{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T12:14:29Z","timestamp":1788869669743,"version":"build-2803163510"},"reference-count":73,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T00:00:00Z","timestamp":1763337600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2025,11,17]],"date-time":"2025-11-17T00:00:00Z","timestamp":1763337600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"University of Bern"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Virchows Arch"],"published-print":{"date-parts":[[2026,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Thyroid nodules represent a common clinical challenge, with 20\u201330% of fine-needle aspiration biopsies yielding indeterminate cytology results that complicate management decisions. While fine-needle aspiration cytology (FNAC) remains the gold standard for initial evaluation, up to 30% of cases produce indeterminate results, often leading to unnecessary diagnostic surgeries. This comprehensive review examines the transformative role of molecular diagnostics in thyroid pathology, focusing on their clinical utility, prognostic implications, and future directions. Molecular testing platforms, including Afirma GSC, ThyroSeq v3, and ThyroidPrint, have transformed the management of indeterminate thyroid nodules through gene expression profiling, mutation analysis, and microRNA signatures. The third-generation tests exhibit high sensitivity (91\u2013100%) and negative predictive values (90\u2013100%), thereby enabling surgical avoidance rates of 50.3\u201368.6% for patients with indeterminate cytology. The platforms employ both \u201crule-out\u201d strategies (high sensitivity\/NPV) and \u201crule-in\u201d approaches (high specificity\/PPV) to guide clinical decision-making. The paradigm of classifying thyroid tumors based on BRAF-like and RAS-like molecular profiles is becoming increasingly entrenched in clinical and diagnostic practice, affording pathologists and clinicians the ability to render diagnoses that are both more precise and reproducible. Within this molecular framework, the identification of markers such as TERT promoter and TP53 mutations, along with gene fusions, provides not only refined prognostic information but also facilitates the selection of patients for targeted therapeutic regimens including BRAF\/MEK inhibitors and RET inhibitors. Nevertheless, the implementation of these advances is not without its impediments. The field continues to grapple with platform heterogeneity, economic constraints, and geographic disparities affecting access to comprehensive molecular diagnostics\u2014factors that necessitate ongoing efforts to standardize testing and expand global availability. The future of this field is marked by several key developments, including the expansion of next-generation sequencing, the advancement of liquid biopsy technologies, the integration of artificial intelligence, and the adoption of multi-omic approaches. International guidelines are increasingly recommending molecular testing for advanced thyroid cancers and indeterminate nodules. These guidelines emphasize the need for standardized protocols and equitable access to such testing. Molecular diagnostics should be embraced as complementary tools within multidisciplinary care to optimize patient outcomes while reducing unnecessary interventions in thyroid nodule management.<\/jats:p>","DOI":"10.1007\/s00428-025-04334-9","type":"journal-article","created":{"date-parts":[[2025,11,16]],"date-time":"2025-11-16T23:41:46Z","timestamp":1763336506000},"page":"113-128","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["The actual and future role of molecular tests in thyroid pathology"],"prefix":"10.1007","volume":"488","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0948-1392","authenticated-orcid":false,"given":"Matthias S.","family":"Dettmer","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,11,17]]},"reference":[{"key":"4334_CR1","doi-asserted-by":"publisher","unstructured":"Agarwal S, Bychkov A, Jung CK (2021) Emerging biomarkers in thyroid practice and research. Cancers (Basel) 14. https:\/\/doi.org\/10.3390\/cancers14010204","DOI":"10.3390\/cancers14010204"},{"key":"4334_CR2","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1016\/S2213-8587(22)00101-2","volume":"10","author":"EK Alexander","year":"2022","unstructured":"Alexander EK, Cibas ES (2022) Diagnosis of thyroid nodules. Lancet Diabetes Endocrinol 10:533\u2013539. https:\/\/doi.org\/10.1016\/S2213-8587(22)00101-2","journal-title":"Lancet Diabetes Endocrinol"},{"key":"4334_CR3","doi-asserted-by":"publisher","first-page":"2759","DOI":"10.1210\/clinem\/dgad282","volume":"108","author":"AS Alzahrani","year":"2023","unstructured":"Alzahrani AS (2023) Clinical use of molecular data in thyroid nodules and cancer. J Clin Endocrinol Metab 108:2759\u20132771. https:\/\/doi.org\/10.1210\/clinem\/dgad282","journal-title":"J