Thyroid cancer is associated with a broad range of different mutations, including RET (rearranged during transfection) fusion genes. The importance of characterizing RET fusion-positive tumors has recently increased due to the possibility of targeted treatment. The aim of this study was to identify RET fusion-positive thyroid tumors, correlate them with clinicopathological features, compare them with other mutated carcinomas, and evaluate long-term follow-up of patients. The cohort consisted of 1564 different thyroid tissue samples (including 1164 thyroid carcinoma samples) from pediatric and adult patients. Samples were analyzed for known driver mutations occurring in thyroid cancer. Negative samples were subjected to extensive RET fusion gene analyses using next-generation sequencing and real-time PCR. RET fusion genes were not detected in any low-risk neoplasm or benign thyroid tissue and were detected only in papillary thyroid carcinomas (PTCs), in 113/993 (11.4%) patients, three times more frequently in pediatric and adolescent patients (29.8%) than in adult patients (8.7%). A total of 20 types of RET fusions were identified. RET fusion-positive carcinomas were associated with aggressive tumor behavior, including high rates of lymph node (75.2%) and distant metastases (18.6%), significantly higher than in NTRK fusion, BRAF V600E and RAS-positive carcinomas. Local and distant metastases were also frequently found in patients with microcarcinomas positive for the RET fusions. 'True recurrences' occurred rarely (2.4%) and only in adult patients. The 2-, 5-, 10-year disease-specific survival rates were 99%, 96%, and 95%, respectively. RET fusion-positive carcinomas were associated with high invasiveness and metastatic activity, but probably due to intensive treatment with low patient mortality.

Department of Ear Nose and Throat 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Molecular Endocrinology Institute of Endocrinology Prague Czech Republic

Department of Nuclear Medicine and Endocrinology 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Otorhinolaryngology 3rd Faculty of Medicine University Hospital Kralovske Vinohrady Prague Czech Republic

Department of Otorhinolaryngology and Maxillofacial Surgery 3rd Faculty of Medicine and Military University Hospital Prague Czech Republic

Department of Pathology 3rd Faculty of Medicine University Hospital Kralovske Vinohrady Prague Czech Republic

Department of Pathology and Molecular Medicine 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Pathology Military University Hospital Prague Czech Republic

Department of Surgery 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Departments of Otorhinolaryngology and Head and Neck Surgery 1st Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

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Adeniran AJ Zhu Z Gandhi M Steward DL Fidler JP Giordano TJ Biddinger PW & Nikiforov YE. 2006Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas. American Journal of Surgical Pathology 30216–222. (10.1097/01.pas.0000176432.73455.1b) PubMed DOI

Arighi E Borrello MG & Sariola H. 2005RET tyrosine kinase signaling in development and cancer. Cytokine and Growth Factor Reviews 16441–467. (10.1016/j.cytogfr.2005.05.010) PubMed DOI

Babli S Payne RJ Mitmaker E & Rivera J. 2018Effects of chronic lymphocytic thyroiditis on the clinicopathological features of papillary thyroid cancer. European Thyroid Journal 795–101. (10.1159/000486367) PubMed DOI PMC

Bongarzone I Monzini N Borrello MG Carcano C Ferraresi G Arighi E Mondellini P Della Porta G & Pierotti MA. 1993Molecular characterization of a thyroid tumor-specific transforming sequence formed by the fusion of ret tyrosine kinase and the regulatory subunit RI alpha of cyclic AMP-dependent protein kinase A. Molecular and Cellular Biology 13358–366. (10.1128/mcb.13.1.358-366.1993) PubMed DOI PMC

Agrawal N Akbani R Aksoy BA Ally A Arachchi H Asa SL Auman JT Balasundaram M Balu S & Baylin SB. 2014Integrated genomic characterization of papillary thyroid carcinoma. Cell 159676–690. (10.1016/j.cell.2014.09.050) PubMed DOI PMC

Elisei R, Romei C, Vorontsova T, Cosci B, Veremeychik V, Kuchinskaya E, Basolo F, Demidchik EP, Miccoli P, Pinchera A, et al.2001RET/PTC rearrangements in thyroid nodules: studies in irradiated and not irradiated, malignant and benign thyroid lesions in children and adults. Journal of Clinical Endocrinology and Metabolism 863211–3216. (10.1210/jcem.86.7.7678) PubMed DOI

