{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T22:32:17Z","timestamp":1791412337467,"version":"4.3.3"},"reference-count":39,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2023,6,23]],"date-time":"2023-06-23T00:00:00Z","timestamp":1687478400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Recherche en Mati\u00e8res de S\u00fbret\u00e9 Nucl\u00e9aire et Radioprotection program from the French National Research Agency and the Conseil D\u00e9partemental 06"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Although it is the gold standard for assessing the malignancy of thyroid nodules (TNs) preoperatively, the cytological analysis of fine-needle aspiration cytology (FNAC) samples results in 20\u201330% of cases in indeterminate lesions (ITNs). As two-thirds of these lesions will appear benign after diagnostic surgery, improved preoperative diagnostic methods need to be developed. In this pilot study, we evaluate if the metabolomic profiles of liquid-based (CytoRich\u00ae) FNAC samples of benign and malignant nodules can allow the molecular diagnosis of TNs. We performed untargeted metabolomic analyses with CytoRich\u00ae FNAC in a monocentric retrospective study. The cohort was composed of cytologically benign TNs, histologically benign or papillary thyroid carcinomas (PTCs) cytologically ITNs, and suspicious\/malignant TNs histologically confirmed as PTCs. The diagnostic performance of the identified metabolomic signature was assessed using several supervised classification methods. Seventy-eight patients were enrolled in the study. We identified 7690 peaks, of which 2697 ions were included for further analysis. We selected a metabolomic signature composed of the top 15 metabolites. Among all the supervised classification methods, the supervised autoencoder deep neural network exhibited the best performance, with an accuracy of 0.957 (0.842\u20131), an AUC of 0.945 (0.833\u20131), and an F1 score of 0.947 (0.842\u20131). Here, we report a promising new ancillary molecular technique to differentiate PTCs from benign TNs (including among ITNs) based on the metabolomic signature of FNAC sample fluids. Further studies with larger cohorts are now needed to identify a larger number of biomarkers and obtain more robust signatures.<\/jats:p>","DOI":"10.3390\/metabo13070782","type":"journal-article","created":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T05:28:02Z","timestamp":1687757282000},"page":"782","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Pilot Study on the Use of Untargeted Metabolomic Fingerprinting of Liquid-Cytology Fluids as a Diagnostic Tool of Malignancy for Thyroid Nodules"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3838-513X","authenticated-orcid":false,"given":"Gr\u00e9goire","family":"D\u2019Andr\u00e9a","sequence":"first","affiliation":[{"name":"Otorhinolaryngology and Head and Neck Surgery Department, Institut Universitaire de la Face et du Cou, GCS Nice University Hospital\u2014Antoine Lacassagne Center, C\u00f4te d\u2019Azur University, 31 Avenue de Valombrose, 06103 Nice, France"},{"name":"Laboratory Transporter in Imaging and Radiotherapy in Oncology (TIRO), UMR E4320 TIRO-MATOs, Direction de la Recherche Fondamentale (DRF), Institut des Sciences du Vivant Fr\u00e9deric Joliot, Commissariat \u00e0 l\u2019Energie Atomique et aux Energies Alternatives (CEA), Facult\u00e9 de M\u00e9decine, C\u00f4te d\u2019Azur University, 28 Avenue de Valombrose, CEDEX 2, 06107 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6397-0627","authenticated-orcid":false,"given":"Lun","family":"Jing","sequence":"additional","affiliation":[{"name":"Laboratory Transporter in Imaging and Radiotherapy in Oncology (TIRO), UMR E4320 TIRO-MATOs, Direction de la Recherche Fondamentale (DRF), Institut des Sciences du Vivant Fr\u00e9deric Joliot, Commissariat \u00e0 l\u2019Energie Atomique et aux Energies Alternatives (CEA), Facult\u00e9 de M\u00e9decine, C\u00f4te d\u2019Azur University, 28 Avenue de Valombrose, CEDEX 2, 06107 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabelle","family":"Peyrottes","sequence":"additional","affiliation":[{"name":"Department of Cytopathology and Anatomopathology, Antoine Lacassagne Center, 33 Av. de Valombrose, 06189 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Marie","family":"Guigonis","sequence":"additional","affiliation":[{"name":"Laboratory Transporter in Imaging and Radiotherapy in Oncology (TIRO), UMR E4320 TIRO-MATOs, Direction de la Recherche Fondamentale (DRF), Institut des Sciences du Vivant Fr\u00e9deric Joliot, Commissariat \u00e0 l\u2019Energie