Hysek Martin, Hellgren L Samuel, Stenman Adam, Darai-Ramqvist Eva, Ljung Elin, Schliemann Igor, Condello Vincenzo, Larsson Catharina, Zedenius Jan, Jatta Kenbugul, Juhlin C Christofer
Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
Department of Pathology and Cancer Diagnostics, Karolinska University Hospital, Stockholm, Sweden.
Diagn Cytopathol. 2023 Jun;51(6):331-340. doi: 10.1002/dc.25120. Epub 2023 Mar 4.
Despite the advent of comprehensive molecular testing in surgical pathology, most centers still rely on the morphological assessment of fine-needle aspiration cytology (FNAC) to triage patients with thyroid nodules for surgery. Subsets of patients could benefit from the inclusion of molecular testing to increase the diagnostic and/or prognostic properties of the cytology analysis, including the assessment of TERT promoter mutations, an event coupled with thyroid malignancy, and poor prognosis.
In this prospective study, preoperative FNAC material from 65 cases was assessed for TERT promoter hotspot mutations C228T and C250T using the digital droplet PCR (ddPCR) technique on frozen pellets and re-evaluated postoperatively.
Our cohort consisted of 15 B-III (23%), 26 B-IV (40%), 1 B-V (2%), and 23 (35%) B-VI lesions according to the Bethesda System for Reporting Thyroid Cytopathology. TERT promoter mutations were detected in 7 cases; 4 papillary thyroid carcinomas (all with preoperative B-VI status), two follicular thyroid carcinomas (one B-IV and one B-V status), and one poorly differentiated thyroid carcinoma (with B-VI status). All mutated cases were verified by mutational analysis of tumor tissue derived from postoperative formalin-fixed paraffin-embedded tissue, while all cases identified as wild-type on FNAC remained wild-type postoperatively. Moreover, the occurrence of a TERT promoter mutation was significantly associated with malignant disease and higher Ki-67 proliferation indices.
In the present cohort, we found that ddPCR is a highly specific method for detecting high-risk TERT promoter mutations on thyroid FNAC material that could guide different surgical approaches in subsets of indeterminate lesions if reproduced in larger materials.
尽管外科病理学中出现了全面的分子检测，但大多数中心在对甲状腺结节患者进行手术分流时，仍依赖细针穿刺抽吸细胞学检查（FNAC）的形态学评估。部分患者可能受益于分子检测的纳入，以提高细胞学分析的诊断和/或预后特性，包括评估TERT启动子突变，这一事件与甲状腺恶性肿瘤及不良预后相关。
在这项前瞻性研究中，使用数字液滴PCR（ddPCR）技术对65例患者术前FNAC样本的冷冻颗粒进行TERT启动子热点突变C228T和C250T评估，并在术后重新评估。
根据甲状腺细胞病理学报告的贝塞斯达系统，我们的队列包括15例B-III级（23%）、26例B-IV级（40%）、1例B-V级（2%）和23例（35%）B-VI级病变。7例检测到TERT启动子突变；4例甲状腺乳头状癌（术前均为B-VI级）、2例甲状腺滤泡状癌（1例B-IV级和1例B-V级）和1例低分化甲状腺癌（B-VI级）。所有突变病例均通过对术后福尔马林固定石蜡包埋组织的肿瘤组织进行突变分析得到验证，而FNAC鉴定为野生型的所有病例术后仍为野生型。此外，TERT启动子突变的发生与恶性疾病及较高的Ki-67增殖指数显著相关。
在本队列中，我们发现ddPCR是一种检测甲状腺FNAC样本上高危TERT启动子突变的高度特异性方法，如果在更大样本中得到验证，可指导对不确定病变亚组采取不同的手术方法。
