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Kathleen A Luckett Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA

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Jennifer R Cracchiolo Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA

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Gnana P Krishnamoorthy Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA

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Luis Javier Leandro-Garcia Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA

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James Nagarajah Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA

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Mahesh Saqcena Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA

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Rona Lester Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA

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Soo Y Im Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA

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Zhen Zhao Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA

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Scott W Lowe Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA

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Elisa de Stanchina Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, New York, USA

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Eric J Sherman Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
Weill-Cornell Medical College, New York, New York, USA

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Alan L Ho Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
Weill-Cornell Medical College, New York, New York, USA

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Steven D Leach Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA
Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York, USA

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Jeffrey A Knauf Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA

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James A Fagin Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA
Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA
Weill-Cornell Medical College, New York, New York, USA

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most prevalent form of the disease, are associated with clonal non-overlapping activating mutations of genes encoding MAPK pathway signaling effectors, primarily point mutations of BRAF and of the three RAS genes, as well as fusions of receptor

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Samantha K McCarty Division of Endocrinology, Department of Molecular Virology, Center for Biostatistics, Diabetes and Metabolism, Department of Internal Medicine

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Motoyasu Saji Division of Endocrinology, Department of Molecular Virology, Center for Biostatistics, Diabetes and Metabolism, Department of Internal Medicine

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Xiaoli Zhang Division of Endocrinology, Department of Molecular Virology, Center for Biostatistics, Diabetes and Metabolism, Department of Internal Medicine

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Christina M Knippler Division of Endocrinology, Department of Molecular Virology, Center for Biostatistics, Diabetes and Metabolism, Department of Internal Medicine

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Lawrence S Kirschner Division of Endocrinology, Department of Molecular Virology, Center for Biostatistics, Diabetes and Metabolism, Department of Internal Medicine
Division of Endocrinology, Department of Molecular Virology, Center for Biostatistics, Diabetes and Metabolism, Department of Internal Medicine

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Soledad Fernandez Division of Endocrinology, Department of Molecular Virology, Center for Biostatistics, Diabetes and Metabolism, Department of Internal Medicine

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Matthew D Ringel Division of Endocrinology, Department of Molecular Virology, Center for Biostatistics, Diabetes and Metabolism, Department of Internal Medicine
Division of Endocrinology, Department of Molecular Virology, Center for Biostatistics, Diabetes and Metabolism, Department of Internal Medicine

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, invasion, and metastases is important in order to develop effective targeted therapies. PTC tumorigenesis is driven largely by activation of the MAP kinase pathway through several genetic events, the most common of which are activating mutations in BRAF

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Matthias S Dettmer Institute of Pathology, Division of Nuclear Medicine, Department of Neuropathology, Institute of Surgical Pathology, Institute of Surgical Pathology, University of Bern, Murtenstrasse 31, 3010 Bern, Switzerland

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Anja Schmitt Institute of Pathology, Division of Nuclear Medicine, Department of Neuropathology, Institute of Surgical Pathology, Institute of Surgical Pathology, University of Bern, Murtenstrasse 31, 3010 Bern, Switzerland

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Hans Steinert Institute of Pathology, Division of Nuclear Medicine, Department of Neuropathology, Institute of Surgical Pathology, Institute of Surgical Pathology, University of Bern, Murtenstrasse 31, 3010 Bern, Switzerland

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David Capper Institute of Pathology, Division of Nuclear Medicine, Department of Neuropathology, Institute of Surgical Pathology, Institute of Surgical Pathology, University of Bern, Murtenstrasse 31, 3010 Bern, Switzerland

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Holger Moch Institute of Pathology, Division of Nuclear Medicine, Department of Neuropathology, Institute of Surgical Pathology, Institute of Surgical Pathology, University of Bern, Murtenstrasse 31, 3010 Bern, Switzerland

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Paul Komminoth Institute of Pathology, Division of Nuclear Medicine, Department of Neuropathology, Institute of Surgical Pathology, Institute of Surgical Pathology, University of Bern, Murtenstrasse 31, 3010 Bern, Switzerland

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Aurel Perren Institute of Pathology, Division of Nuclear Medicine, Department of Neuropathology, Institute of Surgical Pathology, Institute of Surgical Pathology, University of Bern, Murtenstrasse 31, 3010 Bern, Switzerland

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times their widths.’), and the percentage of tall cells (TCs) needed in a given tumor is defined variably in the literature ( Ostrowski & Merino 1996 , DeLellis et al . 2004 ). The oncogenic BRAF V600E mutation occurs in about 40–45% of PTCs

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Luca Morandi Department of Biomedical and Neuromotor Sciences, Section of Anatomic Pathology ‘M. Malpighi’ at Bellaria Hospital, University of Bologna, Bologna, Italy

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Alberto Righi Department of Pathology, Rizzoli Institute, (IRCCS), Bologna, Italy

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Francesca Maletta Department of Medical Sciences, University of Turin, Turin, Italy

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Paola Rucci Section of Hygiene and Biostatistics, University of Bologna, Bologna, Italy

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Fabio Pagni Department of Pathology, University of Milano Bicocca, Monza, Italy

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Marco Gallo Oncological Endocrinology Unit, Department of Medical Sciences, AOU Città della Salute e della Scienza di Torino, University of Turin, Turin, Italy

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Sabrina Rossi Department of Pathology, Regional Hospital, Treviso, Italy

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Leonardo Caporali Istituto delle Scienze Neurologiche di Bologna (IRCCS), Bellaria Hospital, Bologna, Italy

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Anna Sapino Institute for Cancer Research and Treatment (IRCCS), Candiolo, Italy

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Ricardo V Lloyd University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin, USA

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Sofia Asioli Department of Biomedical and Neuromotor Sciences, Section of Anatomic Pathology ‘M. Malpighi’ at Bellaria Hospital, University of Bologna, