hobnail, and columnar cell variants. The other examines the additional molecular events acquired during the progression of PTC toward poorly differentiated or anaplastic thyroid carcinoma. Taken together, these findings suggest that aggressive histological variants are not simply caused by a single genetic alteration. Instead, they are more likely to represent an invasive phenotype that develops through the accumulation of progression-related events and cooperative network remodeling on the background of MAPK pathway-initiating drivers. Aberrant activation of the MAPK pathway, including BRAF and RAS mutations and RET fusions, is widely regarded as a common initiating event in PTC. In contrast, TERT promoter alterations, TP53 abnormalities, EIF1AX mutations, and changes involving the PI3K/AKT pathway are more often linked to increased aggressiveness, dedifferentiation, and unfavorable prognosis. This review summarizes the definition of aggressive histological variants, their shared molecular background, classic progression-related events, candidate cooperative alterations, and the evolving understanding driven by high-throughput sequencing. Our aim is to provide a useful reference for risk assessment and for improving molecular classification in high-risk patients.