1995中国普通外科杂志Chinese Journal of General SurgeryChinese Journal of General Surgery中国普通外科杂志1005-694743-1213/R湖南省长沙市1005-6947(2021)08-0955-0910.7659/j.issn.1005-6947.2021.08.01121-0102余幼林(ST)临床研究R736.1CLINICAL RESEARCH基于血浆循环游离DNA与甲状腺结节超声特征构建甲状腺癌诊断模型及其验证Establishment of diagnosis model for thyroid cancer based on plasma circulating cell-free DNA and ultrasound characteristic of thyroid nodules and its verification余幼林YUYoulin1沈雄山SHENXiongshan1胡超华HUChaohua1余军林YUJunlin2卢婷LUTing1杨峰YANGFeng5张文杰ZHANGWenjie1张小莉ZHANGXiaoli1刘汉忠LIUHanzhong3陶溢潮TAOYichao4武汉科技大学附属孝感医院,甲状腺乳腺外科,辽宁锦州121000Department of Thyroid and Breast Surgery, Jinzhou, Liaoning121000, China武汉科技大学附属孝感医院,肿瘤科,辽宁锦州121000Department of Oncology, Jinzhou, Liaoning121000, China武汉科技大学附属孝感医院,病理科,辽宁锦州121000Department of Pathology, Jinzhou, Liaoning121000, China武汉科技大学附属孝感医院,超声科,湖北 孝感 432000,辽宁锦州121000Department of Ultrasound Imaging, Xiaogan Hospital Affiliated to Wuhan University of Science and Technology, Xiaogan, Hubei 432000, China, Jinzhou, Liaoning121000, China武汉科技大学附属孝感医院,锦州医科大学,辽宁锦州121000JJinzhou Medical University, Jinzhou, Liaoning121000, China姜晖沈雄山, Email: shenxs@medmail.com.cn
Studies have demonstrated that the circulating cell-free DNA (cfDNA) may be a potential biomarker for diagnosis of thyroid cancer. Therefore, this study was performed to investigate the value of a scoring model established by plasma circulating cfDNA and changes in ultrasound characteristics of the thyroid nodules in differential diagnosis between benign and malignant thyroid nodules.
Methods
Two hundred and forty patients with thyroid nodules (132 cases of thyroid cancer and 108 cases of benign thyroid nodules) admitted from June 2018 to October 2020 were enrolled for this study. They were randomly divided into the modeling group and validation group using a 1∶1 ratio. The plasma cfDNAs were extracted from the 240 patients by blood DNA extraction kit, and the DNA concentrations were further detected by qRT-PCR. Thyroid ultrasound was performed in all patients. The scoring model was constructed based on the cfDNA concentration and thyroid ultrasound characteristics, and then, its sensitivity, specificity, positive predictive value and negative predictive value for diagnosis of thyroid cancer were analyzed. The effectiveness of the model was evaluated in the validation group.
Results
The cfDNA concentration in patients with thyroid cancer was significantly higher than that in patients with benign nodules (P<0.001). The results of univariate analysis showed that there were significant differences in cfDNA concentration and ultrasound imaging features that included the aspect ratio, internal echo, integrity of the capsule, calcification and cystic lesions between patients with malignant and benign nodules (all P<0.05). The results of multivariate Logistic regression analysis showed that cfDNA≥56.84 ng/mL, and thyroid ultrasound presenting the aspect ratio ≥1, incomplete capsule, hypoechoic, calcification, and non-cystic lesions were independent risk factors for diagnosis of thyroid cancer (all P<0.05). According to the standard regression coefficients of above variables, a scoring model was established. The area under the ROC curve (AUC) of the model for diagnosis of thyroid cancer was 0.958 (95% CI=0.926-0.989), and its optimal cut-off value was 5.5, with a diagnostic sensitivity, specificity, positive predictive value, and negative predictive value of 85.5%, 89.7%, 89.8%, and 85.2%, respectively, which were all superior to those of the predictive power of each single variable. The validation results showed that the AUC was 0.902 (95% CI=0.848-0.957) in validation group.
