ketendoКлиническая и экспериментальная тиреоидологияClinical and experimental thyroidology1995-54722310-3787Endocrinology Research Centre10.14341/ket12715ketendo-12715Research ArticleНаучный обзорReviewЛабораторные биомаркеры дифференцированного рака щитовидной железыAlternative biomarkers of thyroid cancerhttps://orcid.org/0000-0003-1792-6419БуйваленкоУ. В.BuyvalenkoU. V.

Буйваленко Ульяна Валерьевна, ординатор

117292, Москва, ул. Дм.  Ульянова, д.11 

eLibrary SPIN: 5772-5683

Uliana V. Buyvalenko, resident

11 Dm. Ulyanova street, 117292, Moscow

eLibrary SPIN: 5772-5683

ulibu@list.ruhttps://orcid.org/0000-0002-9315-3801ЛевшинаА. Р.LevshinaA. R.

Левшина Анна Романовна 

eLibrary SPIN 6503-1969

Москва

Anna R. Levshina

eLibrary SPIN 6503-1969

Moscow

lewschinaa@yandex.ruhttps://orcid.org/0000-0002-7102-5323СахноваЕ. Е.SakhnovaE. E.

Сахнова Екатерина Евгеньевна

eLibrary SPIN: 4777-7937

Москва

Ekaterina E. Sakhnova, MD

eLibrary SPIN: 4777-7937

Moscow

katerisaa_29@mail.ruФГБУ «НМИЦ эндокринологии» Минздрава РоссииРоссияEndocrinology Research CentreRussian FederationФГАОУ ВО «Первый МГМУ им. И.М. Сеченова» Минздрава России (Сеченовский университет)Russian FederationFederal State Autonomous Educational Institution of Higher Education I.M.Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation (Sechenov University)Russian Federation2022110720221812128Copyright © Буйваленко У.В., Левшина А.Р., Сахнова Е.Е., 20222022Буйваленко У.В., Левшина А.Р., Сахнова Е.Е.Buyvalenko U.V., Levshina A.R., Sakhnova E.E.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.cet-endojournals.ru/jour/article/view/12715

Сывороточный тиреоглобулин является основным биомаркером послеоперационного мониторинга рецидива папиллярного рака щитовидной железы, однако высокая распространенность заболевания диктует необходимость поиска надежного показателя для лабораторной диагностики опухолевого процесса. Присутствие антител к тиреоглобулину оказывает влияние на прогноз заболевания и определяет вероятность рецидива, вместе с тем повлиять на уровень антител с помощью доступных в настоящее время методов невозможно. Чаще рассматриваются тенденции уровня антител к тиреоглобулину во время выявления заболевания и после радикального лечения, но существуют разногласия по интерпретации результатов. В настоящее время предлагаются и исследуются различные альтернативные биомаркеры, оценке и сравнению которых будет посвящен настоящий литературный обзор.

Serum thyroglobulin is the main biomarker for postoperative monitoring of papillary thyroid cancer recurrence however, the high prevalence of the disease dictates the need to find a reliable indicator for laboratory diagnosis of the tumor process. The presence of antibodies to thyroglobulin affects the prognosis of the disease and determines the likelihood of relapse; however, it is impossible to influence the level of antibodies using currently available methods. More commonly, trends in anti-thyroglobulin levels at the time of disease detection and after radical treatment are considered, but there is disagreement on the interpretation of the results. Currently, various alternative biomarkers are being proposed and studied, the evaluation and comparison of which will be the subject of this literature review.