Clin Endocrinol Metab"},{"key":"4334_CR4","doi-asserted-by":"publisher","DOI":"10.3390\/genes14071314","author":"B Alzumaili","year":"2023","unstructured":"Alzumaili B, Sadow PM (2023) Update on molecular diagnostics in thyroid pathology: a review. Genes. https:\/\/doi.org\/10.3390\/genes14071314","journal-title":"Genes"},{"key":"4334_CR5","doi-asserted-by":"publisher","DOI":"10.1002\/path.6456","author":"SL Asa","year":"2025","unstructured":"Asa SL, Baloch Z, Jung CK, Cipriani NA, Gamboa-Dominguez A, Juhlin CC, Riddle ND, Stojanov IJ, Mete O (2025) Revisionist history uncovers a simplified molecular-based classification of differentiated thyroid cancer. J Pathol. https:\/\/doi.org\/10.1002\/path.6456","journal-title":"J Pathol"},{"key":"4334_CR6","unstructured":"Baloch ZW, Ghossein RA, Mete O, Tallini G et al (2025) Thyroid tumours. In: WHO Classification of Tumours Editorial Board. Endocrine and neuroendocrine tumours. International Agency for Research on Cancer, Lyon. (WHO classification of tumours series, 5th ed., vol 10). https:\/\/publications.iarc.who.int\/645"},{"issue":"2","key":"4334_CR7","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1007\/s12022-018-9532-9","volume":"29","author":"Z Baloch","year":"2018","unstructured":"Baloch Z, Mete O, Asa SL (2018) Immunohistochemical biomarkers in thyroid pathology. Endocr Pathol 29(2):91\u2013112. https:\/\/doi.org\/10.1007\/s12022-018-9532-9","journal-title":"Endocr Pathol"},{"key":"4334_CR8","doi-asserted-by":"publisher","first-page":"769","DOI":"10.1016\/j.ejso.2006.12.004","volume":"33","author":"F Basolo","year":"2007","unstructured":"Basolo F, Ugolini C, Proietti A, Iacconi P, Berti P, Miccoli P (2007) Role of frozen section associated with intraoperative cytology in comparison to FNA and FS alone in the management of thyroid nodules. Eur J Surg Oncol 33:769\u2013775. https:\/\/doi.org\/10.1016\/j.ejso.2006.12.004","journal-title":"Eur J Surg Oncol"},{"key":"4334_CR9","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1016\/j.annonc.2020.11.021","volume":"32","author":"C Belli","year":"2021","unstructured":"Belli C, Penault-Llorca F, Ladanyi M, Normanno N, Scoazec JY, Lacroix L, Reis-Filho JS, Subbiah V, Gainor JF, Endris V, Repetto M, Drilon A, Scarpa A, Andre F, Douillard JY, Curigliano G (2021) Esmo recommendations on the standard methods to detect RET fusions and mutations in daily practice and clinical research. Ann Oncol 32:337\u2013350. https:\/\/doi.org\/10.1016\/j.annonc.2020.11.021","journal-title":"Ann Oncol"},{"key":"4334_CR10","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1053\/j.semdp.2023.05.001","volume":"40","author":"B Belovarac","year":"2023","unstructured":"Belovarac B, Zhou F, Sharma J, Brandler TC (2023) Indeterminate thyroid nodules and advances in molecular pathology. Semin Diagn Pathol 40:349\u2013352. https:\/\/doi.org\/10.1053\/j.semdp.2023.05.001","journal-title":"Semin Diagn Pathol"},{"key":"4334_CR11","doi-asserted-by":"publisher","first-page":"337","DOI":"10.1089\/thy.2020.0944","volume":"31","author":"KC Bible","year":"2021","unstructured":"Bible KC, Kebebew E, Brierley J, Brito JP, Cabanillas ME, Clark TJ Jr., Di Cristofano A, Foote R, Giordano T, Kasperbauer J, Newbold K, Nikiforov YE, Randolph G, Rosenthal MS, Sawka AM, Shah M, Shaha A, Smallridge R, Wong-Clark CK (2021) 2021 American Thyroid Association guidelines for management of patients with anaplastic thyroid cancer. Thyroid 31:337\u2013386. https:\/\/doi.org\/10.1089\/thy.2020.0944","journal-title":"Thyroid"},{"key":"4334_CR12","doi-asserted-by":"publisher","first-page":"234","DOI":"10.1111\/his.12150","volume":"63","author":"LA Boos","year":"2013","unstructured":"Boos LA, Dettmer M, Schmitt A, Rudolph T, Steinert H, Moch H, Sobrinho-Simoes M, Komminoth P, Perren A (2013) Diagnostic and prognostic implications of the PAX8-PPARgamma translocation in thyroid carcinomas-a TMA-based study of 226 cases. Histopathology 63:234\u2013241. https:\/\/doi.org\/10.1111\/his.12150","journal-title":"Histopathology"},{"key":"4334_CR13","doi-asserted-by":"publisher","unstructured":"Boos LA, Schmitt A, Moch H, Komminoth P, Simillion C, Marinoni I, Nikiforov YE, Nikiforova MN, Perren A, Dettmer MS (2019) MiRNAs are involved in tall cell morphology in papillary thyroid carcinoma cancers (Basel) 11. https:\/\/doi.org\/10.1007\/s00292-019-0600-9","DOI":"10.1007\/s00292-019-0600-9"},{"key":"4334_CR14","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1016\/j.cell.2014.09.050","volume":"159","author":"Cancer Genome Atlas Research N","year":"2014","unstructured":"Cancer Genome Atlas Research N (2014) Integrated genomic characterization of papillary thyroid carcinoma. Cell 159:676\u2013690. https:\/\/doi.org\/10.1016\/j.cell.2014.09.050","journal-title":"Cell"},{"key":"4334_CR15","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26094225","author":"M Capezzone","year":"2025","unstructured":"Capezzone