Conclusion
The scoring model based on plasm cfDNA and ultrasound features of the thyroid nodules has high predictive value for diagnosis of thyroid cancer, and it provides a reference for the differential diagnosis of thyroid benign and malignant nodules. Clinical intervention should be aggressively performed when the score of a thyroid nodule ≥5.5.
Ultrasound images of the thyroid nodules A: A benign thyroid nodule (shown by the arrow); B-C: A malignant thyroid nodule (shown by the arrow)1.2.2 cfDNA检测
Yu YL, Shen XS, Hu CH, et al. Establishment of diagnosis model for thyroid cancer based on plasma circulating cell-free DNA and ultrasound characteristic of thyroid nodules and its verification[J]. Chin J Gen Surg, 2021, 30(8):955-963.
参考文献WangJ, YuF, ShangY, et al. Thyroid cancer: incidence and mortality trends in China,2005-2015[J]. , 2020, 68(1):163-173. doi:10.1007/s12020-020-02207-6。SiegelRL, MillerKD, JemalA. Cancer statistics,2020[J]. , 2020, 70(1):7-30. doi:10.3322/caac.21590.薛明淼, 尚梦园, 王志化, 等. 良恶性甲状腺结节的临床特点分析[J]. , 2020, 10(21):14-17. doi:10.3969/j.issn.2095-0616.2020.21.005.XueMM, ShangMY, WangZH, et al. Analysis on the clinical feature of benign and malignant thyroid nodules[J]. , 2020, 10(21):14-17. doi:10.3969/j.issn.2095-0616.2020.21.005.张启才. 彩色多普勒超声对甲状腺癌的临床检测分析[J]. , 2020, 4(21):246-247. doi:10.3969/j.issn.2096-3807.2020.21.140.ZhangQC. Analysis of color Doppler ultrasonography in clinical detection of thyroid cancer[J]. , 2020, 4(21):246-247. doi:10.3969/j.issn.2096-3807.2020.21.140.叶舰佩, 金晓可, 叶水根. 超声引导下甲状腺细针穿刺活检的临床价值分析[J]. , 2020, 30(7):1305-1307.YeJP, JinXK, YeSG. Analysis of clinical value of ultrasound-guided thyroid fine needle biopsy[J]. , 2020, 30(7):1305-1307.XingM, HaugenBR, SchlumbergerM. Progress in molecular-based management of differentiated thyroid cancer[J]. , 2013, 381(9871):1058-1069. doi:10.1016/S0140-6736(13)60109-9.GilsonP. Enrichment and Analysis of ctDNA[J]. , 2020, 215:181-211. doi:10.1007/978-3-030-26439-0_10.SzilágyiM, PösO, MártonÉ, et al. Circulating Cell-Free Nucleic Acids: Main Characteristics and Clinical Application[J]. , 2020, 21(18):6827. doi:10.3390/ijms21186827.PessoaLS, HeringerM, FerrerVP. ctDNA as a cancer biomarker: A broad overview[J]. , 2020, 155:103109. doi:10.1016/j.critrevonc.2020.103109.李威威, 刘金龙. 循环肿瘤DNA在胰腺癌中的临床应用进展[J]. , 2021, 30(3):337-342. doi:10.7659/j.issn. 1005-6947.2021.03.012.LiWW, LiuJL. Advances in clinical application of circulating tumor DNA in pancreatic cancer[J]. , 2021, 30(3):337-342. doi:10.7659/j.issn.1005-6947.2021.03.012.KhatamiF, TavangarSM. Liquid Biopsy in Thyroid Cancer: New Insight[J]., 2018, 12(3):235-248.SalviantiF, GiulianiC, PetroneL, et al. Integrity and Quantity of Total Cell-Free DNA in the Diagnosis of Thyroid Cancer: Correlation with Cytological Classification[J]. , 2017, 18(7):1350. doi:10.3390/ijms18071350.ZaneM, AgostiniM, EnzoMV, et al. Circulating cell-free DNA, SLC5A8 and SLC26A4 hypermethylation, BRAF(V600E): A non-invasive tool panel for early detection of thyroid cancer[J]. , 2013, 67(8):723-730. doi:10.1016/j.biopha.2013.06.007.