тиреоглобулинантитела к тиреоглобулинурак щитовидной железымутация BRAF (T1799A)циркулирующая миРНК(miRNA/miR)длинная некодирующая РНК (lncRNA)мидкинмРНКthyroid cancerthyroglobulinalternative biomarkersBRAF (T1799A) mutationcirculating miRNA (miRNA/miR)long noncoding RNA (lncRNA)MidkineTg mRNAthyroglobulin antibodyReferencesMiller KD, Nogueira L, Mariotto AB, et al. Cancer treatment and survivorship statistics, 2019. CA Cancer J Clin. 2019;69(5):363-385. doi: https://doi.org/10.3322/caac.21565.Miller KD, Nogueira L, Mariotto AB, et al. Cancer treatment and survivorship statistics, 2019. CA Cancer J Clin. 2019;69(5):363-385. doi: https://doi.org/10.3322/caac.21565.Haugen BR, Alexander EK, Bible KC, 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. Thyroid. 2016;26(1):1-133. doi: https://doi.org/10.1089/thy.2015.0020Haugen BR, Alexander EK, Bible KC, 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. Thyroid. 2016;26(1):1-133. doi: https://doi.org/10.1089/thy.2015.0020Каприн А.Д., Старинский В.В., Петрова Г.В. Злокачественные новообразования в России в 2015 году (заболеваемость и смертность). — М.: МНИОИ им. П.А. Герцена; 2017.Kaprin AD, Starinskij VV, Petrova GV. ZlokachestvennyenovoobrazovanijavRossiiv 2015 godu (zabolevaemost’ ismertnost’). Moscow: MNIOI im. P.A. Gercena; 2017. (In Russ.).Cheng SP, Lee JJ, Lin JL. et al. Characterization of thyroid nodules using the proposed thyroid imaging reporting and data system (TI-RADS) Shih-Ping. Head Neck. 2012;35:541-547. doi: https://doi.org/10.1002/hed.22985.Cheng SP, Lee JJ, Lin JL. et al. Characterization of thyroid nodules using the proposed thyroid imaging reporting and data system (TI-RADS) Shih-Ping. Head Neck. 2012;35:541-547. doi: https://doi.org/10.1002/hed.22985.Verburg FA, Luster M, Cupini C, et al. Implications of thyroglobulin antibody positivity in patients with differentiated thyroid cancer: A clinical position statement. Thyroid. 2013;23(10):1211-1225. doi: https://doi.org/10.1089/thy.2012.0606Verburg FA, Luster M, Cupini C, et al. Implications of thyroglobulin antibody positivity in patients with differentiated thyroid cancer: A clinical position statement. Thyroid. 2013;23(10):1211-1225. doi: https://doi.org/10.1089/thy.2012.0606Spencer CA. Clinical utility of Thyroglobulin antibody (TgAb) measurements for patients with differentiated thyroid cancers (DTC). J Clin Endocrinol Metab. 2011;96(12):3615-3627. doi: https://doi.org/10.1210/jc.2011-1740Spencer CA. Clinical utility of Thyroglobulin antibody (TgAb) measurements for patients with differentiated thyroid cancers (DTC). J Clin Endocrinol Metab. 2011;96(12):3615-3627. doi: https://doi.org/10.1210/jc.2011-1740Giovanella L, Feldt-Rasmussen U, Verburg FA, et al. Thyroglobulin measurement by highly sensitive assays: Focus on laboratory challenges. Clin Chem Lab Med. 2015;53(9):1301-1314. doi: https://doi.org/10.1515/cclm-2014-0813Giovanella L, Feldt-Rasmussen U, Verburg FA, et al. Thyroglobulin measurement by highly sensitive assays: Focus on laboratory challenges. Clin Chem Lab Med. 2015;53(9):1301-1314. doi: https://doi.org/10.1515/cclm-2014-0813Algeciras-Schimnich A. Thyroglobulin measurement in the management of patients with differentiated thyroid cancer. Crit Rev Clin Lab Sci. 2018;55(3):205-218. doi: https://doi.org/10.1080/10408363.2018.1450830Algeciras-Schimnich A. Thyroglobulin measurement in the management of patients with differentiated thyroid cancer. Crit Rev Clin Lab Sci. 2018;55(3):205-218. doi: https://doi.org/10.1080/10408363.2018.1450830Van Herle AJ, Uller RP, Matthews NI, et al. Radioimmunoassay for measurement of triiodothyronine in human serum. J Clin Invest. 