Background: Thyroid cancer (TC) remains a significant clinical challenge worldwide, with a subset of patients facing aggressive disease progression and therapeutic resistance. Immune checkpoint inhibitors targeting programmed death-ligand 1 (PD-L1) have emerged as promising therapeutic approaches for various malignancies, yet their efficacy in TC remains uncertain. The objective of this study was to investigate PD-L1 expression in aggressive TC and its association with histological subtypes, molecular mutation, and progression-free survival. Methods: This is a retrospective study of patients with advanced TC seen in two tertiary health care centers. Included in this study were patients with advanced TC with recurrence or progression on therapy for whom tumor molecular profiling and PD-L1 status were available. Kaplan–Meier estimators were utilized to analyze the progression-free survival (PFS) between patients with PD-L1 positive and negative status in Anaplastic TC (ATC) subgroup. Results: A total of 176 patients with advanced thyroid cancer were included (48.9% female). Of the patients, 13 had ATC, 11 Medullary TC (MTC), 81 Papillary TC Classic Variant (PTCCV), 20 Follicular TC (FTC), 8 Oncocytic TC (OTC), 10 Poorly Differentiated TC (PDTC), and 30 had the Papillary TC Follicular Variant (PTCFV).BRAFmutation was present in 41%,TERTin 30%,RASin 19%,TP53in 10%, andRETin 8.6% of patients. PD-L1 positivity was significantly different across different TC types and histological subtypes (p< 0.01): Patients with OTC had the highest frequency of PD-L1 positivity (71%), followed by ATC (69%), PTCCV (28.5%), and FTC (11%). Patients with MTC and PTCFV did not exhibit any PD-L1 positivity.TP53mutation was positively associated with PD-L1 expression (21.6% vs. 7.5%,p= 0.03), andRASmutation was negatively associated with PD-L1 expression (8.1% vs. 24.2%p= 0.04). Among patients with ATC, positive PD-L1 expression was associated with lower PFS (p= 0.002). Conclusions: PD-L1 expression varies across different TC types and histological subtypes and may be modulated by the mutational landscape. PD-L1 expression in ATC is associated with shorter PFS. Follow up studies are warranted to elucidate the molecular mechanism driving the observed differences in immune pathways, potentially paving the way for the development of more effective and personalized immune therapies for patients with aggressive TC.
背景：甲状腺癌（TC）在全球范围内仍是一项重大的临床挑战，部分患者面临疾病进展迅速和治疗抵抗的问题。针对程序性死亡配体1（PD-L1）的免疫检查点抑制剂已成为多种恶性肿瘤的有前景的治疗方法，但其在甲状腺癌中的疗效尚不明确。本研究旨在探讨侵袭性甲状腺癌中PD-L1的表达情况，及其与组织学亚型、分子突变和无进展生存期的关联。 方法：本研究是一项回顾性研究，纳入了两家三级医疗中心收治的晚期甲状腺癌患者。研究对象为治疗期间出现复发或进展、且可获得肿瘤分子谱和PD-L1状态的晚期甲状腺癌患者。采用Kaplan-Meier估计量分析间变性甲状腺癌（ATC）亚组中PD-L1阳性与阴性患者的无进展生存期（PFS）。 结果：共纳入176例晚期甲状腺癌患者（女性占48.9%）。其中，间变性甲状腺癌（ATC）13例，髓样癌（MTC）11例，经典型甲状腺乳头状癌（PTCCV）81例，滤泡状癌（FTC）20例，嗜酸细胞癌（OTC）8例，低分化癌（PDTC）10例，滤泡亚型甲状腺乳头状癌（PTCFV）30例。患者中BRAF突变率为41%，TERT为30%，RAS为19%，TP53为10%，RET为8.6%。PD-L1阳性率在不同甲状腺癌类型和组织学亚型间存在显著差异（p<0.01）：嗜酸细胞癌（OTC）患者的PD-L1阳性率最高（71%），其次为间变性甲状腺癌（ATC）（69%）、经典型甲状腺乳头状癌（PTCCV）（28.5%）和滤泡状癌（FTC）（11%）。髓样癌（MTC）和滤泡亚型甲状腺乳头状癌（PTCFV）患者未显示任何PD-L1阳性。TP53突变与PD-L1表达呈正相关（21.6% vs. 7.5%，p=0.03），而RAS突变与PD-L1表达呈负相关（8.1% vs. 24.2%，p=0.04）。在间变性甲状腺癌（ATC）患者中，PD-L1阳性表达与较低的无进展生存期相关（p=0.002）。 结论：PD-L1表达在不同甲状腺癌类型和组织学亚型中存在差异，并可能受突变谱的调控。间变性甲状腺癌（ATC）中的PD-L1表达与较短的无进展生存期相关。有必要开展后续研究以阐明驱动免疫通路中观察到的差异的分子机制，这可能为侵袭性甲状腺癌患者开发更有效和个性化的免疫疗法铺平道路。
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