M, Rossi M, Bardi S, Morabito EM, Dalmazio G, Iapichino G, Galassi S, Seralessandri S, Torregrossa L, Tosti Balducci M, Marchetti E, Alessandri M, Ognibene A, De Napoli L, Materazzi G, Cantara S, Poma AM (2025) Diagnostic performance of next-generation sequencing (NGS) in indeterminate thyroid nodules: a single hospital experience. Int J Mol Sci. https:\/\/doi.org\/10.3390\/ijms26094225","journal-title":"Int J Mol Sci"},{"key":"4334_CR16","doi-asserted-by":"publisher","first-page":"621","DOI":"10.1097\/SLA.0000000000004130","volume":"272","author":"SE Carty","year":"2020","unstructured":"Carty SE, Ohori NP, Hilko DA, McCoy KL, French EK, Manroa P, Morariu E, Sridharan S, Seethala RR, Yip L (2020) The clinical utility of molecular testing in the management of thyroid follicular neoplasms (Bethesda IV nodules). Ann Surg 272:621\u2013627. https:\/\/doi.org\/10.1097\/SLA.0000000000004130","journal-title":"Ann Surg"},{"key":"4334_CR17","doi-asserted-by":"publisher","DOI":"10.3390\/cancers17071156","author":"R Chowdhury","year":"2025","unstructured":"Chowdhury R, Hier J, Payne KE, Abdulhaleem M, Dimitstein O, Eisenbach N, Forest VI, Payne RJ (2025) Impact of molecular testing on surgical decision-making in indeterminate thyroid nodules: a systematic review and meta-analysis of recent advancements. Cancers (Basel). https:\/\/doi.org\/10.3390\/cancers17071156","journal-title":"Cancers (Basel)"},{"key":"4334_CR18","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1007\/s00428-024-03953-y","volume":"485","author":"A Coca-Pelaz","year":"2024","unstructured":"Coca-Pelaz A, Rodrigo JP, Agaimy A, Hartl DM, Stenman G, Vander Poorten V, Makitie AA, Zafereo M, Rao KN, Randolph GW, Rinaldo A, Ferlito A (2024) Non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP): what do we need to know? Virchows Arch 485:977\u2013987. https:\/\/doi.org\/10.1007\/s00428-024-03953-y","journal-title":"Virchows Arch"},{"key":"4334_CR19","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1016\/j.jasc.2025.04.003","volume":"14","author":"CF Connelly","year":"2025","unstructured":"Connelly CF, Smithgall MC, Desai N, Cimic A, Baskota SU (2025) Performance characteristics of ThyroSeq, ThyGeNEXT\/ThyraMIR, and Afirma molecular platforms in evaluation of 1252 cytologically-indeterminate thyroid nodules. J Am Soc Cytopathol 14:243\u2013254. https:\/\/doi.org\/10.1016\/j.jasc.2025.04.003","journal-title":"J Am Soc Cytopathol"},{"key":"4334_CR20","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1097\/PAS.0000000000001208","volume":"43","author":"V Cracolici","year":"2019","unstructured":"Cracolici V, Kadri S, Ritterhouse LL, Segal JP, Wanjari P, Cipriani NA (2019) Clinicopathologic and molecular features of metastatic follicular thyroid carcinoma in patients presenting with a thyroid nodule versus a distant metastasis. Am J Surg Pathol 43:514\u2013522. https:\/\/doi.org\/10.1097\/PAS.0000000000001208","journal-title":"Am J Surg Pathol"},{"key":"4334_CR21","doi-asserted-by":"publisher","first-page":"881","DOI":"10.1097\/PAS.0000000000001489","volume":"44","author":"V Cracolici","year":"2020","unstructured":"Cracolici V, Ritterhouse LL, Segal JP, Puranik R, Wanjari P, Kadri S, Parilla M, Cipriani NA (2020) Follicular thyroid neoplasms: comparison of clinicopathologic and molecular features of atypical adenomas and follicular thyroid carcinomas. Am J Surg Pathol 44:881\u2013892. https:\/\/doi.org\/10.1097\/PAS.0000000000001489","journal-title":"Am J Surg Pathol"},{"key":"4334_CR22","doi-asserted-by":"publisher","first-page":"1383","DOI":"10.1089\/thy.2012.0632","volume":"23","author":"M Dettmer","year":"2013","unstructured":"Dettmer M, Perren A, Moch H, Komminoth P, Nikiforov YE, Nikiforova MN (2013) Comprehensive microrna expression profiling identifies novel markers in follicular variant of papillary thyroid carcinoma. Thyroid 23:1383\u20131389. https:\/\/doi.org\/10.1089\/thy.2012.0632","journal-title":"Thyroid"},{"key":"4334_CR23","doi-asserted-by":"publisher","first-page":"E1","DOI":"10.1210\/jc.2012-2694jc.2012-2694[pii]","volume":"98","author":"M Dettmer","year":"2013","unstructured":"Dettmer M, Vogetseder A, Durso MB, Moch H, Komminoth P, Perren A, Nikiforov YE, Nikiforova MN (2013) MicroRNA expression array identifies novel diagnostic markers for conventional and oncocytic follicular thyroid carcinomas. J Clin Endocrinol Metab 98:E1-7. https:\/\/doi.org\/10.1210\/jc.2012-2694jc.2012-2694[pii]","journal-title":"J Clin Endocrinol Metab"},{"key":"4334_CR24","doi-asserted-by":"publisher","first-page":"342","DOI":"10.1016\/j.dib.2023.110020","volume":"34","author":"MS Dettmer","year":"2023","unstructured":"Dettmer MS, H\u00fcrlimann S, Scheuble L, Vassella E, Perren A, Wicke C (2023) Cribriform Morular Thyroid Carcinoma - Ultimobranchial Pouch-Related? Deep Molecular Insights of a Unique Case. Endocr Pathol 34:342\u2013348. https:\/\/doi.org\/10.1016\/j.dib.2023.110020","journal-title":"Endocr