Background:Medullary thyroid cancer (MTC) is a heterogeneous disease. While the International MTC Grading System (IMTCGS) provides baseline risk stratification, it lacks therapeutic relevance. In several cancers, EZH2 overexpression harbors an adverse prognosis, with several EZH2 inhibitors undergoing investigation. This study validated the IMTCGS and examined the prognostic value of EZH2 and other biomarkers.Methods:Clinical data were collected and MTC specimens were retrospectively reviewed and morphologically assessed. Immunohistochemistry (IHC) of Ki-67 allowed IMTCGS validation. IHC of EZH2, PD-L1 and PSMA was evaluated on a tissue microarray (TMA).Results:Of 64 MTCs, the median tumor size was 28 mm (IQR 15–40). Coagulative necrosis, ≥5 mitoses, and Ki-67 ≥ 5% was seen in nineteen (30%), three (5%) and seven (11%) cases. Median Ki-67 was 0.9% (IQR 0.4–2.1). Forty-three (67%) and twenty-one (33%) were classified as IMTCGS low- and high-risk, respectively. High-risk tumors were associated with lower distant metastasis-free survival (DMFS) (HR 5.651,p= 0.017), locoregional recurrence-free survival (LRFS) (HR 18.323,p< 0.001) and disease-specific survival (DSS) (HR 10.001,p= 0.002), but not with overall survival (OS) (HR 2.109,p= 0.146). EZH2 expression was identified in 39/46 (85%) cases on the TMA. An expression of ≥10% (9/46, 20%) was predictive for DMFS (HR 4.747,p= 0.030), LRFS (HR 4.242, 0.039), DSS (HR 19.736,p< 0.001) and OS (HR 8.386,p= 0.004). PD-L1 and PSMA had no prognostic value.Conclusions:This study validates the prognostic value of the IMTCGS and identifies EZH2 as a novel prognostic biomarker in MTC patients. The therapeutic potential of EZH2 warrants further investigation in larger cohorts.
背景：甲状腺髓样癌（MTC）是一种异质性疾病。虽然国际MTC分级系统（IMTCGS）提供了基线风险分层，但其缺乏治疗相关性。在多种癌症中，EZH2过表达提示不良预后，目前已有多种EZH2抑制剂正在研究中。本研究旨在验证IMTCGS并探讨EZH2及其他生物标志物的预后价值。 方法：收集临床资料，对MTC标本进行回顾性审查和形态学评估。通过Ki-67免疫组化（IHC）验证IMTCGS。在组织微阵列（TMA）上评估EZH2、PD-L1和PSMA的IHC表达。 结果：在64例MTC中，中位肿瘤大小为28毫米（IQR 15-40）。凝固性坏死、≥5个核分裂象和Ki-67 ≥ 5%分别见于19例（30%）、3例（5%）和7例（11%）。中位Ki-67为0.9%（IQR 0.4-2.1）。根据IMTCGS，43例（67%）和21例（33%）分别被归类为低风险和高风险。高风险肿瘤与较低的无远处转移生存率（DMFS）（HR 5.651，p=0.017）、无局部区域复发生存率（LRFS）（HR 18.323，p<0.001）和疾病特异性生存率（DSS）（HR 10.001，p=0.002）相关，但与总生存率（OS）无关（HR 2.109，p=0.146）。在TMA上，39/46例（85%）检测到EZH2表达。表达≥10%（9/46，20%）可预测DMFS（HR 4.747，p=0.030）、LRFS（HR 4.242，p=0.039）、DSS（HR 19.736，p<0.001）和OS（HR 8.386，p=0.004）。PD-L1和PSMA无预后价值。 结论：本研究验证了IMTCGS的预后价值，并确定EZH2为MTC患者的新型预后生物标志物。EZH2的治疗潜力值得在更大队列中进一步研究。
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