Franco AT, Ricarte-Filho JC, Isaza A, Jones Z, Jain N, Mostoufi-Moab S, Surrey L, Laetsch TW, Li MM, DeHart JC, et al.2022Fusion oncogenes are associated with increased metastatic capacity and persistent disease in pediatric thyroid cancers. Journal of Clinical Oncology 401081–1090. (10.1200/JCO.21.01861) PubMed DOI PMC

Fusco A Grieco M Santoro M Berlingieri MT Pilotti S Pierotti MA Porta GD & Vecchio G. 1987A new oncogene in human thyroid papillary carcinomas and their lymph-nodal metastases. Nature 328170–172. (10.1038/328170a0) PubMed DOI

Galuppini F, Vianello F, Censi S, Barollo S, Bertazza L, Carducci S, Colato C, Manso J, Rugge M, Iacobone M, et al.2019Differentiated thyroid carcinoma in pediatric age: genetic and clinical scenario. Frontiers in Endocrinology (Lausanne) 10552. (10.3389/fendo.2019.00552) PubMed DOI PMC

Grieco M Santoro M Berlingieri MT Melillo RM Donghi R Bongarzone I Pierotti MA Della Ports G Fusco A & Vecchiot G. 1990PTC is a novel rearranged form of the RET proto-oncogene and is frequently detected in vivo in human thyroid papillary carcinomas. Cell 60557–563. (10.1016/0092-8674(9090659-3) PubMed DOI

Grubbs EG, Ng PK, Bui J, Busaidy NL, Chen K, Lee JE, Lu X, Lu H, Meric-Bernstam F, Mills GB, et al.2015RET fusion as a novel driver of medullary thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism 100788–793. (10.1210/jc.2014-4153) PubMed DOI PMC

Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, et al.2015American 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 261–133. (10.1089/thy.2015.0020) PubMed DOI PMC

Ito Y Miyauchi A Kihara M Fukushima M Higashiyama T & Miya A. 2018Overall survival of papillary thyroid carcinoma patients: a single-institution long-term follow-up of 5897 patients. World Journal of Surgery 42615–622. (10.1007/s00268-018-4479-z) PubMed DOI PMC

Kim EY Kim WG Kim WB Kim TY Kim JM Ryu JS Hong SJ Gong G & Shong YK. 2009Coexistence of chronic lymphocytic thyroiditis is associated with lower recurrence rates in patients with papillary thyroid carcinoma. Clinical Endocrinology 71581–586. (10.1111/j.1365-2265.2009.03537.x) PubMed DOI

Landa I, Ibrahimpasic T, Boucai L, Sinha R, Knauf JA, Shah RH, Dogan S, Ricarte-Filho JC, Krishnamoorthy GP, Xu B, et al.2016Genomic and transcriptomic hallmarks of poorly differentiated and anaplastic thyroid cancers. Journal of Clinical Investigation 1261052–1066. (10.1172/JCI85271) PubMed DOI PMC

Lee I Kim HK Soh EY & Lee J. 2020The association between chronic lymphocytic thyroiditis and the progress of papillary thyroid cancer. World Journal of Surgery 441506–1513. (10.1007/s00268-019-05337-9) PubMed DOI

Lee YA, Lee H, Im SW, Song YS, Oh DY, Kang HJ, Won JK, Jung KC, Kwon D, Chung EJ, et al.2021NTRK and RET fusion-directed therapy in pediatric thyroid cancer yields a tumor response and radioiodine uptake. Journal of Clinical Investigation 131e144847. (10.1172/JCI144847) PubMed DOI PMC

Liang J, Cai W, Feng D, Teng H, Mao F, Jiang Y, Hu S, Li X, Zhang Y, Liu B, et al.2018Genetic landscape of papillary thyroid carcinoma in the Chinese population. Journal of Pathology 244215–226. (10.1002/path.5005) PubMed DOI

Lu Z Zhang Y Feng D Sheng J Yang W & Liu B. 2017Targeted next generation sequencing identifies somatic mutations and gene fusions in papillary thyroid carcinoma. Oncotarget 845784–45792. (10.18632/oncotarget.17412) PubMed DOI PMC