Pathol"},{"key":"4334_CR25","doi-asserted-by":"publisher","first-page":"181","DOI":"10.1530\/JME-13-0266","volume":"52","author":"MS Dettmer","year":"2014","unstructured":"Dettmer MS, Perren A, Moch H, Komminoth P, Nikiforov YE, Nikiforova MN (2014) Microrna profile of poorly differentiated thyroid carcinomas: new diagnostic and prognostic insights. J Mol Endocrinol 52:181\u2013189. https:\/\/doi.org\/10.1530\/JME-13-0266","journal-title":"J Mol Endocrinol"},{"key":"4334_CR26","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s00292-019-0600-9","volume":"41","author":"MS Dettmer","year":"2020","unstructured":"Dettmer MS, Schmitt A, Komminoth P, Perren A (2020) Poorly differentiated thyroid carcinoma\u202f: an underdiagnosed entity. Pathologe 41:1\u20138. https:\/\/doi.org\/10.1007\/s00292-019-0600-9","journal-title":"Pathologe"},{"key":"4334_CR27","doi-asserted-by":"publisher","first-page":"419","DOI":"10.1530\/erc-15-0057","volume":"22","author":"MS Dettmer","year":"2015","unstructured":"Dettmer MS, Schmitt A, Steinert H, Capper D, Moch H, Komminoth P, Perren A (2015) Tall cell papillary thyroid carcinoma: new diagnostic criteria and mutations in BRAF and TERT. Endocr Relat Cancer 22:419\u2013429. https:\/\/doi.org\/10.1530\/erc-15-0057","journal-title":"Endocr Relat Cancer"},{"key":"4334_CR28","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1186\/s40463-022-00604-7","volume":"51","author":"N Dharampal","year":"2022","unstructured":"Dharampal N, Smith K, Harvey A, Paschke R, Rudmik L, Chandarana S (2022) Cost-effectiveness analysis of molecular testing for cytologically indeterminate thyroid nodules. J Otolaryngol Head Neck Surg 51:46. https:\/\/doi.org\/10.1186\/s40463-022-00604-7","journal-title":"J Otolaryngol Head Neck Surg"},{"key":"4334_CR29","doi-asserted-by":"publisher","first-page":"1115","DOI":"10.1089\/thy.2018.0733","volume":"29","author":"M Endo","year":"2019","unstructured":"Endo M, Nabhan F, Porter K, Roll K, Shirley LA, Azaryan I, Tonkovich D, Perlick J, Ryan LE, Khawaja R, Meng S, Phay JE, Ringel MD, Sipos JA (2019) Afirma gene sequencing classifier compared with gene expression classifier in indeterminate thyroid nodules. Thyroid 29:1115\u20131124. https:\/\/doi.org\/10.1089\/thy.2018.0733","journal-title":"Thyroid"},{"key":"4334_CR30","doi-asserted-by":"publisher","first-page":"149","DOI":"10.1007\/s11154-023-09842-0","volume":"25","author":"C Ferraz","year":"2024","unstructured":"Ferraz C (2024) Molecular testing for thyroid nodules: where are we now? Rev Endocr Metab Disord 25:149\u2013159. https:\/\/doi.org\/10.1007\/s11154-023-09842-0","journal-title":"Rev Endocr Metab Disord"},{"key":"4334_CR31","doi-asserted-by":"publisher","first-page":"100166","DOI":"10.1016\/j.acpath.2025.100166","volume":"12","author":"H Gaffney","year":"2025","unstructured":"Gaffney H, Mirza KM (2025) Pathology in the artificial intelligence era: guiding innovation and implementation to preserve human insight. Acad Pathol 12:100166. https:\/\/doi.org\/10.1016\/j.acpath.2025.100166","journal-title":"Acad Pathol"},{"key":"4334_CR32","doi-asserted-by":"publisher","first-page":"210","DOI":"10.1093\/ajcp\/aqz152","volume":"153","author":"J Grisales","year":"2020","unstructured":"Grisales J, Sanabria A (2020) Utility of routine frozen section of thyroid nodules classified as follicular neoplasm. Am J Clin Pathol 153:210\u2013220. https:\/\/doi.org\/10.1093\/ajcp\/aqz152","journal-title":"Am J Clin Pathol"},{"key":"4334_CR33","doi-asserted-by":"publisher","DOI":"10.3390\/jcm13061759","author":"ZC Hannoush","year":"2024","unstructured":"Hannoush ZC, Ruiz-Cordero R, Jara M, Kargi AY (2024) Current state of molecular cytology in thyroid nodules: platforms and their diagnostic and theranostic utility. J Clin Med. https:\/\/doi.org\/10.3390\/jcm13061759","journal-title":"J Clin Med"},{"key":"4334_CR34","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1016\/j.path.2019.08.002","volume":"12","author":"MR Haroon Al Rasheed","year":"2019","unstructured":"Haroon Al Rasheed MR, Xu B (2019) Molecular alterations in thyroid carcinoma. Surg Pathol Clin 12:921\u2013930. https:\/\/doi.org\/10.1016\/j.path.2019.08.002","journal-title":"Surg Pathol Clin"},{"issue":"1","key":"4334_CR35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1089\/thy.2015.0020","volume":"26","author":"BR Haugen","year":"2016","unstructured":"Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, Schuff KG, Sherman SI, Sosa JA, Steward DL, Tuttle RM, Wartofsky L (2016) 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 26(1):1\u2013133. https:\/\/doi.org\/10.1089\/thy.2015.0020","journal-title":"Thyroid"},{"key":"4334_CR36","doi-asserted-by":"publisher","first-page":"874","DOI":"10.1001\/archotol.133.9.874","volume":"133","author":"GF Huber","year":"2007","unstructured":"Huber GF, Dziegielewski P, Matthews TW, Warshawski SJ, Kmet LM, Faris