刘晓莉, 李芳, 孙辉. 分子检测技术在甲状腺结节诊治中的价值[J]. , 2015, 35(6):624-629. doi:10.7504/CJPS.ISSN1005-2208.2015.06.10.LiuXL, LiF, SunH. Value of molecular testing technique in diagnosis and management of thyroid nodule[J]. , 2015, 35(6):624-629. doi:10.7504/CJPS.ISSN1005-2208.2015.06.10.李长霖, 周乐, 孙辉. 我国甲状腺结节细针穿刺活检技术应用现状及进展[J]. , 2020, 40(2):195-198. doi:10.19538/j.cjps.issn1005-2208.2020.02.13.LiCL, ZhouL, SunH. Status and progress of fine needle aspiration biopsy for thyroid nodules in China[J]. , 2020, 40(2):195-198. doi:10.19538/j.cjps.issn1005-2208.2020.02.13.NikiforovYE, OhoriNP, HodakSP, et al. Impact of mutational testing on the diagnosis and management of patients with cytologically indeterminate thyroid nodules:a prospective analysis of 1056 FNA samples[J]. , 2011, 96(11):3390-3397.doi:10.1210/jc.2011-1469.Beaudenon-HuibregtseS, AlexanderEK, GuttlerRB, et al. Centralized molecular testing for oncogenic gene mutations complements the local cytopathologic diagnosis of thyroid nodules[J]. , 2014, 24(10):1479-1487. doi: 10.1089/thy.2013.0640.AlexanderEK, KennedyGC, BalochZW, et al. Preoperative diagnosis of benign thyroid nodules with indeterminate cytology[J]. , 2012, 367(8):705-715. doi:10.1056/NEJMoa1203208.ErkinuresinT, DemirciH. Diagnostic accuracy of fine needle aspiration cytology of thyroid nodules[J]. , 2020, 7(1):61-66. doi:10.1515/dx-2019-0039.VolckmarAL, SültmannH, RiedigerA, et al. A field guide for cancer diagnostics using cell-free DNA: From principles to practice and clinical applications[J]. , 2018, 57(3):123-139. doi: 10.1002/gcc.22517.KerachianMA, PoudinehA, ThieryJP. Cell free circulating tumor nucleic acids, a revolution in personalized cancer medicine[J]. , 2019, 144:102827. doi: 10.1016/j.critrevonc.2019.102827.GaiW, SunK. Epigenetic Biomarkers in Cell-Free DNA and Applications in Liquid Biopsy[J]. , 2019, 10(1):32. doi:10.3390/genes10010032.Seton-RogersS. Closing in on cfDNA-based detection and diagnosis[J]. , 2020, 20(9):481. doi:10.1038/s41568-020-0293-7.RolfoC, CardonaAF, CristofanilliM, et al. Challenges and opportunities of cfDNA analysis implementation in clinical practice: Perspective of the International Society of Liquid Biopsy (ISLB)[J]. , 2020, 151:102978.doi: 10.1016/j.critrevonc.2020.102978.CirilloM, CraigAFM, BorchmannS, et al. Liquid biopsy in lymphoma:Molecular methods and clinical applications[J]. , 2020, 91:102106. doi: 10.1016/j.ctrv.2020.102106.ValpioneS, GremelG, MundraP, et al. Plasma total cell-free DNA (cfDNA) is a surrogate biomarker for tumour burden and a prognostic biomarker for survival in metastatic melanoma patients[J]. , 2018, 