{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T03:49:52Z","timestamp":1782791392110,"version":"3.54.5"},"reference-count":40,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2019,4,5]],"date-time":"2019-04-05T00:00:00Z","timestamp":1554422400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Fine needle aspiration cytology (FNAC) and washout thyroglobulin (Tg) measurements are the standard for evaluating a metastatic lymph node (LN) in thyroid cancer. However, patients rarely benefit from these procedures due to false results. This study aims to identify a reliable biomarker that significantly improves the diagnosis of metastatic LNs, in addition to FNAC and washout Tg. This study analyzed 130 LNs that were suspected to have metastases on thyroid ultrasonography, from June 2016 to December 2017. All subjects underwent FNAC, washout Tg measurements and a new biomarker, washout Cytokeratin fragment 21-1 (CYFRA 21-1) measurement. The final LN outcomes were confirmed by surgical histology, repeat FNAC, or follow-up image. The diagnostic values of the presence of washout CYFRA 21-1 for diagnosing metastatic LNs were evaluated according to final LN outcomes. Among the 130 LNs, 42 were metastatic lesions and 88 were benign. The washout CYFRA 21-1 levels were significantly higher in metastatic LNs than in benign LNs. In contrast to the findings of washout Tg, washout CYFRA 21-1 showed little overlap between benign and malignant LNs, and its diagnostic cutoff values were not affected by surgery. The combinations of FNAC and washout CYFRA 21-1 showed higher sensitivity (91.9%), specificity (96.5%), negative predictive value (98.8%), and diagnostic accuracy (94.2%) than FNAC with washout Tg. The combination of FNAC, washout Tg, and washout CYFRA 21-1 showed the best sensitivity (98.8%). When washout CYFRA 21-1 was applied to the discordant results that were observed between FNAC and washout Tg, 20 of 22 LNs were correctly diagnosed. Washout CYFRA 21-1 measurements in thyroid LNs provide a diagnostic modality.<\/jats:p>","DOI":"10.3390\/cancers11040487","type":"journal-article","created":{"date-parts":[[2019,4,5]],"date-time":"2019-04-05T11:36:01Z","timestamp":1554464161000},"page":"487","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["CYFRA 21-1 in Lymph Node Fine Needle Aspiration Washout Improves Diagnostic Accuracy for Metastatic Lymph Nodes of Differentiated Thyroid Cancer"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9074-8087","authenticated-orcid":false,"given":"Jeongmin","family":"Lee","sequence":"first","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul KS013, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1089-6261","authenticated-orcid":false,"given":"Hye Lim","family":"Park","sequence":"additional","affiliation":[{"name":"Division of Nuclear Medicine, Department of Radiology, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul KS013, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chan-Wook","family":"Jeong","sequence":"additional","affiliation":[{"name":"Division of Nuclear Medicine, Department of Radiology, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul KS013, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9219-7135","authenticated-orcid":false,"given":"Jeonghoon","family":"Ha","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul KS013, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwanhoon","family":"Jo","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Internal Medicine, Incheon St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul KS013, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min-Hee","family":"Kim","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul KS013, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4491-626X","authenticated-orcid":false,"given":"Jeong-Sun","family":"Han","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul KS013, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sohee","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Surgery, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul KS013, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaseong","family":"Bae","sequence":"additional","affiliation":[{"name":"Department of Surgery, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul KS013, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6843-3708","authenticated-orcid":false,"given":"Chan Kwon","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Hospital Pathology, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul KS013, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3267-8399","authenticated-orcid":false,"given":"So Lyung","family":"Jung","sequence":"additional","affiliation":[{"name":"Department of Hospital Radiology, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul KS013, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Moo Il","family":"Kang","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul KS013, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0995-6482","authenticated-orcid":false,"given":"Dong-Jun","family":"Lim","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Internal Medicine, Seoul St. Mary\u2019s Hospital, College of Medicine, The Catholic University of Korea, Seoul KS013, Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,4,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21442","article-title":"Cancer statistics, 2018","volume":"68","author":"Siegel","year":"2018","journal-title":"CA Cancer J. Clin."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"e57","DOI":"10.1016\/j.suronc.2009.04.002","article-title":"Cervical lymph node dissection in papillary thyroid cancer: Current trends, persisting controversies, and unclarified uncertainties","volume":"19","author":"Sakorafas","year":"2010","journal-title":"Surg. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/thy.2015.0020","article-title":"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","volume":"26","author":"Haugen","year":"2016","journal-title":"Thyroid"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1970","DOI":"10.1210\/jc.2014-1098","article-title":"Thyroglobulin in lymph node fine-needle aspiration washout: A systematic review and meta-analysis of diagnostic accuracy","volume":"99","author":"Grani","year":"2014","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1002\/dc.20964","article-title":"Thyroglobulin measurement on fine-needle washout fluids: Influence of sample collection methods","volume":"37","author":"Giovanella","year":"2009","journal-title":"Diagn. Cytopathol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1530\/EJE-07-0088","article-title":"Thyroglobulin detection in fine-needle aspirates of cervical lymph nodes: A technique for the diagnosis of metastatic differentiated thyroid cancer","volume":"157","author":"Cunha","year":"2007","journal-title":"Eur. J. Endocrinol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"106","DOI":"10.3348\/kjr.2009.10.2.106","article-title":"Diagnostic benefit of thyroglobulin measurement in fine-needle aspiration for diagnosing metastatic cervical lymph nodes from papillary thyroid cancer: Correlations with US features","volume":"10","author":"Jeon","year":"2009","journal-title":"Korean J. Radiol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1089\/10507250360731578","article-title":"Diagnostic utility of thyroglobulin detection in fine-needle aspiration of cervical cystic metastatic lymph nodes from papillary thyroid cancer with negative cytology","volume":"13","author":"Cignarelli","year":"2003","journal-title":"Thyroid"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1089\/thy.2004.14.959","article-title":"Detection of recurrent papillary thyroid carcinoma by thyroglobulin assessment in the needle washout after fine-needle aspiration of suspicious lymph nodes","volume":"14","author":"Jack","year":"2004","journal-title":"Thyroid"},{"key":"ref_10","first-page":"1401","article-title":"Detection of thyroglobulin in fine needle aspirates of nonthyroidal neck masses: A clue to the diagnosis of metastatic differentiated thyroid cancer","volume":"74","author":"Pacini","year":"1992","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1364","DOI":"10.1210\/jc.2005-1705","article-title":"The diagnostic value for differentiated thyroid carcinoma metastases of thyroglobulin (Tg) measurement in washout fluid from fine-needle aspiration biopsy of neck lymph nodes is maintained in the presence of circulating anti-Tg antibodies","volume":"91","author":"Boi","year":"2006","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1111\/j.1365-2265.2008.03297.x","article-title":"Thyroglobulin measurement in fine-needle aspirate washouts: The criteria for neck node dissection for patients with thyroid cancer","volume":"70","author":"Kim","year":"2009","journal-title":"Clin. Endocrinol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4278","DOI":"10.1210\/jc.2007-1075","article-title":"Serum thyroglobulin, high-resolution ultrasound, and lymph node thyroglobulin in diagnosis of differentiated thyroid carcinoma nodal metastases","volume":"92","author":"Snozek","year":"2007","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1530\/EJE-07-0749","article-title":"Significance of low levels of thyroglobulin in fine needle aspirates from cervical lymph nodes of patients with a history of differentiated thyroid cancer","volume":"158","author":"Borel","year":"2008","journal-title":"Eur. J. Endocrinol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4254","DOI":"10.12659\/MSM.908647","article-title":"In Vitro Expression of Cytokeratin 19 in Adipose-Derived Stem Cells Is Induced by Epidermal Growth Factor","volume":"24","author":"Chen","year":"2018","journal-title":"Med. Sci. Monit."},{"key":"ref_16","first-page":"2609767","article-title":"Increased Cytokeratin 19 Fragment Levels Are Positively Correlated with Adenosine Deaminase Activity in Malignant Pleural Effusions from Adenocarcinomas","volume":"2018","author":"Barillo","year":"2018","journal-title":"Dis. Mark."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1016\/j.tranon.2017.12.005","article-title":"Expression Profile of Three Splicing Factors in Pleural Cells Based on the Underlying Etiology and Its Clinical Values in Patients with Pleural Effusion","volume":"11","author":"Han","year":"2018","journal-title":"Transl. Oncol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Yoon, J.H., Han, K.H., Kim, E.-K., Moon, H.J., Kim, M.J., Suh, Y.J., Choi, J.S., and Park, B.W. (2013). Fine-needle aspirates CYFRA 21-1 is a useful tumor marker for detecting axillary lymph node metastasis in breast cancer patients. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0057248"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Dinets, A., Pernemalm, M., Kjellin, H., Sviatoha, V., Sofiadis, A., Juhlin, C.C., Zedenius, J., Larsson, C., Lehti\u00f6, J., and H\u00f6\u00f6g, A.J. (2015). Differential protein expression profiles of cyst fluid from papillary thyroid carcinoma and benign thyroid lesions. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0126472"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"108","DOI":"10.1590\/2359-3997000000241","article-title":"Clinical impact of thyroglobulin (Tg) and Tg autoantibody (TgAb) measurements in needle washouts of neck lymph node biopsies in the management of patients with papillary thyroid carcinoma","volume":"61","author":"Maciel","year":"2017","journal-title":"Arch. Endocrinol. Metab."