P, Khalil M, Dort JC (2007) Intraoperative frozen-section analysis for thyroid nodules: a step toward clarity or confusion? Arch Otolaryngol Head Neck Surg 133:874\u2013881. https:\/\/doi.org\/10.1001\/archotol.133.9.874","journal-title":"Arch Otolaryngol Head Neck Surg"},{"key":"4334_CR37","doi-asserted-by":"publisher","first-page":"e698","DOI":"10.1210\/clinem\/dgad181","volume":"108","author":"NE Kim","year":"2023","unstructured":"Kim NE, Raghunathan RS, Hughes EG, Longstaff XR, Tseng CH, Li S, Cheung DS, Gofnung YA, Famini P, Wu JX, Yeh MW, Livhits MJ (2023) Bethesda III and IV thyroid nodules managed nonoperatively after molecular testing with Afirma GSC or Thyroseq v3. J Clin Endocrinol Metab 108:e698\u2013e703. https:\/\/doi.org\/10.1210\/clinem\/dgad181","journal-title":"J Clin Endocrinol Metab"},{"key":"4334_CR38","doi-asserted-by":"publisher","first-page":"1144","DOI":"10.1002\/dc.24522","volume":"48","author":"N Kumar","year":"2020","unstructured":"Kumar N, Gupta R, Gupta S (2020) Molecular testing in diagnosis of indeterminate thyroid cytology: trends and drivers. Diagn Cytopathol 48:1144\u20131151. https:\/\/doi.org\/10.1002\/dc.24522","journal-title":"Diagn Cytopathol"},{"key":"4334_CR39","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1001\/jamaoncol.2020.5935","volume":"7","author":"MJ Livhits","year":"2021","unstructured":"Livhits MJ, Zhu CY, Kuo EJ, Nguyen DT, Kim J, Tseng CH, Leung AM, Rao J, Levin M, Douek ML, Beckett KR, Cheung DS, Gofnung YA, Smooke-Praw S, Yeh MW (2021) Effectiveness of molecular testing techniques for diagnosis of indeterminate thyroid nodules: a randomized clinical trial. JAMA Oncol 7:70\u201377. https:\/\/doi.org\/10.1001\/jamaoncol.2020.5935","journal-title":"JAMA Oncol"},{"key":"4334_CR40","doi-asserted-by":"publisher","unstructured":"Lixandru-Petre IO, Dima A, Musat M, Dascalu M, GradisteanuPircalabioru G, Iliescu FS, Iliescu C (2025) Machine learning for thyroid cancer detection, presence of metastasis, and recurrence predictions-a scoping review. Cancers (Basel) 17. https:\/\/doi.org\/10.3390\/cancers17081308","DOI":"10.3390\/cancers17081308"},{"key":"4334_CR41","doi-asserted-by":"publisher","first-page":"531","DOI":"10.1067\/mhn.2001.115372","volume":"124","author":"DL Mandell","year":"2001","unstructured":"Mandell DL, Genden EM, Mechanick JI, Bergman DA, Biller HF, Urken ML (2001) Diagnostic accuracy of fine-needle aspiration and frozen section in nodular thyroid disease. Otolaryngol Head Neck Surg 124:531\u2013536. https:\/\/doi.org\/10.1067\/mhn.2001.115372","journal-title":"Otolaryngol Head Neck Surg"},{"key":"4334_CR42","doi-asserted-by":"publisher","first-page":"1417","DOI":"10.1093\/annonc\/mdz204","volume":"30","author":"C Marchio","year":"2019","unstructured":"Marchio C, Scaltriti M, Ladanyi M, Iafrate AJ, Bibeau F, Dietel M, Hechtman JF, Troiani T, Lopez-Rios F, Douillard JY, Andre F, Reis-Filho JS (2019) Esmo recommendations on the standard methods to detect NTRK fusions in daily practice and clinical research. Ann Oncol 30:1417\u20131427. https:\/\/doi.org\/10.1093\/annonc\/mdz204","journal-title":"Ann Oncol"},{"key":"4334_CR43","doi-asserted-by":"publisher","first-page":"e2400321","DOI":"10.1200\/PO.24.00321","volume":"9","author":"VR Marczyk","year":"2025","unstructured":"Marczyk VR, Fazeli S, Dadu R, Busaidy NL, Iyer P, Hu MI, Sherman SI, Hamidi S, Hosseini SM, Williams MD, Ahmed S, Routbort MJ, Luthra R, Roy-Chowdhuri S, San Lucas FA, Patel KP, Hong DS, Zafereo M, Wang JR, Maniakas A, Waguespack SG, Cabanillas ME (2025) NTRK fusion-positive thyroid carcinoma: from diagnosis to targeted therapy. JCO Precis Oncol 9:e2400321. https:\/\/doi.org\/10.1200\/PO.24.00321","journal-title":"JCO Precis Oncol"},{"key":"4334_CR44","doi-asserted-by":"publisher","unstructured":"Mavromati M, Saiji E, Demarchi MS, Lenoir V, Seipel A, Kuczma P, Jornayvaz FR, Becker M, Fernandez E, De Vito C, Triponez F, Leboulleux S (2023) Unnecessary thyroid surgery rate for suspicious nodule in the absence of molecular testing. Eur Thyroid J 12. https:\/\/doi.org\/10.1530\/ETJ-23-0114","DOI":"10.1530\/ETJ-23-0114"},{"key":"4334_CR45","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1016\/j.annonc.2024.04.005","volume":"35","author":"MF Mosele","year":"2024","unstructured":"Mosele MF, Westphalen CB, Stenzinger A, Barlesi F, Bayle A, Bieche I, Bonastre J, Castro E, Dienstmann R, Kramer A, Czarnecka AM, Meric-Bernstam F, Michiels S, Miller R, Normanno N, Reis-Filho J, Remon J, Robson M, Rouleau E, Scarpa A, Serrano C, Mateo J, Andre F (2024) Recommendations for the use of next-generation sequencing (NGS) for patients with advanced cancer in 2024: a report from the ESMO precision medicine working group. Ann Oncol 35:588\u2013606. https:\/\/doi.org\/10.1016\/j.annonc.2024.04.005","journal-title":"Ann Oncol"},{"key":"4334_CR46","doi-asserted-by":"publisher","first-page":"1526","DOI":"10.1210\/clinem\/dgac688","volume":"108","author":"CE