Fang Xiaolian, Luo Peng, Kai Zhentian, Li Pingdong, Chen Xiaohong, Huang Junwei
Department of Otorhinolaryngology, Head and Neck Surgery, Beijing Tongren Hospital, Capital Medical University, Beijing, 100730, China.
Department of Research and Development, Zhejiang Shaoxing Topgen Biomedical Technology Co. Ltd., Shanghai, 201321, China.
Clin Endocrinol (Oxf). 2025 Aug;103(2):251-259. doi: 10.1111/cen.15251. Epub 2025 Apr 15.
To analyze the relationship between clinical characteristics and pathogenic gene mutations in multifocal papillary thyroid carcinoma (MPTC) and to investigate the proportion of independent primary tumors (IP) versus intrathyroidal metastases (ITM) in MPTC. Additionally, to explore the correlation between specific gene mutations and clinical features such as multifocality, tumor size, and lymph node metastasis.
Patients with multifocal thyroid tumor meeting inclusion criteria were consecutively enrolled. Two lesions per case were selected for preoperative ultrasound-guided fine-needle aspiration biopsy (FNAB). All lesions were pathologically confirmed as papillary thyroid carcinoma postoperatively. FNAB samples were subjected to multi-gene panel testing and classified into three groups based on mutational profiles of 26 thyroid-related genes: (1) identical mutations in both lesions (intrathyroidal metastasis), (2) completely discordant mutations (independent primary tumors), and (3) shared mutations with an additional mutation in one lesion (uncertain origin).
Among 58 initially enrolled MPTC patients, 8 were excluded due to noncompliant specimens. The final cohort included 50 patients (37 females, 13 males) with a mean age of 42.64 ± 11.12 years. The median tumor diameter was 12.5 (IQR: 7.6, 20.0) mm, with 38.0% (19/50) classified as papillary thyroid microcarcinoma. A total of 128 mutations, 4 gene fusions, and 3 gene amplifications were detected across 100 qualified FNAB samples. BRAF V600E was the most prevalent mutation (84.0%, 84/100), followed by DICER1 (7.0%), PTEN (6.0%), and RET (4.0%). Identical mutational profiles (intrathyroidal metastasis) were observed in 64.0% (32/50) of cases, while 18.0% (9/50) exhibited completely discordant mutations (independent primary tumor). The remaining 18.0% (9/50) showed shared mutations with an additional mutation, predominantly in smaller lesions. The incidence of completely different mutations in ipsilateral lesions and bilateral lesions was different (p = 0.030). No significant correlation between BRAF V600E and clinical characteristics such as tumor size, multifocality, capsular invasion or lymph node metastasis (p > 0.05).
Multi-gene panel testing of preoperative FNAB samples effectively discriminates clonal relationships in MPTC, revealing distinct molecular profiles between ITM and IP. The high prevalence of BRAF V600E mutations and frequent clonal homogeneity underscore the necessity of comprehensive genetic profiling to guide personalized management. Routine multi-lesion sampling is advocated for optimizing risk stratification and surgical decision-making.
分析多灶性甲状腺乳头状癌（MPTC）的临床特征与致病基因突变之间的关系，探讨MPTC中独立原发性肿瘤（IP）与甲状腺内转移瘤（ITM）的比例。此外，探索特定基因突变与多灶性、肿瘤大小及淋巴结转移等临床特征之间的相关性。
连续纳入符合纳入标准的多灶性甲状腺肿瘤患者。每例患者选取两个病灶进行术前超声引导下细针穿刺活检（FNAB）。所有病灶术后经病理确诊为甲状腺乳头状癌。对FNAB样本进行多基因检测，并根据26个甲状腺相关基因的突变谱分为三组：（1）两个病灶突变相同（甲状腺内转移）；（2）完全不一致的突变（独立原发性肿瘤）；（3）一个病灶有共享突变且另一个病灶有额外突变（起源不确定）。
在最初纳入的58例MPTC患者中，8例因标本不符合要求被排除。最终队列包括50例患者（女性37例，男性13例），平均年龄42.64±11.12岁。肿瘤直径中位数为12.5（四分位间距：7.6，20.0）mm，38.0%（19/50）为甲状腺微小乳头状癌。在100份合格的FNAB样本中共检测到128个突变、4个基因融合和3个基因扩增。BRAF V600E是最常见的突变（84.0%，84/100），其次是DICER1（7.0%）、PTEN（6.0%）和RET（4.0%）。64.0%（32/50）的病例观察到相同的突变谱（甲状腺内转移），而18.0%（9/50）表现为完全不一致的突变（独立原发性肿瘤）。其余18.0%（9/50）显示有共享突变且伴有额外突变，主要见于较小的病灶。同侧病灶和双侧病灶中完全不同突变的发生率不同（p = 0.030）。BRAF V600E与肿瘤大小、多灶性、包膜侵犯或淋巴结转移等临床特征之间无显著相关性（p > 0.05）。
术前FNAB样本的多基因检测能有效区分MPTC中的克隆关系，揭示ITM和IP之间不同的分子特征。BRAF V600E突变的高发生率和频繁的克隆同质性强调了全面基因分析以指导个体化管理的必要性。提倡常规多病灶采样以优化风险分层和手术决策。