1973;52:1320-1327. doi: https://doi.org/10.1172/JCI107303Van Herle AJ, Uller RP, Matthews NI, et al. Radioimmunoassay for measurement of triiodothyronine in human serum. J Clin Invest. 1973;52:1320-1327. doi: https://doi.org/10.1172/JCI107303Van Herle AJ, Uller RP. Elevated serum thyroglobulin. A marker of metastases in differentiated thyroid carcinomas. J Clin Invest. 1975;56(2):272-277. doi: https://doi.org/10.1172/jci108090Van Herle AJ, Uller RP. Elevated serum thyroglobulin. A marker of metastases in differentiated thyroid carcinomas. J Clin Invest. 1975;56(2):272-277. doi: https://doi.org/10.1172/jci108090Giovanella L, Treglia G, Sadeghi R, et al. Unstimulated highly sensitive thyroglobulin in follow-up of differentiated thyroid cancer patients: A meta-analysis. J Clin Endocrinol Metab. 2014;99(2):440-447. doi: https://doi.org/10.1210/jc.2013-3156Giovanella L, Treglia G, Sadeghi R, et al. Unstimulated highly sensitive thyroglobulin in follow-up of differentiated thyroid cancer patients: A meta-analysis. J Clin Endocrinol Metab. 2014;99(2):440-447. doi: https://doi.org/10.1210/jc.2013-3156Spencer C, LoPresti J, Fatemi S. How sensitive (second-generation) thyroglobulin measurement is changing paradigms for monitoring patients with differentiated thyroid cancer, in the absence or presence of thyroglobulin autoantibodies. CurrOpin Endocrinol Diabetes Obes. 2014;21(5):394-404. doi: https://doi.org/10.1097/MED.0000000000000092Spencer C, LoPresti J, Fatemi S. How sensitive (second-generation) thyroglobulin measurement is changing paradigms for monitoring patients with differentiated thyroid cancer, in the absence or presence of thyroglobulin autoantibodies. CurrOpin Endocrinol Diabetes Obes. 2014;21(5):394-404. doi: https://doi.org/10.1097/MED.0000000000000092Kushnir MM, Rockwood AL, Roberts WL, et al. Measurement of Thyroglobulin by LC-MS/MS in Serum and Plasma in Presence of Anti-Thyroglobulin Autoantibodies. Clin Chem. 2013;59(6):982-990. doi: https://doi.org/10.1373/clinchem.2012.195594Kushnir MM, Rockwood AL, Roberts WL, et al. Measurement of Thyroglobulin by LC-MS/MS in Serum and Plasma in Presence of Anti-Thyroglobulin Autoantibodies. Clin Chem. 2013;59(6):982-990. doi: https://doi.org/10.1373/clinchem.2012.195594Murphy DM, Castellanos-Rizaldos E, Makrigiorgos GM. Usefulness of a Thyroglobulin Liquid Chromatography — Tandem Mass SpectrometryAssay for Evaluation ofSuspected Heterophile Interference. Clin Chem. 2014;60(7):1014-1016. doi: https://doi.org/10.1373/clinchem.2014.221465Murphy DM, Castellanos-Rizaldos E, Makrigiorgos GM. Usefulness of a Thyroglobulin Liquid Chromatography — Tandem Mass SpectrometryAssay for Evaluation ofSuspected Heterophile Interference. Clin Chem. 2014;60(7):1014-1016. doi: https://doi.org/10.1373/clinchem.2014.221465Azmat U, Porter K, Senter L, et al. Thyroglobulin Liquid ChromatographyTandem Mass Spectrometry Has a Low Sensitivity for Detecting Structural Disease in Patients with Antithyroglobulin Antibodies. Thyroid. 2017;27(1):74-80. doi: https://doi.org/10.1089/thy.2016.0210Azmat U, Porter K, Senter L, et al. Thyroglobulin Liquid ChromatographyTandem Mass Spectrometry Has a Low Sensitivity for Detecting Structural Disease in Patients with Antithyroglobulin Antibodies. Thyroid. 2017;27(1):74-80. doi: https://doi.org/10.1089/thy.2016.0210Brian C. Netzel, Russell P. Grant ANH, et al. First steps towards harmonization of LC-MS/MS thyroglobulin assays. Clin Chem. 2017;62(1):297-299. doi: https://doi.org/10.1373/clinchem.2015.245266Brian C. Netzel, Russell P. Grant ANH, et al. First steps towards harmonization of LC-MS/MS thyroglobulin assays. Clin Chem. 2017;62(1):297-299. doi: https://doi.org/10.1373/clinchem.2015.245266Spencer C, Fatemi S. Thyroglobulin antibody (TgAb) methods — Strengths, pitfalls and clinical utility for monitoring TgAb-positive patients with differentiated thyroid cancer. Best Pract Res Clin Endocrinol Metab. 