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"126","DOI":"10.3349\/ymj.2012.53.1.126","article-title":"Diagnostic performance of thyroglobulin value in indeterminate range in fine needle aspiration washout fluid from lymph nodes of thyroid cancer","volume":"53","author":"Sohn","year":"2012","journal-title":"Yonsei Med. J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1061","DOI":"10.1210\/jc.2012-3291","article-title":"Thyroglobulin in Washout Fluid From Lymph Node Fine-needle Aspiration Biopsy in Papillary Thyroid Cancer: Large-scale Validation of the Cutoff Value to Determine Malignancy and Evaluation of Discrepant Results","volume":"98","author":"Moon","year":"2013","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1007\/s12020-012-9636-9","article-title":"Usefulness of thyroglobulin measurement in needle washouts of fine-needle aspiration biopsy for the diagnosis of cervical lymph node metastases from papillary thyroid cancer before thyroidectomy","volume":"42","author":"Kim","year":"2012","journal-title":"Endocrine"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1530\/EJE-15-0344","article-title":"Lowered cutoff of lymph node fine-needle aspiration thyroglobulin in thyroid cancer patients with serum anti-thyroglobulin antibody","volume":"173","author":"Jo","year":"2015","journal-title":"Eur. J. Endocrinol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1186\/1559-0275-9-14","article-title":"Ovarian cyst fluid is a rich proteome resource for detection of new tumor biomarkers","volume":"9","author":"Kristjansdottir","year":"2012","journal-title":"Clin. Proteom."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1251","DOI":"10.5858\/2004-128-1251-DOTMIC","article-title":"Detection of tumor markers including carcinoembryonic antigen, APC, and cyclin D2 in fine-needle aspiration fluid of breast","volume":"128","author":"Lee","year":"2004","journal-title":"Arch. Pathol. Lab. Med."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e147","DOI":"10.1016\/j.ejim.2009.07.015","article-title":"High levels of tumor markers in pleural fluid correlate with poor survival in patients with adenocarcinomatous or squamous malignant effusions","volume":"20","author":"Singh","year":"2009","journal-title":"Eur. J. Intern. Med."},{"key":"ref_28","first-page":"e521","article-title":"Correlation of serum and salivary CA15-3 levels in patients with breast cancer","volume":"14","author":"Rahimi","year":"2009","journal-title":"Med. Oral Patol. Oral Cir. Bucal"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"705","DOI":"10.1007\/s00418-008-0435-6","article-title":"The human keratins: Biology and pathology","volume":"129","author":"Moll","year":"2008","journal-title":"Histochem. Cell Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.tjog.2013.02.002","article-title":"Serum cytokeratin-19 fragment (Cyfra 21-1) is a prognostic indicator for epithelial ovarian cancer","volume":"53","author":"Wu","year":"2014","journal-title":"Taiwan J. Obstet. Gynecol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2298","DOI":"10.1378\/chest.128.4.2298","article-title":"Diagnostic utility of serum and pleural fluid carcinoembryonic antigen, neuron-specific enolase, and cytokeratin 19 fragments in patients with effusions from primary lung cancer","volume":"128","author":"Lee","year":"2005","journal-title":"Chest"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1285","DOI":"10.1002\/1097-0142(20000915)89:6<1285::AID-CNCR13>3.0.CO;2-G","article-title":"Serum CYFRA 21-1 is one of the most reliable tumor markers for breast carcinoma","volume":"89","author":"Nakata","year":"2000","journal-title":"Cancer"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1097\/PAI.0000000000000287","article-title":"The Use of CYFRA 21-1 for the Detection of Breast Cancer Axillary Lymph Node Metastases in Needle Washouts of Fine-Needle Aspiration Biopsies","volume":"25","author":"Liscia","year":"2017","journal-title":"Appl. Immunohistochem. Mol. Morphol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1038\/modpathol.3880312","article-title":"Immunohistochemical diagnosis of papillary thyroid carcinoma","volume":"14","author":"Cheung","year":"2001","journal-title":"Mod. Pathol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1177\/172460080802300109","article-title":"Circulating cytokeratin 19 fragments in patients with benign nodules and carcinomas of the thyroid gland","volume":"23","author":"Giovanella","year":"2008","journal-title":"Int. J. Biol. Mark."},{"key":"ref_36","first-page":"2","article-title":"Serum Cytokeratins Determination in Differentiated Thyroid","volume":"20","author":"Appetecchia","year":"2001","journal-title":"J. Exp. Clin. Cancer Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"7359","DOI":"10.1038\/s41598-017-07915-0","article-title":"Role of serum cytokeratin 19 fragment (Cyfra 21.1) as a prognostic biomarker in patients with differentiated thyroid cancer","volume":"7","author":"Giovanella","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"81","DOI":"10.4331\/wjbc.v8.i1.81","article-title":"Use of thyroglobulin as a tumour marker","volume":"8","author":"Indrasena","year":"2017","journal-title":"World J. Biol. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"370","DOI":"10.3348\/kjr.2016.17.3.370","article-title":"Ultrasonography diagnosis and imaging-based management of thyroid nodules: Revised Korean Society of Thyroid Radiology consensus statement and recommendations","volume":"17","author":"Shin","year":"2016","journal-title":"Korean J. Radiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1210\/jc.2012-2369","article-title":"Serum antithyroglobulin antibodies interfere with thyroglobulin detection in fine-needle aspirates of metastatic neck nodes in papillary thyroid carcinoma","volume":"98","author":"Jeon","year":"2013","journal-title":"J. Clin. Endocrinol. Metab."}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/4\/487\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:43:16Z","timestamp":1760186596000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/11\/4\/487"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,5]]},"references-count":40,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2019,4]]}},"alternative-id":["cancers11040487"],"URL":"https:\/\/doi.org\/10.3390\/cancers11040487","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,4,5]]}}}