88:1-9. doi:10.1016/j.ejca.2017.10.029.SpindlerKG, BoysenAK, PallisgårdN, et al. Cell-Free DNA in Metastatic Colorectal Cancer: A Systematic Review and Meta-Analysis[J]. , 2017, 22(9):1049-1055. doi:10.1634/theoncologist.2016-0178.BuJ, LeeTH, JeongWJ, et al. Enhanced detection of cell-free DNA (cfDNA) enables its use as a reliable biomarker for diagnosis and prognosis of gastric cancer[J]. , 2020, 15(12):e0242145. doi: 10.1371/journal.pone.0242145.AiB, LiuH, HuangY, et al. Circulating cell-free DNA as a prognostic and predictive biomarker in non-small cell lung cancer[J]. , 2016, 7(28):44583-44595. doi:10.18632/oncotarget.10069.SidawayP. cfDNA monitoring is feasible in SCLC[J]. , 2020, 17(1):7. doi:10.1038/s41571-019-0300-7.YangJ, ChengL, ZhangJ, et al. Predictive value of circulating cell-free DNA in the survival of breast cancer patients: A systemic review and meta-analysis[J]. , 2018, 97(28):e11417. doi: 10.1097/MD.0000000000011417.TesslerFN, MiddletonWD, GrantEG, et al. ACR Thyroid Imaging, Reporting and Data System (TI-RADS): White Paper of the ACR TI-RADS Committee[J]. , 2017, 14(5):587-595. doi: 10.1016/j.jacr.2017.01.046.AhnHS, LeeJB, SeoM, et al. Distinguishing benign from malignant thyroid nodules using thyroid ultrasonography: utility of adding superb microvascular imaging and elastography[J]. , 2018, 123(4):260-270. doi:10.1007/s11547-017-0839-2.ShayganfarA, HashemiP, EsfahaniMM, et al. Prediction of thyroid nodule malignancy using thyroid imaging reporting and data system (TIRADS) and nodule size[J]. , 2020, 60(2):222-227. doi:10.1016/j.clinimag.2019.10.004.秦岭, 张章, 齐志峰, 等. 血清胸苷激酶1、游离DNA联合检测与晚期胃癌化疗效果及预后的相关性[J]. , 2020, 18(12):1240-1243. doi:10.11877/j.issn.1672-1535.2020.18.12.13.QinL, ZhangZ, QiZF, et al. Correlation of serum thymidine kinase 1 and cell-free DNA co-detection and postoperative chemotherapy and prognosis of advanced gastric cancer[J]. 2020, 18(12):1240-1243. doi:10.11877/j.issn.1672-1535.2020.18.12.13.RashidFA, MunkhdelgerJ, FukuokaJ, et al. Prevalence of BRAFV600E mutation in Asian series of papillary thyroid carcinoma-a contemporary systematic review[J]. , 2020, 9(5):1878-1900. doi:10.21037/gs-20-430.黄万泽, 张哲嘉, 白宁, 等. 超声引导下细针穿刺对甲状腺结节的诊断价值及其影响因素[J]. , 2019, 28(11):1347-1353. doi:10.7659/j.issn.1005-6947.2019.11.005.HuangWZ, ZhangZJ, BaiN, et al. Diagnostic value of ultrasound-guided fine needle aspiration for thyroid nodules and the influential factors[J]. , 2019, 28(11):1347-1353. doi:10.7659/j.issn.1005-6947.2019.11.005.卢鑫, 田双明, 赵永锋, 等. 穿刺针型号及甲状腺结节血供类型与超声引导下细针穿刺活检取材满意率的关系[J]. , 2019, 28(5):543-550. doi:10.7659/j.issn.1005-6947.2019.05.005.LuX, TianSM, ZhaoYF, et al. Relations of puncture needle gauge and type of vascularity of thyroid nodule with sample satisfaction rate of ultrasound-guided fine needle aspiration biopsy[J]. , 2019, 28(5):543-550. doi:10.7659/j.issn.1005-6947.2019.05.005.