2013;27(5):701-712. doi: https://doi.org/10.1016/j.beem.2013.07.003Spencer C, Fatemi S. Thyroglobulin antibody (TgAb) methods — Strengths, pitfalls and clinical utility for monitoring TgAb-positive patients with differentiated thyroid cancer. Best Pract Res Clin Endocrinol Metab. 2013;27(5):701-712. doi: https://doi.org/10.1016/j.beem.2013.07.003Tae YK, Won BK, Eun SK, et al. Serum thyroglobulin levels at the time of 131I remnant ablation just after thyroidectomy are useful for early prediction of clinical recurrence in low-risk patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab. 2005;90(3):1440-1445. doi: https://doi.org/10.1210/jc.2004-1771Tae YK, Won BK, Eun SK, et al. Serum thyroglobulin levels at the time of 131I remnant ablation just after thyroidectomy are useful for early prediction of clinical recurrence in low-risk patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab. 2005;90(3):1440-1445. doi: https://doi.org/10.1210/jc.2004-1771Piccardo A, Arecco F, Puntoni M, et al. Focus on high-risk DTC patients: High postoperative serum thyroglobulin level is a strong predictor of disease persistence and is associated to progressionfree survival and overall survival. Clin Nucl Med. 2013;38(1):18-24. doi: https://doi.org/10.1097/RLU.0b013e318266d4d8Piccardo A, Arecco F, Puntoni M, et al. Focus on high-risk DTC patients: High postoperative serum thyroglobulin level is a strong predictor of disease persistence and is associated to progressionfree survival and overall survival. Clin Nucl Med. 2013;38(1):18-24. doi: https://doi.org/10.1097/RLU.0b013e318266d4d8Latrofa F, Ricci D, Montanelli L, et al. Thyroglobulin autoantibodies in patients with papillary thyroid carcinoma: Comparison of different assays and evaluation of causes of discrepancies. J Clin Endocrinol Metab. 2012;97(11):3974-3982. doi: https://doi.org/10.1210/jc.2012-2406Latrofa F, Ricci D, Montanelli L, et al. Thyroglobulin autoantibodies in patients with papillary thyroid carcinoma: Comparison of different assays and evaluation of causes of discrepancies. J Clin Endocrinol Metab. 2012;97(11):3974-3982. doi: https://doi.org/10.1210/jc.2012-2406Zhao L, Liu M, Gao Y, et al. Glycosylation of sera thyroglobulin antibody in patients with thyroid diseases. Eur J Endocrinol. 2013;168(4):585-592. doi: https://doi.org/10.1530/EJE-12-0964Zhao L, Liu M, Gao Y, et al. Glycosylation of sera thyroglobulin antibody in patients with thyroid diseases. Eur J Endocrinol. 2013;168(4):585-592. doi: https://doi.org/10.1530/EJE-12-0964Spencer CA, Bergoglio LM, Kazarosyan M, et al. Clinical impact of thyroglobulin (Tg) and Tg autoantibody method differences on the management of patients with differentiated thyroid carcinomas. J Clin Endocrinol Metab. 2005;90(10):5566-5575. doi: https://doi.org/10.1210/jc.2005-0671Spencer CA, Bergoglio LM, Kazarosyan M, et al. Clinical impact of thyroglobulin (Tg) and Tg autoantibody method differences on the management of patients with differentiated thyroid carcinomas. J Clin Endocrinol Metab. 2005;90(10):5566-5575. doi: https://doi.org/10.1210/jc.2005-0671Phan HTT, Jager PL, van der Wal JE, et al. The follow-up of patients with differentiated thyroid cancer and undetectable thyroglobulin (Tg) and Tg antibodies during ablation. Eur J Endocrinol. 2008;158(1):77-83. doi: https://doi.org/10.1530/EJE-07-0399Phan HTT, Jager PL, van der Wal JE, et al. The follow-up of patients with differentiated thyroid cancer and undetectable thyroglobulin (Tg) and Tg antibodies during ablation. Eur J Endocrinol. 