Background: Molecular assays serve as a potential risk stratification tool for cytologically indeterminate thyroid nodules (ITNs).BRAF V600Emutations are nearly always associated with thyroid cancer. However, the malignancy risk for ITNs with other less commonBRAFalterations is less well understood. In this retrospective cohort study, we examine the risk of malignancy (ROM), histopathologic diagnoses, and clinical outcomes for non-V600EBRAF-altered ITNs. Methods: Genomic profiling data obtained from 1034 pre-operative fine-needle aspiration samples from 955 patients were reviewed. Nodules harboringBRAF V600Ewere excluded. Clinical, radiographic, and histopathologic data were analyzed retrospectively fromBRAF-altered ITNs managed surgically at one comprehensive cancer center (2014–2024). Diagnoses were subdivided based on American Thyroid Association (ATA) risk categories. Results: Thirty-seven patients (3.9%) with non-V600EBRAF-altered ITNs were identified (isolatedBRAFmutation:n= 29 [78.4%],BRAF+ other mutation:n= 3 [8.1%],BRAFfusion:n= 4 [10.8%],BRAF-like gene expression:n= 1 [2.7%]). AllBRAFmutations identified in the cohort were class II (RAS-independent, intermediate to high kinase activity). Nodules had a median pre-operative diameter of 1.8 cm (interquartile range [IQR] 1.4–2.5). Patients presented with nodal metastases in 2.7% (n= 1) of cases, and local invasion was not identified in any patients in the cohort. Approximately half of patients (54.1%) were initially treated with a partial thyroidectomy (lobectomy:n= 17 [45.9%], isthmusectomy:n= 3 [8.1%]), and the remaining patients underwent total thyroidectomy (n= 17 [45.9%]). Median post-operative follow-up was 28 months (IQR 17.8–45.5). ROM forBRAFalterations was 73% (95%CI 59–87%; ATA low risk: 64.9%/ATA int risk: 5.4%/ATA high risk: 2.7%). There were no high-risk cancers identified in patients with isolatedBRAFmutation (benign:n= 10 [34.5%], ATA low risk:n= 19 [65.5%]), and the most common isolated mutation wasK601E(n= 17, 45.9%) which had a 58.8% ROM (all ATA low risk). Patients with isolatedBRAFmutations had a significantly lower rate of ATA intermediate or high risk pathology when compared to all otherBRAFalterations (0% vs. 37.5%,p= 0.0072). Only three patients were treated with radioactive iodine post-operatively (8.1%), and no completion thyroidectomy procedures were performed in those who did not initially undergo total thyroidectomy. No patients in the cohort were found to have distant metastatic disease or recurrence, and there were no deaths during the follow-up interval. Conclusions: ITNs harboring non-V600EBRAFalterations were rare (3.9% of patients) and typically malignant (73%). Nearly all nodules were benign or ATA low-risk cancers. Only 8% of such nodules were ATA intermediate or high risk cancers. In ITNs with isolated non-V600EBRAFand no other genetic alterations, one-third were non-malignant, and all cancers were ATA low risk. In the appropriate clinical context, thyroid lobectomy or active surveillance can be considered for initial management of non-V600EBRAF-altered ITNs.
背景：分子检测可作为细胞学不确定甲状腺结节（ITNs）的潜在风险分层工具。BRAF V600E突变几乎总是与甲状腺癌相关。然而，对于携带其他较少见BRAF变异的ITNs，其恶性风险尚不明确。本回顾性队列研究旨在探讨非V600E BRAF变异ITNs的恶性风险（ROM）、组织病理学诊断及临床结局。 方法：研究回顾了来自955例患者的1034份术前细针穿刺样本的基因组分析数据。排除携带BRAF V600E的结节。对在一家综合性癌症中心（2014–2024年）接受手术治疗的BRAF变异ITNs的临床、影像学和组织病理学数据进行回顾性分析。诊断根据美国甲状腺协会（ATA）风险类别进行细分。 结果：共识别出37例（3.9%）携带非V600E BRAF变异的ITNs患者（孤立BRAF突变：n = 29 [78.4%]；BRAF合并其他突变：n = 3 [8.1%]；BRAF融合：n = 4 [10.8%]；BRAF样基因表达：n = 1 [2.7%]）。队列中所有BRAF突变均为II类（RAS非依赖性，具有中至高激酶活性）。结节术前中位直径为1.8 cm（四分位距[IQR] 1.4–2.5）。2.7%（n = 1）的患者出现淋巴结转移，队列中未发现任何患者存在局部侵犯。约半数患者（54.1%）初始接受部分甲状腺切除术（腺叶切除术：n = 17 [45.9%]；峡部切除术：n = 3 [8.1%]），其余患者接受全甲状腺切除术（n = 17 [45.9%]）。术后中位随访时间为28个月（IQR 17.8–45.5）。BRAF变异的ROM为73%（95%CI 59–87%；ATA低风险：64.9%/ATA中风险：5.4%/ATA高风险：2.7%）。孤立BRAF突变患者中未发现高风险癌症（良性：n = 10 [34.5%]；ATA低风险：n = 19 [65.5%]），最常见的孤立突变为K601E（n = 17，45.9%），其ROM为58.8%（均为ATA低风险）。与所有其他BRAF变异相比，孤立BRAF突变患者的ATA中或高风险病理率显著更低（0% vs. 37.5%，p = 0.0072）。仅3例患者（8.1%）术后接受了放射性碘治疗，且初始未行全甲状腺切除术的患者均未进行补充性全甲状腺切除术。队列中未发现患者存在远处转移或复发，随访期间无死亡病例。 结论：携带非V600E BRAF变异的ITNs较为罕见（占患者3.9%），且通常为恶性（73%）。几乎所有结节均为良性或ATA低风险癌症。仅8%的此类结节为ATA中或高风险癌症。在孤立非V600E BRAF变异且无其他遗传改变的ITNs中，三分之一为非恶性，所有癌症均为ATA低风险。在适当的临床背景下，对于非V600E BRAF变异ITNs的初始管理，可考虑甲状腺腺叶切除术或主动监测。
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