Macerola E, Proietti A, Poma AM, Ugolini C, Torregrossa L, Vignali P, Basolo A, Materazzi G, Elisei R, Santini F, et al.2021Molecular alterations in relation to histopathological characteristics in a large series of pediatric papillary thyroid carcinoma from a single institution. Cancers 133123. (10.3390/cancers13133123) PubMed DOI PMC

Markham A.2020aPralsetinib: first approval. Drugs 801865–1870. (10.1007/s40265-020-01427-4) PubMed DOI

Markham A.2020bSelpercatinib: first approval. Drugs 801119–1124. (10.1007/s40265-020-01343-7) PubMed DOI PMC

Nacchio M, Pisapia P, Pepe F, Russo G, Vigliar E, Porcelli T, Luongo C, Iaccarino A, Pagni F, Salvatore D, et al.2022Predictive molecular pathology in metastatic thyroid cancer: the role of RET fusions. Expert Review of Endocrinology and Metabolism 17167–178. (10.1080/17446651.2022.2060819) PubMed DOI

Nikiforov YE Rowland JM Bove KE Monforte-Munoz H & Fagin JA. 1997Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children. Cancer Research 571690–1694. PubMed

Nikiforov YE.2006RET/PTC Rearrangement--a link between Hashimoto's thyroiditis and thyroid cancer...or not. Journal of Clinical Endocrinology and Metabolism 912040–2042. (10.1210/jc.2006-0791) PubMed DOI

Nikiforov YE.2011Molecular analysis of thyroid tumors. Modern Pathology 24(Supplement 2) S34–S43. (10.1038/modpathol.2010.167) PubMed DOI

Nikiforova MN Caudill CM Biddinger P & Nikiforov YE. 2002Prevalence of RET/PTC rearrangements in Hashimoto's thyroiditis and papillary thyroid carcinomas. International Journal of Surgical Pathology 1015–22. (10.1177/106689690201000104) PubMed DOI

Parimi V, Tolba K, Danziger N, Kuang Z, Sun D, Lin DI, Hiemenz MC, Schrock AB, Ross JS, Oxnard GR, et al.2023Genomic landscape of 891 RET fusions detected across diverse solid tumor types. npj Precision Oncology 710. (10.1038/s41698-023-00347-2) PubMed DOI PMC

Pekova B, Dvorakova S, Sykorova V, Vacinova G, Vaclavikova E, Moravcova J, Katra R, Vlcek P, Sykorova P, Kodetova D, et al.2019Somatic genetic alterations in a large cohort of pediatric thyroid nodules. Endocrine Connections 8796–805. (10.1530/EC-19-0069) PubMed DOI PMC

Pekova B, Sykorova V, Dvorakova S, Vaclavikova E, Moravcova J, Katra R, Astl J, Vlcek P, Kodetova D, Vcelak J, et al.2020RET, NTRK, ALK, BRAF, and MET fusions in a large cohort of pediatric papillary thyroid carcinomas. Thyroid 301771–1780. (10.1089/thy.2019.0802) PubMed DOI

Pekova B, Sykorova V, Mastnikova K, Vaclavikova E, Moravcova J, Vlcek P, Lastuvka P, Taudy M, Katra R, Bavor P, et al.2021NTRK fusion genes in thyroid carcinomas: clinicopathological characteristics and their impacts on prognosis. Cancers 131932. (10.3390/cancers13081932) PubMed DOI PMC

Rangel-Pozzo A Sisdelli L Cordioli MIV Vaisman F Caria P Mai S & Cerutti JM. 2020Genetic landscape of papillary thyroid carcinoma and nuclear architecture: an overview comparing pediatric and adult populations. Cancers 123146. (10.3390/cancers12113146) PubMed DOI PMC

Ricarte-Filho JC, Li S, Garcia-Rendueles ME, Montero-Conde C, Voza F, Knauf JA, Heguy A, Viale A, Bogdanova T, Thomas GA, et al.2013Identification of kinase fusion oncogenes in post-Chernobyl radiation-induced thyroid cancers. Journal of Clinical Investigation 1234935–4944. (10.1172/JCI69766) PubMed DOI PMC

Rogounovitch TI Mankovskaya SV Fridman MV Leonova TA Kondratovitch VA Konoplya NE Yamashita S Mitsutake N & Saenko VA. 2021Major oncogenic drivers and their clinicopathological correlations in sporadic childhood papillary thyroid carcinoma in Belarus. Cancers 133374. (10.3390/cancers13133374) PubMed DOI PMC