Atomique et aux Energies Alternatives (CEA), Facult\u00e9 de M\u00e9decine, C\u00f4te d\u2019Azur University, 28 Avenue de Valombrose, CEDEX 2, 06107 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fanny","family":"Graslin","sequence":"additional","affiliation":[{"name":"Laboratory Transporter in Imaging and Radiotherapy in Oncology (TIRO), UMR E4320 TIRO-MATOs, Direction de la Recherche Fondamentale (DRF), Institut des Sciences du Vivant Fr\u00e9deric Joliot, Commissariat \u00e0 l\u2019Energie Atomique et aux Energies Alternatives (CEA), Facult\u00e9 de M\u00e9decine, C\u00f4te d\u2019Azur University, 28 Avenue de Valombrose, CEDEX 2, 06107 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Lindenthal","sequence":"additional","affiliation":[{"name":"Laboratory Transporter in Imaging and Radiotherapy in Oncology (TIRO), UMR E4320 TIRO-MATOs, Direction de la Recherche Fondamentale (DRF), Institut des Sciences du Vivant Fr\u00e9deric Joliot, Commissariat \u00e0 l\u2019Energie Atomique et aux Energies Alternatives (CEA), Facult\u00e9 de M\u00e9decine, C\u00f4te d\u2019Azur University, 28 Avenue de Valombrose, CEDEX 2, 06107 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Sanglier","sequence":"additional","affiliation":[{"name":"Department of Radiology, Antoine Lacassagne Center, 33 Av. de Valombrose, 06189 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabel","family":"Gimenez","sequence":"additional","affiliation":[{"name":"Department of Cytopathology and Anatomopathology, Antoine Lacassagne Center, 33 Av. de Valombrose, 06189 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juliette","family":"Haudebourg","sequence":"additional","affiliation":[{"name":"Department of Cytopathology and Anatomopathology, Antoine Lacassagne Center, 33 Av. de Valombrose, 06189 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5597-2040","authenticated-orcid":false,"given":"Clair","family":"Vandersteen","sequence":"additional","affiliation":[{"name":"Otorhinolaryngology and Head and Neck Surgery Department, Institut Universitaire de la Face et du Cou, GCS Nice University Hospital\u2014Antoine Lacassagne Center, C\u00f4te d\u2019Azur University, 31 Avenue de Valombrose, 06103 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8576-3052","authenticated-orcid":false,"given":"Alexandre","family":"Bozec","sequence":"additional","affiliation":[{"name":"Otorhinolaryngology and Head and Neck Surgery Department, Institut Universitaire de la Face et du Cou, GCS Nice University Hospital\u2014Antoine Lacassagne Center, C\u00f4te d\u2019Azur University, 31 Avenue de Valombrose, 06103 Nice, France"},{"name":"Laboratory Transporter in Imaging and Radiotherapy in 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France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2839-4622","authenticated-orcid":false,"given":"Thierry","family":"Pourcher","sequence":"additional","affiliation":[{"name":"Laboratory Transporter in Imaging and Radiotherapy in Oncology (TIRO), UMR E4320 TIRO-MATOs, Direction de la Recherche Fondamentale (DRF), Institut des Sciences du Vivant Fr\u00e9deric Joliot, Commissariat \u00e0 l\u2019Energie Atomique et aux Energies Alternatives (CEA), Facult\u00e9 de M\u00e9decine, C\u00f4te d\u2019Azur University, 28 Avenue de Valombrose, CEDEX 2, 06107 Nice, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/j.ecl.2007.04.009","article-title":"Thyroid Nodules: Clinical Importance, Assessment, and Treatment","volume":"36","author":"Gharib","year":"2007","journal-title":"Endocrinol. Metab. Clin. N. Am."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"622","DOI":"10.4158\/EP161208.GL","article-title":"American Association of Clinical Endocrinologists, American College of Endocrinology, and Associazione Medici Endocrinologi Medical Guidelines for Clinical Practice for the Diagnosis and Management of Thyroid Nodules-2016 Update","volume":"22","author":"Gharib","year":"2016","journal-title":"Endocr. Pract."