目的： 探讨BRAF单基因与多基因检测辅助甲状腺结节诊断的价值及其联合临床病理学的应用模式。方法： 回顾性收集实施甲状腺结节切除手术的2 166例患者，术前均行细针穿刺活检(FNAC)进行细胞病理学检查及基因检测，以术后病理结果为诊断标准。比较单基因BRAF V600E和多基因检测的诊断准确度，并结合甲状腺细胞病理学Bethesda报告系统(BSRTC)分类，分析基因检测在不同BSRTC分类的甲状腺结节诊断中的价值。结果： 术后病理结果显示，甲状腺癌为2 157例，良性结节为9例。多基因检测的敏感性和准确度分别为90.68%和90.72%，显著高于BRAF V600E单基因检测的敏感性(86.46%)和准确度(86.52%)。除BRAF V600E突变外，在91例样本中发现其他基因突变，包括CCDC6RET融合，NRAS、KRAS等基因突变。无论是甲状腺乳头状癌(PTC)还是非PTC中，多基因检测的敏感性都更高(P<0.05)，且非PTC中未发现BRAF V600E突变。对于BSRTC Ⅰ~Ⅴ类结节中，无论多基因还是BRAF V600E单基因突变的甲状腺结节的恶性风险都显著高于野生型。且在BSRTC Ⅰ/Ⅳ/Ⅴ类结节中，多基因检测展示出相对BRAF单基因检测更高的敏感性。结论： 多基因检测可作为甲状腺结节良恶性诊断的有效辅助工具，且多基因的诊断性能优于BRAF单基因检测。

[1] HAUGEN B R,ALEXANDER E K,BIBLE K C,et al.2015 American thyroid association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer:the american thyroid association guidelines task force on thyroid nodules and differentiated thyroid cancer[J].Thyroid,2016,26(1):1-133.
[2] CIBAS E S,ALI S Z.The 2017 bethesda system for reporting thyroid cytopathology[J].Thyroid,2017,27(11):1341-1346.
[3] ERKINURESIN T,DEMIRCI H.Diagnostic accuracy of fine needle aspiration cytology of thyroid nodules[J].Diagnosis,2020,7(1):61-66.
[4] BALDINI E,SORRENTI S,TARTAGLIA F,et al.New perspectives in the diagnosis of thyroid follicular lesions[J].Int J Surg,2017,41(1):7-12.
[5] LIVHITS M J,ZHU C Y,KUO E J,et al.Effectiveness of molecular testing techniques for diagnosis of indeterminate thyroid nodules:a randomized clinical trial[J].JAMA Oncol,2021,7(1):70-77.
[6] QIU Y,XING Z,LIU J,et al.Diagnostic reliability of elastography in thyroid nodules reported as indeterminate at prior fine-needle aspiration cytology(FNAC):a systematic review and Bayesian meta-analysis[J].Eur Radiol,2020,30(12):6624-6634.
[7] YOO W S,AHN H Y,AHN H S,et al.Malignancy rate of bethesda category Ⅲ thyroid nodules according to ultrasound risk stratification system and cytological subtype[J].Medicine(Baltimore),2020,99(2):e18780-19012.
[8] SCHUMM M A,SHU M L,HUGHES E G,et al.Prognostic value of preoperative molecular testing and implications for initial surgical management in thyroid nodules harboring suspected(bethesda V) or known(bethesda VI) papillary thyroid cancer[J].JAMA Otolaryngol Head Neck Surg,2023,149(8):735-742.
[9] DECAUSSIN-PETRUCCI M,DESCOTES F,DEPAEPE L,et al.Molecular testing of BRAF,RAS and TERT on thyroid FNAs with indeterminate cytology improves diagnostic accuracy[J].Cytopathology,2017,28(6):482-487.
[10] ZHOU L,ZHENG L L,ZHANG C J,et al.Comparison of S-detect and thyroid imaging reporting and data system classifications in the diagnosis of cytologically indeterminate thyroid nodules[J].Front Endocrinol(Lausanne),2023,14(1):1098031-1098033.