Nasr","year":"2023","unstructured":"Nasr CE, Andrioli M, Endo M, Harrell RM, Livhits MJ, Osakwe I, Polavarapu P, Siperstein A, Wei S, Zheng X, Jiang R, Hao Y, Huang JIN, Klopper JP, Kloos RT, Kennedy G, Angell TE (2023) Real-world performance of the Afirma genomic sequencing classifier (GSC)-a meta-analysis. J Clin Endocrinol Metab 108:1526\u20131532. https:\/\/doi.org\/10.1210\/clinem\/dgac688","journal-title":"J Clin Endocrinol Metab"},{"key":"4334_CR47","doi-asserted-by":"publisher","unstructured":"Nguyen LTT, Thompson EK, Bhimani N, Duong MC, Nguyen HG, Bullock M, Gild ML, Glover A (2025) Prognostic significance of key molecular markers in thyroid cancer: a systematic literature review and meta-analysis. Cancers (Basel) 17. https:\/\/doi.org\/10.3390\/cancers17060939","DOI":"10.3390\/cancers17060939"},{"key":"4334_CR48","doi-asserted-by":"publisher","unstructured":"Nikiforov YE (2023) Molecular Testing for Indeterminate Thyroid Nodules: It Is Necessary VideoEndocrinology\u2122 10:21\u201321. https:\/\/doi.org\/10.1089\/ve.2023.0018","DOI":"10.1089\/ve.2023.0018"},{"key":"4334_CR49","doi-asserted-by":"publisher","first-page":"3627","DOI":"10.1002\/cncr.29038","volume":"120","author":"YE Nikiforov","year":"2014","unstructured":"Nikiforov YE, Carty SE, Chiosea SI, Coyne C, Duvvuri U, Ferris RL, Gooding WE, Hodak SP, LeBeau SO, Ohori NP, Seethala RR, Tublin ME, Yip L, Nikiforova MN (2014) Highly accurate diagnosis of cancer in thyroid nodules with follicular neoplasm\/suspicious for a follicular neoplasm cytology by ThyroSeq v2 next-generation sequencing assay. Cancer 120:3627\u20133634. https:\/\/doi.org\/10.1002\/cncr.29038","journal-title":"Cancer"},{"key":"4334_CR50","doi-asserted-by":"publisher","first-page":"1217","DOI":"10.1089\/thy.2015.0305","volume":"25","author":"YE Nikiforov","year":"2015","unstructured":"Nikiforov YE, Carty SE, Chiosea SI, Coyne C, Duvvuri U, Ferris RL, Gooding WE, LeBeau SO, Ohori NP, Seethala RR, Tublin ME, Yip L, Nikiforova MN (2015) Impact of the multi-gene ThyroSeq next-generation sequencing assay on cancer diagnosis in thyroid nodules with atypia of undetermined significance\/follicular lesion of undetermined significance cytology. Thyroid 25:1217\u20131223. https:\/\/doi.org\/10.1089\/thy.2015.0305","journal-title":"Thyroid"},{"key":"4334_CR51","doi-asserted-by":"publisher","first-page":"1682","DOI":"10.1002\/cncr.31245","volume":"124","author":"MN Nikiforova","year":"2018","unstructured":"Nikiforova MN, Mercurio S, Wald AI, Barbi de Moura M, Callenberg K, Santana-Santos L, Gooding WE, Yip L, Ferris RL, Nikiforov YE (2018) Analytical performance of the ThyroSeq v3 genomic classifier for cancer diagnosis in thyroid nodules. Cancer 124:1682\u20131690. https:\/\/doi.org\/10.1002\/cncr.31245","journal-title":"Cancer"},{"key":"4334_CR52","doi-asserted-by":"publisher","DOI":"10.3390\/cancers12082164","author":"C Nylen","year":"2020","unstructured":"Nylen C, Mechera R, Marechal-Ross I, Tsang V, Chou A, Gill AJ, Clifton-Bligh RJ, Robinson BG, Sywak MS, Sidhu SB, Glover AR (2020) Molecular markers guiding thyroid cancer management. Cancers (Basel). https:\/\/doi.org\/10.3390\/cancers12082164","journal-title":"Cancers (Basel)"},{"key":"4334_CR53","doi-asserted-by":"publisher","unstructured":"Olmos R, Dominguez JM, Vargas-Salas S, Mosso L, Fardella CE, Gonzalez G, Baudrand R, Guarda F, Valenzuela F, Arteaga E, Florenzano P, Nilo F, Lustig N, Martinez A, Lopez JM, Cruz F, Loyola S, Leon A, Droppelmann N, Montero P, Dominguez F, Camus M, Solar A, Zoroquiain P, Roa JC, Munoz E, Bruce E, Gajardo R, Miranda G, Riquelme F, Mena N, Gonzalez HE (2023) ThyroidPrint(R): clinical utility for indeterminate thyroid cytology. Endocr Relat Cancer 30. https:\/\/doi.org\/10.1530\/ERC-22-0409","DOI":"10.1530\/ERC-22-0409"},{"key":"4334_CR54","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1530\/ERC-19-0325","volume":"26","author":"F Panebianco","year":"2019","unstructured":"Panebianco F, Nikitski AV, Nikiforova MN, Kaya C, Yip L, Condello V, Wald AI, Nikiforov YE, Chiosea SI (2019) Characterization of thyroid cancer driven by known and novel ALK fusions. Endocr Relat Cancer 26:803\u2013814. https:\/\/doi.org\/10.1530\/ERC-19-0325","journal-title":"Endocr Relat Cancer"},{"key":"4334_CR55","doi-asserted-by":"publisher","DOI":"10.1038\/s41746-022-00609-6","volume":"5","author":"RB Parikh","year":"2022","unstructured":"Parikh RB, Helmchen LA (2022) Paying for artificial intelligence in medicine. NPJ Digit Med 5:63. https:\/\/doi.org\/10.1038\/s41746-022-00609-6","journal-title":"NPJ Digit Med"},{"key":"4334_CR56","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2023.1101410","volume":"14","author":"J Patel","year":"2023","unstructured":"Patel J, Klopper J, Cottrill EE (2023) Molecular diagnostics in the evaluation of thyroid nodules: current use and prospective opportunities. Front Endocrinol 