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2783","DOI":"10.1016\/S0140-6736(16)30172-6","article-title":"Thyroid cancer","volume":"388","author":"Cabanillas","year":"2016","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/S2213-8587(21)00049-8","article-title":"A worldwide journey of thyroid cancer incidence centred on tumour histology","volume":"9","author":"Rossi","year":"2021","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1089\/thy.2017.0500","article-title":"The 2017 Bethesda System for Reporting Thyroid Cytopathology","volume":"27","author":"Cibas","year":"2017","journal-title":"Thyroid"},{"key":"ref_6","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_7","doi-asserted-by":"crossref","first-page":"590128","DOI":"10.3389\/fendo.2020.590128","article-title":"Thyroid Nodule Molecular Testing: Is It Ready for Prime Time?","volume":"11","author":"Khan","year":"2020","journal-title":"Front. Endocrinol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1089\/thy.2018.0779","article-title":"Molecular Testing Versus Diagnostic Lobectomy in Bethesda III\/IV Thyroid Nodules: A Cost-Effectiveness Analysis","volume":"29","author":"Nicholson","year":"2019","journal-title":"Thyroid"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Rossi, E.D., Pantanowitz, L., and Faquin, W.C. (2019). The Role of Molecular Testing for the Indeterminate Thyroid FNA. Genes, 10.","DOI":"10.3390\/genes10100736"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2014","DOI":"10.1001\/jamaoncol.2018.4616","article-title":"Performance of a Multigene Genomic Classifier in Thyroid Nodules with Indeterminate Cytology: A Prospective Blinded Multicenter Study","volume":"5","author":"Steward","year":"2019","journal-title":"JAMA Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1115","DOI":"10.1089\/thy.2018.0733","article-title":"Afirma Gene Sequencing Classifier Compared with Gene Expression Classifier in Indeterminate Thyroid Nodules","volume":"29","author":"Endo","year":"2019","journal-title":"Thyroid"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.jasc.2021.07.002","article-title":"Performance of Afirma Gene Sequencing Classifier versus Gene Expression Classifier in thyroid nodules with indeterminate cytology","volume":"11","author":"Yang","year":"2022","journal-title":"J. Am. Soc. Cytopathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/S0167-7799(98)01214-1","article-title":"Systematic functional analysis of the yeast genome","volume":"16","author":"Oliver","year":"1998","journal-title":"Trends Biotechnol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1016\/S0958-1669(02)00299-9","article-title":"Can we discover novel pathways using metabolomic analysis?","volume":"13","author":"Weckwerth","year":"2002","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.cmet.2007.10.002","article-title":"The Biology of Cancer: Metabolic Reprogramming Fuels Cell Growth and Proliferation","volume":"7","author":"DeBerardinis","year":"2008","journal-title":"Cell Metab."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1016\/j.gde.2008.02.003","article-title":"Brick by brick: Metabolism and tumor cell growth","volume":"18","author":"Deberardinis","year":"2008","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Deja, S., Dawiskiba, T., Balcerzak, W., Orczyk-Pawi\u0142owicz, M., G\u0142\u00f3d, M., Pawe\u0142ka, D., and M\u0142ynarz, P. (2013). Follicular Adenomas Exhibit a Unique Metabolic Profile. 1H NMR Studies of Thyroid Lesions. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0084637"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1118","DOI":"10.1016\/j.surg.2012.08.037","article-title":"Metabolomics approach to thyroid nodules: A high-resolution magic-angle spinning nuclear magnetic resonance\u2013based study","volume":"152","author":"Miccoli","year":"2012","journal-title":"Surgery"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"30075","DOI":"10.1038\/srep30075","article-title":"Metabolomic analysis of percutaneous fine-needle aspiration specimens of thyroid nodules: Potential application for the preoperative diagnosis of thyroid cancer","volume":"6","author":"Ryoo","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3317","DOI":"10.1021\/pr300105e","article-title":"Toward the Reliable Diagnosis of Indeterminate Thyroid Lesions: A HRMAS NMR-Based Metabolomics Case of Study","volume":"11","author":"Torregrossa","year":"2012","journal-title":"J. Proteome Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.3892\/ijmm.2015.2368","article-title":"GC-MS-based metabolomic analysis of human papillary thyroid carcinoma tissue","volume":"36","author":"Chen","year":"2015","journal-title":"Int. J. Mol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"3315","DOI":"10.1021\/acs.jproteome.5b00351","article-title":"Distinct Metabolomic Profiles of Papillary Thyroid Carcinoma and Benign Thyroid Adenoma","volume":"14","author":"Xu","year":"2015","journal-title":"J. Proteome Res."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"225","DOI":"10.1159\/000478927","article-title":"European Thyroid Association Guidelines for Ultrasound Malignancy Risk Stratification of Thyroid Nodules in Adults: The EU-TIRADS","volume":"6","author":"Russ","year":"2017","journal-title":"Eur. Thyroid. J."