[11] LIU S,GAO A,ZHANG B,et al.Assessment of molecular testing in fine-needle aspiration biopsy samples:an experience in a Chinese population[J].Exp Mol Pathol,2014,97(2):292-297.
[12] XING M,HAUGEN B R,SCHLUMBERGER M.Progress in molecular-based management of differentiated thyroid cancer[J].Lancet,2013,381(9871):1058-1069.
[13] PATEL K N,ANGELL T E,BABIARZ J,et al.Performance of a genomic sequencing classifier for the preoperative diagnosis of cytologically indeterminate thyroid nodules[J].JAMA Surg,2018,153(9):817-824.
[14] ALEXANDER E K,CIBAS E S.Diagnosis of thyroid nodules[J].Lancet Diabetes Endocrinol,2022,10(7):533-539.
[15] ZHANG Q,LIU S Z,ZHANG Q,et al.Meta-analyses of association between BRAF(V600E) mutation and clinicopathological features of papillary thyroid carcinoma[J].Cell Physiol Biochem,2016,38(2):763-776.
[16] DU Y,ZHANG S,ZHANG G,et al.Mutational profiling of Chinese patients with thyroid cancer[J].Front Endocrinol(Lausanne),2023,14(1):1156999-1157022.
[17] BAE J S,KIM Y,JEON S,et al.Clinical utility of TERT promoter mutations and ALK rearrangement in thyroid cancer patients with a high prevalence of the BRAF V600E mutation[J].Diagn Pathol,2016,11(2):21-25.
[18] MOORE M D,PANJWANI S,GRAY K D,et al.The role of molecular diagnostic testing in the management of thyroid nodules[J].Expert Rev Mol Diagn,2017,17(6):567-576.
[19] DUICK D S.Overview of molecular biomarkers for enhancing the management of cytologically indeterminate thyroid nodules and thyroid cancer[J].Endocr Pract,2012,18(4):611-615.
[20] BARILE A,QUARCHIONI S,BRUNO F,et al.Interventional radiology of the thyroid gland:critical review and state of the art[J].Gland Surg,2018,7(2):132-146.
[21] DUAN H,LI Y,HU P,et al.Mutational profiling of poorly differentiated and anaplastic thyroid carcinoma by the use of targeted next-generation sequencing[J].Histopathology,2019,75(6):890-899.
[22] BIKAS A,AHMADI S,PAPPA T,et al.Additional oncogenic alterations in RAS-driven differentiated thyroid cancers associate with worse clinicopathologic outcomes[J].Clin Cancer Res,2023,29(14):2678-2685.
[23] DONALDSON L B,YAN F,MORGAN P F,et al.Hobnail variant of papillary thyroid carcinoma:a systematic review and meta-analysis[J].Endocrine,2021,72(1):27-39.
[24] TENG L,DENG W,LU J,et al.Hobnail variant of papillary thyroid carcinoma:molecular profiling and comparison to classical papillary thyroid carcinoma,poorly differentiated thyroid carcinoma and anaplastic thyroid carcinoma[J].Oncotarget,2017,8(13):22023-22033.
[25] BONGIOVANNI M,SPITALE A,FAQUIN W C,et al.The bethesda system for reporting thyroid cytopathology:a meta-analysis[J].Acta Cytol,2012,56(4):333-339.
[26] WONG L Q,BALOCH Z W.Analysis of the bethesda system for reporting thyroid cytopathology and similar precursor thyroid cytopathology reporting schemes[J].Adv Anat Pathol,2012,19(5):313-319.
[27] SHRESTHA R T,EVASOVICH M R,AMIN K,et al.Correlation between histological diagnosis and mutational panel testing of thyroid nodules:a two-year institutional experience[J].Thyroid,2016,26(8):1068-1076.
[28] HO A S,SARTI E E,JAIN K S,et al.Malignancy rate in thyroid nodules classified as Bethesda category Ⅲ(AUS/FLUS)[J].Thyroid,2014,24(5):832-839.