14:1101410. https:\/\/doi.org\/10.3389\/fendo.2023.1101410","journal-title":"Front Endocrinol"},{"key":"4334_CR57","doi-asserted-by":"publisher","unstructured":"Pekova B, Sykorova V, Mastnikova K, Vaclavikova E, Moravcova J, Vlcek P, Lastuvka P, Taudy M, Katra R, Bavor P, Kodetova D, Chovanec M, Drozenova J, Astl J, Hrabal P, Vcelak J, Bendlova B (2021) NTRK fusion genes in thyroid carcinomas: clinicopathological characteristics and their impacts on prognosis. Cancers (Basel) 13. https:\/\/doi.org\/10.3390\/cancers13081932","DOI":"10.3390\/cancers13081932"},{"key":"4334_CR58","doi-asserted-by":"publisher","first-page":"bvab148","DOI":"10.1210\/jendso\/bvab148","volume":"5","author":"P Polavarapu","year":"2021","unstructured":"Polavarapu P, Fingeret A, Yuil-Valdes A, Olson D, Patel A, Shivaswamy V, Matthias TD, Goldner W (2021) Comparison of Afirma GEC and GSC to nodules without molecular testing in cytologically indeterminate thyroid nodules. J Endocr Soc 5:bvab148. https:\/\/doi.org\/10.1210\/jendso\/bvab148","journal-title":"J Endocr Soc"},{"key":"4334_CR59","doi-asserted-by":"publisher","unstructured":"Prades JM, Querat C, Dumollard JM, Richard C, Gavid M, Timoshenko AA, Peoc\u2019h M, Martin C (2013) Thyroid nodule surgery: predictive diagnostic value of fine-needle aspiration cytology and frozen section. Eur Ann Otorhinolaryngol Head Neck Dis 130:195\u2013199. https:\/\/doi.org\/10.1016\/j.anorl.2012.12.005","DOI":"10.1016\/j.anorl.2012.12.005"},{"key":"4334_CR60","doi-asserted-by":"publisher","first-page":"888","DOI":"10.1002\/cncr.30708","volume":"124","author":"MY Roth","year":"2018","unstructured":"Roth MY, Witt RL, Steward DL (2018) Molecular testing for thyroid nodules: review and current state. Cancer 124:888\u2013898. https:\/\/doi.org\/10.1002\/cncr.30708","journal-title":"Cancer"},{"key":"4334_CR61","doi-asserted-by":"publisher","DOI":"10.1530\/ETJ-25-0024","author":"A Ryska","year":"2025","unstructured":"Ryska A, Capdevila J, Dettmer MS, Elisei R, Fuhrer D, Hadoux J, Jarzab B, Locati LD, Newbold K, Tallini G, Uccella S, Wirth L, Singh R, Simon IM, Camacho P, Fugazzola L (2025) Molecular predictive biomarker testing in advanced thyroid cancer - a European consensus. Eur Thyroid J. https:\/\/doi.org\/10.1530\/ETJ-25-0024","journal-title":"Eur Thyroid J"},{"key":"4334_CR62","doi-asserted-by":"publisher","DOI":"10.1210\/clinem\/dgz099","author":"VT San Martin","year":"2020","unstructured":"San Martin VT, Lawrence L, Bena J, Madhun NZ, Berber E, Elsheikh TM, Nasr CE (2020) Real-world comparison of Afirma GEC and GSC for the assessment of cytologically indeterminate thyroid nodules. J Clin Endocrinol Metab. https:\/\/doi.org\/10.1210\/clinem\/dgz099","journal-title":"J Clin Endocrinol Metab"},{"key":"4334_CR63","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.suronc.2020.12.005","volume":"36","author":"A Sanabria","year":"2021","unstructured":"Sanabria A, Zafereo M, Thompson LDR, Hernandez-Prera JC, Kowalski LP, Nixon IJ, Shaha A, Rodrigo JP, Makitie A, Poorten VV, Suarez C, Zbaren P, Rinaldo A, Ferlito A (2021) Frozen section in thyroid gland follicular neoplasms: it\u2019s high time to abandon it! Surg Oncol 36:76\u201381. https:\/\/doi.org\/10.1016\/j.suronc.2020.12.005","journal-title":"Surg Oncol"},{"key":"4334_CR64","doi-asserted-by":"publisher","first-page":"649522","DOI":"10.3389\/fendo.2021.649522","volume":"12","author":"CA Silaghi","year":"2021","unstructured":"Silaghi CA, Lozovanu V, Georgescu CE, Georgescu RD, Susman S, Nasui BA, Dobrean A, Silaghi H (2021) Thyroseq v3. Afirma GSC, and microRNA panels versus previous molecular tests in the preoperative diagnosis of indeterminate thyroid nodules: a systematic review and meta-analysis. Frontiers in endocrinology 12:649522. https:\/\/doi.org\/10.3389\/fendo.2021.649522","journal-title":"Frontiers in endocrinology"},{"key":"4334_CR65","doi-asserted-by":"publisher","DOI":"10.1016\/j.jpi.2024.100366","volume":"15","author":"S Stenman","year":"2024","unstructured":"Stenman S, B\u00e9trisey S, Vainio P, Huvila J, Lundin M, Linder N, Schmitt A, Perren A, Dettmer MS, Haglund C, Arola J, Lundin J (2024) External validation of a deep learning-based algorithm for detection of tall cells in papillary thyroid carcinoma: a multicenter study. J Pathol Inform 15:100366. https:\/\/doi.org\/10.1016\/j.jpi.2024.100366","journal-title":"J Pathol Inform"},{"key":"4334_CR66","doi-asserted-by":"publisher","first-page":"204","DOI":"10.1001\/jamaoncol.2018.4616","volume":"5","author":"DL Steward","year":"2019","unstructured":"Steward DL, Carty SE, Sippel RS, Yang SP, Sosa JA, Sipos JA, Figge JJ, Mandel S, Haugen BR, Burman KD, Baloch ZW, Lloyd RV, Seethala RR, Gooding WE, Chiosea SI, Gomes-Lima C, Ferris RL, Folek JM, Khawaja RA, Kundra P, Loh KS, Marshall CB, Mayson S, McCoy KL, Nga ME, Ngiam KY, Nikiforova MN, Poehls JL, Ringel MD, Yang H, Yip L, Nikiforov YE (2019) Performance of a multigene genomic