Santoro M Dathan NA Berlingieri MT Bongarzone I Paulin C Grieco M Pierotti MA Vecchio G & Fusco A. 1994Molecular characterization of RET/PTC3; a novel rearranged version of the RETproto-oncogene in a human thyroid papillary carcinoma. Oncogene 9509–516. PubMed

Santoro M Moccia M Federico G & Carlomagno F. 2020RET gene fusions in malignancies of the thyroid and other tissues. Genes 11424. (10.3390/genes11040424) PubMed DOI PMC

Satapathy S & Bal C. 2022Genomic landscape of sporadic pediatric differentiated thyroid cancers: a systematic review and meta-analysis. Journal of Pediatric Endocrinology and Metabolism 35749–760. (10.1515/jpem-2021-0741) PubMed DOI

Sciuto R Romano L Rea S Marandino F Sperduti I & Maini CL. 2009Natural history and clinical outcome of differentiated thyroid carcinoma: a retrospective analysis of 1503 patients treated at a single institution. Annals of Oncology 201728–1735. (10.1093/annonc/mdp050) PubMed DOI

Sheils OM O'Eary JJ Uhlmann V Lattich K & Sweeney EC. 2000Ret/PTC-1 activation in Hashimoto thyroiditis. International Journal of Surgical Pathology 8185–189. (10.1177/106689690000800305) PubMed DOI

Shi M Wang W Zhang J Li B Lv D Wang D Wang S Cheng D & Ma T. 2022Identification of RET fusions in a Chinese multicancer retrospective analysis by next-generation sequencing. Cancer Science 113308–318. (10.1111/cas.15181) PubMed DOI PMC

Tuttle RM, Ahuja S, Avram AM, Bernet VJ, Bourguet P, Daniels GH, Dillehay G, Draganescu C, Flux G, Führer D, et al.2019Controversies, consensus, and collaboration in the use of 131I therapy in differentiated thyroid cancer: a joint statement from the American Thyroid Association, the European Association of Nuclear Medicine, the Society of Nuclear Medicine and Molecular Imaging, and the European Thyroid Association. Thyroid 29461–470. (10.1089/thy.2018.0597) PubMed DOI

Ullmann TM Thiesmeyer JW Lee YJ Beg S Mosquera JM Elemento O Fahey TJ Scognamiglio T & Houvras Y. 2022RET fusion-positive papillary thyroid cancers are associated with a more aggressive phenotype. Annals of Surgical Oncology 294266–4273. (10.1245/s10434-022-11418-2) PubMed DOI

Wang Z Tang P Hua S Gao J Zhang B Wan H Wu Q Zhang J & Chen G. 2022Genetic and clinicopathologic characteristics of papillary thyroid carcinoma in the Chinese population: high BRAF mutation allele frequency, multiple driver gene mutations, and RET fusion may indicate more advanced TN stage. OncoTargets and Therapy 15147–157. (10.2147/OTT.S339114) PubMed DOI PMC

Wirtschafter A, Schmidt R, Rosen D, Kundu N, Santoro M, Fusco A, Multhaupt H, Atkins JP, Rosen MR, Keane WM, et al.1997Expression of the RET/PTC fusion gene as a marker for papillary carcinoma in Hashimoto’s thyroiditis. Laryngoscope 10795–100. (10.1097/00005537-199701000-00019) PubMed DOI

Worden F.2014Treatment strategies for radioactive iodine-refractory differentiated thyroid cancer. Therapeutic Advances in Medical Oncology 6267–279. (10.1177/1758834014548188) PubMed DOI PMC

Yakushina VD Lerner LV & Lavrov AV. 2017Gene fusions in thyroid cancer. Thyroid 28158–167. (10.1089/thy.2017.0318) PubMed DOI

Yang SR, Aypar U, Rosen EY, Mata DA, Benayed R, Mullaney K, Jayakumaran G, Zhang Y, Frosina D, Drilon A, et al.2021A performance comparison of commonly used assays to detect RET fusions. Clinical Cancer Research 271316–1328. (10.1158/1078-0432.CCR-20-3208) PubMed DOI PMC

BRAF V600E positive papillary thyroid carcinoma (TERT and TP53 mutation coexistence excluded): Correlation of clinicopathological features and the extent of surgical treatment and its complications