2008;158(1):77-83. doi: https://doi.org/10.1530/EJE-07-0399Tsushima Y, Miyauchi A, Ito Y, et al. Prognostic significance of changes in serum thyroglobulin antibody levels of pre-and post-total thyroidectomy in thyroglobulin antibody-positive papillary thyroid carcinoma patients. EndocrJ. 2013;60(7):871-876. doi: https://doi.org/10.1507/endocrj.EJ12-0410Tsushima Y, Miyauchi A, Ito Y, et al. Prognostic significance of changes in serum thyroglobulin antibody levels of pre-and post-total thyroidectomy in thyroglobulin antibody-positive papillary thyroid carcinoma patients. EndocrJ. 2013;60(7):871-876. doi: https://doi.org/10.1507/endocrj.EJ12-0410Chiovato L, Latrofa F, Braverman LE, et al. Disappearance of Humoral Thyroid Autoimmunity after Complete. Ann Intern Med. 2003;139:346-351. doi: https://doi.org/10.7326/0003-4819-139-5_part_1-200309020-00010Chiovato L, Latrofa F, Braverman LE, et al. Disappearance of Humoral Thyroid Autoimmunity after Complete. Ann Intern Med. 2003;139:346-351. doi: https://doi.org/10.7326/0003-4819-139-5_part_1-200309020-00010Ozkan E, Soydal C, Araz M, et al. The additive clinical value of 18F-FDG PET/CT in defining the recurrence of disease in patients with differentiated thyroid cancer who have isolated increased antithyroglobulin antibody levels. Clin Nucl Med. 2012;37(8):755-758. doi: https://doi.org/10.1097/RLU.0b013e31825ae77bOzkan E, Soydal C, Araz M, et al. The additive clinical value of 18F-FDG PET/CT in defining the recurrence of disease in patients with differentiated thyroid cancer who have isolated increased antithyroglobulin antibody levels. Clin Nucl Med. 2012;37(8):755-758. doi: https://doi.org/10.1097/RLU.0b013e31825ae77bSmooke-Praw S, Ro K, Levin O, et al. Thyroglobulin antibody levels do not predict disease status in papillary thyroid cancer. Clin Endocrinol (Oxf ). 2014;81(2):271-275. doi: https://doi.org/10.1111/cen.12421Smooke-Praw S, Ro K, Levin O, et al. Thyroglobulin antibody levels do not predict disease status in papillary thyroid cancer. Clin Endocrinol (Oxf ). 2014;81(2):271-275. doi: https://doi.org/10.1111/cen.12421Görges R, Maniecki M, Jentzen W, et al. Development and clinical impact of thyroglobulin antibodies in patients with differentiated thyroid carcinoma during the first 3 years after thyroidectomy. Eur J Endocrinol. 2005;153(1):49-55. doi: https://doi.org/10.1530/eje.1.01940Görges R, Maniecki M, Jentzen W, et al. Development and clinical impact of thyroglobulin antibodies in patients with differentiated thyroid carcinoma during the first 3 years after thyroidectomy. Eur J Endocrinol. 2005;153(1):49-55. doi: https://doi.org/10.1530/eje.1.01940Boldarine VT, Maciel RMB, Guimarães GS, et al. Development of a sensitive and specific quantitative reverse transcription-polymerase chain reaction assay for blood thyroglobulin messenger ribonucleic acid in the follow-up of patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab. 2010;95(4):1726-1733. doi: https://doi.org/10.1210/jc.2009-1354Boldarine VT, Maciel RMB, Guimarães GS, et al. Development of a sensitive and specific quantitative reverse transcription-polymerase chain reaction assay for blood thyroglobulin messenger ribonucleic acid in the follow-up of patients with differentiated thyroid carcinoma. J Clin Endocrinol Metab. 2010;95(4):1726-1733. doi: https://doi.org/10.1210/jc.2009-1354Cradic KW, Milosevic D, Rosenberg AM, et al. Mutant BRAFT1799A can be detected in the blood of papillary thyroid carcinoma patients and correlates with disease status. J Clin Endocrinol Metab. 2009;94(12):5001-5009. doi: https://doi.org/10.1210/jc.2009-1349Cradic KW, Milosevic D, Rosenberg AM, et al. Mutant BRAFT1799A can be detected in the blood of papillary thyroid carcinoma patients and correlates with disease status. J Clin Endocrinol Metab. 