},{"key":"ref_25","unstructured":"Lloyd, R.V., Osamura, R.Y., Kl\u00f6ppel, G., and Rosai, J. (2017). WHO Classification of Tumours of Endocrine Organs."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Pluskal, T., Castillo, S., Villar-Briones, A., and Ore\u0161i\u010d, M. (2010). MZmine 2: Modular framework for processing, visualizing, and analyzing mass spectrometry-based molecular profile data. BMC Bioinform., 11.","DOI":"10.1186\/1471-2105-11-395"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"W388","DOI":"10.1093\/nar\/gkab382","article-title":"MetaboAnalyst 5.0: Narrowing the gap between raw spectra and functional insights","volume":"49","author":"Pang","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"D608","DOI":"10.1093\/nar\/gkx1089","article-title":"HMDB 4.0: The human metabolome database for 2018","volume":"46","author":"Wishart","year":"2018","journal-title":"Nucleic Acids Res."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Chardin, D., Gille, C., Pourcher, T., Humbert, O., and Barlaud, M. (2022). Learning a confidence score and the latent space of a new supervised autoencoder for diagnosis and prognosis in clinical metabolomic studies. BMC Bioinform., 23.","DOI":"10.1186\/s12859-022-04900-x"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1001\/jamaoto.2022.0621","article-title":"Complication Rates of Total Thyroidectomy vs Hemithyroidectomy for Treatment of Papillary Thyroid Microcarcinoma: A Systematic Review and Meta-analysis","volume":"148","author":"Hsiao","year":"2022","journal-title":"JAMA Otolaryngol. Head Neck Surg."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/j.ebiom.2017.03.035","article-title":"New Insight in a New Entity: NIFTPS and Valuable Role of Ancillary Techniques. The Role of PD-L1","volume":"18","author":"Rossi","year":"2017","journal-title":"Ebiomedicine"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1310","DOI":"10.7150\/thno.50333","article-title":"From biomarkers to therapeutic targets: The promise of PD-L1 in thyroid autoimmunity and cancer","volume":"11","author":"Lassalle","year":"2021","journal-title":"Theranostics"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"258763","DOI":"10.1155\/2015\/258763","article-title":"Application of Metabolomics in Thyroid Cancer Research","volume":"2015","author":"Wojakowska","year":"2015","journal-title":"Int. J. Endocrinol."},{"key":"ref_34","first-page":"595","article-title":"The metabolomics and lipidomics window into thyroid cancer research","volume":"22","author":"Soroush","year":"2017","journal-title":"Biomarkers"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"187","DOI":"10.5582\/ddt.2020.03062","article-title":"Diagnosis of papillary thyroid carcinoma by 1H NMR spectroscopy-based metabolomic analysis of whole blood","volume":"14","author":"Wang","year":"2020","journal-title":"Drug Discov. Ther."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"122729","DOI":"10.1016\/j.talanta.2021.122729","article-title":"Diagnostic approach to thyroid cancer based on amino acid metabolomics in saliva by ultra-performance liquid chromatography with high resolution mass spectrometry","volume":"235","author":"Zhang","year":"2021","journal-title":"Talanta"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1007\/s00383-019-04584-0","article-title":"Metabolomics as a potential method for predicting thyroid malignancy in children and adolescents","volume":"36","author":"Zhou","year":"2020","journal-title":"Pediatr. Surg. Int."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"2728","DOI":"10.1002\/ijc.32007","article-title":"Alterations in the gut microbiota and metabolite profiles of thyroid carcinoma patients","volume":"144","author":"Feng","year":"2019","journal-title":"Int. J. Cancer"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1007\/s11306-018-1437-6","article-title":"Diagnosis of post-surgical fine-needle aspiration biopsies of thyroid lesions with indeterminate cytology using HRMAS NMR-based metabolomics","volume":"14","author":"Rezig","year":"2018","journal-title":"Metabolomics"}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/13\/7\/782\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:59:04Z","timestamp":1760126344000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/13\/7\/782"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,6,23]]},"references-count":39,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2023,7]]}},"alternative-id":["metabo13070782"],"URL":"https:\/\/doi.org\/10.3390\/metabo13070782","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,6,23]]}}}