classifier in thyroid nodules with indeterminate cytology: a prospective blinded multicenter study. JAMA Oncol 5:204\u2013212. https:\/\/doi.org\/10.1001\/jamaoncol.2018.4616","journal-title":"JAMA Oncol"},{"key":"4334_CR67","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1159\/000544807","volume":"69","author":"N Sureka","year":"2025","unstructured":"Sureka N, Ahluwalia C, Ahuja S, Madan NK, Agrawal M, Ranga S (2025) Assessment of thyroid fine-needle aspirates using 2023 Bethesda system. Acta Cytol 69:280\u2013290. https:\/\/doi.org\/10.1159\/000544807","journal-title":"Acta Cytol"},{"key":"4334_CR68","doi-asserted-by":"publisher","first-page":"1074","DOI":"10.1016\/j.trecan.2021.07.003","volume":"7","author":"KZ Thein","year":"2021","unstructured":"Thein KZ, Velcheti V, Mooers BHM, Wu J, Subbiah V (2021) Precision therapy for RET-altered cancers with RET inhibitors. Trends Cancer 7:1074\u20131088. https:\/\/doi.org\/10.1016\/j.trecan.2021.07.003","journal-title":"Trends Cancer"},{"key":"4334_CR69","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1002\/dc.25474","volume":"53","author":"Z Yang","year":"2025","unstructured":"Yang Z, Ijaz K, Esebua M (2025) Molecular testing using ThyGeNEXT\/ThyraMIR in thyroid nodules with indeterminate cytology: a single medical institute experience. Diagn Cytopathol 53:351\u2013356. https:\/\/doi.org\/10.1002\/dc.25474","journal-title":"Diagn Cytopathol"},{"key":"4334_CR70","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1089\/thy.2019.0490","volume":"30","author":"M Zafereo","year":"2020","unstructured":"Zafereo M, McIver B, Vargas-Salas S, Dominguez JM, Steward DL, Holsinger FC, Kandil E, Williams M, Cruz F, Loyola S, Solar A, Roa JC, Leon A, Droppelman N, Lobos M, Arias T, Kong CS, Busaidy N, Grubbs EG, Graham P, Stewart J, Tang A, Wang J, Orloff L, Henriquez M, Lagos M, Osorio M, Schachter D, Franco C, Medina F, Wohllk N, Diaz RE, Veliz J, Horvath E, Tala H, Pineda P, Arroyo P, Vasquez F, Traipe E, Marin L, Miranda G, Bruce E, Bracamonte M, Mena N, Gonzalez HE (2020) A thyroid genetic classifier correctly predicts benign nodules with indeterminate cytology: two independent, multicenter, prospective validation trials. Thyroid 30:704\u2013712. https:\/\/doi.org\/10.1089\/thy.2019.0490","journal-title":"Thyroid"},{"key":"4334_CR71","doi-asserted-by":"publisher","unstructured":"Zeyghami W, Hansen MU, Jakobsen KK, Groenhoj C, Feldt-Rasmussen U, von Buchwald C, Hahn CH (2023) Liquid biopsies in thyroid cancers: a systematic review and meta-analysis. Endocr Relat Cancer 30. https:\/\/doi.org\/10.1530\/ERC-23-0002","DOI":"10.1530\/ERC-23-0002"},{"key":"4334_CR72","doi-asserted-by":"publisher","first-page":"921","DOI":"10.1002\/dc.24765","volume":"49","author":"L Zhang","year":"2021","unstructured":"Zhang L, Smola B, Lew M, Pang J, Cantley R, Pantanowitz L, Heider A, Jing X (2021) Performance of Afirma genomic sequencing classifier vs gene expression classifier in Bethesda category III thyroid nodules: an institutional experience. Diagn Cytopathol 49:921\u2013927. https:\/\/doi.org\/10.1002\/dc.24765","journal-title":"Diagn Cytopathol"},{"key":"4334_CR73","doi-asserted-by":"publisher","first-page":"1338","DOI":"10.5858\/arpa.2016-0100-RA","volume":"140","author":"M Zhang","year":"2016","unstructured":"Zhang M, Lin O (2016) Molecular testing of thyroid nodules: a review of current available tests for fine-needle aspiration specimens. Arch Pathol Lab Med 140:1338\u20131344. https:\/\/doi.org\/10.5858\/arpa.2016-0100-RA","journal-title":"Arch Pathol Lab Med"}],"container-title":["Virchows Archiv"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00428-025-04334-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00428-025-04334-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00428-025-04334-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,5]],"date-time":"2026-02-05T06:53:56Z","timestamp":1770274436000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00428-025-04334-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,17]]},"references-count":73,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2026,1]]}},"alternative-id":["4334"],"URL":"https:\/\/doi.org\/10.1007\/s00428-025-04334-9","relation":{},"ISSN":["0945-6317","1432-2307"],"issn-type":[{"value":"0945-6317","type":"print"},{"value":"1432-2307","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,17]]},"assertion":[{"value":"4 July 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"10 October 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 October 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 November 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"This article does not contain any studies with human participants or animals performed by the author.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"The author declares no competing interests.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}