2009;94(12):5001-5009. doi: https://doi.org/10.1210/jc.2009-1349Daniotti M, Vallacchi V, Rivoltini L, et al. Detection of mutated BRAFV600E variant in circulating DNA of stage III-IV melanoma patients. Int J Cancer. 2007;120(11):2439-2444. doi: https://doi.org/10.1002/ijc.22598Daniotti M, Vallacchi V, Rivoltini L, et al. Detection of mutated BRAFV600E variant in circulating DNA of stage III-IV melanoma patients. Int J Cancer. 2007;120(11):2439-2444. doi: https://doi.org/10.1002/ijc.22598Lee JC, Zhao JT, Clifton-Bligh RJ, et al. MicroRNA-222 and MicroRNA-146b are tissue and circulating biomarkers of recurrent papillary thyroid cancer. Cancer. 2013;119(24):4358-4365. doi: https://doi.org/10.1002/cncr.28254Lee JC, Zhao JT, Clifton-Bligh RJ, et al. MicroRNA-222 and MicroRNA-146b are tissue and circulating biomarkers of recurrent papillary thyroid cancer. Cancer. 2013;119(24):4358-4365. doi: https://doi.org/10.1002/cncr.28254Dettmer M, Perren A, Moch H, et al. Comprehensive microrna expression profiling identifies novel markers in follicular variant of papillary thyroid carcinoma. Thyroid. 2013;23(11):1383-1389. doi: https://doi.org/10.1089/thy.2012.0632Dettmer M, Perren A, Moch H, et al. Comprehensive microrna expression profiling identifies novel markers in follicular variant of papillary thyroid carcinoma. Thyroid. 2013;23(11):1383-1389. doi: https://doi.org/10.1089/thy.2012.0632Yu S, Liu Y, Wang J, et al. Circulating microRNA profiles as potential biomarkers for diagnosis of papillary thyroid carcinoma. J Clin Endocrinol Metab. 2012;97(6):2084-2092. doi: https://doi.org/10.1210/jc.2011-3059Yu S, Liu Y, Wang J, et al. Circulating microRNA profiles as potential biomarkers for diagnosis of papillary thyroid carcinoma. J Clin Endocrinol Metab. 2012;97(6):2084-2092. doi: https://doi.org/10.1210/jc.2011-3059Cantara S, Pilli T, Sebastiani G, et al. Circulating miRNA95 and miRNA190 are sensitive markers for the differential diagnosis of thyroid nodules in a Caucasian population. J Clin Endocrinol Metab. 2014;99(11):4190-4198. doi: https://doi.org/10.1210/jc.2014-1923Cantara S, Pilli T, Sebastiani G, et al. Circulating miRNA95 and miRNA190 are sensitive markers for the differential diagnosis of thyroid nodules in a Caucasian population. J Clin Endocrinol Metab. 2014;99(11):4190-4198. doi: https://doi.org/10.1210/jc.2014-1923Pan W, Zhou L, Ge M, et al. Whole exome sequencing identifies lncRNA GAS8-AS1 and LPAR4 as novel papillary thyroid carcinoma driver alternations. Hum Mol Genet. 2016;25(9):1875-1884. doi: https://doi.org/10.1093/hmg/ddw056Pan W, Zhou L, Ge M, et al. Whole exome sequencing identifies lncRNA GAS8-AS1 and LPAR4 as novel papillary thyroid carcinoma driver alternations. Hum Mol Genet. 2016;25(9):1875-1884. doi: https://doi.org/10.1093/hmg/ddw056Zhang D, Liu X, Wei B, et al. Plasma lncRNA GAS8-AS1 as a Potential Biomarker of Papillary Thyroid Carcinoma in Chinese Patients. Int J Endocrinol. 2017;2017:1-6. doi: https://doi.org/10.1155/2017/2645904Zhang D, Liu X, Wei B, et al. Plasma lncRNA GAS8-AS1 as a Potential Biomarker of Papillary Thyroid Carcinoma in Chinese Patients. Int J Endocrinol. 2017;2017:1-6. doi: https://doi.org/10.1155/2017/2645904Kuzu F, Arpaci D, Unal M, et al. Midkine: A Novel Biomarker to Predict Malignancy in Patients with Nodular Thyroid Disease. Int J Endocrinol. 2016;2016:1-7. doi: https://doi.org/10.1155/2016/6035024Kuzu F, Arpaci D, Unal M, et al. Midkine: A Novel Biomarker to Predict Malignancy in Patients with Nodular Thyroid Disease. Int J Endocrinol. 2016;2016:1-7. doi: https://doi.org/10.1155/2016/6035024Meng Z, Tan J, Zhang G, et al. Evaluation of serum midkine as a biomarker in differentiated thyroid cancer. Life Sci. 2015;130:18-24. doi: https://doi.org/10.1016/j.lfs.2015.02.028Meng Z, Tan J, Zhang G, et al. Evaluation of serum midkine as a biomarker in differentiated thyroid cancer. Life Sci. 2015;130:18-24. doi: https://doi.org/10.1016/j.lfs.2015.02.028Li N, Zhang C, Meng Z, et al. Changes of serum midkine as a dynamic prognostic factor to monitor disease status in papillary thyroid cancer. Med (United States). 2018;97(36):1-7. doi: https://doi.org/10.1097/MD.0000000000012242Li N, Zhang C, Meng Z, et al. Changes of serum midkine as a dynamic prognostic factor to monitor disease status in papillary thyroid cancer. Med (United States). 2018;97(36):1-7. doi: https://doi.org/10.1097/MD.0000000000012242Shao H, Yu X, Wang C, et al. Midkine expression is associated with clinicopathological features and BRAF mutation in papillary thyroid cancer. Endocrine. 2014;46(2):285-291. doi:10.1007/s12020-013-0068-y.Shao H, Yu X, Wang C, et al. Midkine expression is associated with clinicopathological features and BRAF mutation in papillary thyroid cancer. Endocrine. 2014;46(2):285-291. doi:10.1007/s12020-013-0068-y.Zhang Y, Meng Z, Zhang M, et al. Immunohistochemical evaluation of midkine and nuclear factor-kappa B as diagnostic biomarkers for papillary thyroid cancer and synchronous metastasis. Life Sci. 2014;118(1):39-45. doi: https://doi.org/10.1016/j.lfs.2014.09.025Zhang Y, Meng Z, Zhang M, et al. Immunohistochemical evaluation of midkine and nuclear factor-kappa B as diagnostic biomarkers for papillary thyroid cancer and synchronous metastasis. Life Sci. 2014;118(1):39-45. doi: https://doi.org/10.1016/j.lfs.2014.09.025Moll R, Divo M, Langbein L. The human keratins: Biology and pathology. Histochem Cell Biol. 2008;129(6):705-733. doi: https://doi.org/10.1007/s00418-008-0435-6Moll R, Divo M, Langbein L. The human keratins: Biology and pathology. Histochem Cell Biol. 2008;129(6):705-733. doi: https://doi.org/10.1007/s00418-008-0435-6Giovanella L, Imperiali M, Trimboli P. Role of serum cytokeratin 19 fragment (Cyfra 21.1) as a prognostic biomarker in patients with differentiated thyroid cancer. Sci Rep. 2017;7(1):1-7. doi: https://doi.org/10.1038/s41598-017-07915-0Giovanella L, Imperiali M, Trimboli P. Role of serum cytokeratin 19 fragment (Cyfra 21.1) as a prognostic biomarker in patients with differentiated thyroid cancer. Sci Rep. 2017;7(1):1-7. doi: https://doi.org/10.1038/s41598-017-07915-0Hu Z, Zhao P, Zhang K, et al. Evaluation of Serum Vascular Adhesion Protein-1 as a Potential Biomarker in Thyroid Cancer. Int J Endocrinol. 2016;2016:1-7. doi: https://doi.org/10.1155/2016/6312529Hu Z, Zhao P, Zhang K, et al. Evaluation of Serum Vascular Adhesion Protein-1 as a Potential Biomarker in Thyroid Cancer. Int J Endocrinol. 2016;2016:1-7. doi: https://doi.org/10.1155/2016/6312529Baldane S, Ipekci SH, Sozen M, et al. Mean platelet volume could be a possible biomarker for papillary thyroid carcinomas. Asian Pacific J Cancer Prev. 2015;16(7):2671-2674. doi: https://doi.org/10.7314/APJCP.2015.16.7.2671Baldane S, Ipekci SH, Sozen M, et al. Mean platelet volume could be a possible biomarker for papillary thyroid carcinomas. Asian Pacific J Cancer Prev. 2015;16(7):2671-2674. doi: https://doi.org/10.7314/APJCP.2015.16.7.2671Bayhan Z, Zeren S, Ozbay I, et al. Mean platelet volume as a biomarker for thyroid carcinoma. IntSurg. 2016;101(1):50-53. doi: https://doi.org/10.9738/INTSURG-D-15-00123.1Bayhan Z, Zeren S, Ozbay I, et al. Mean platelet volume as a biomarker for thyroid carcinoma. IntSurg. 2016;101(1):50-53. doi: https://doi.org/10.9738/INTSURG-D-15-00123.1

The authors declare that there are no conflicts of interest present.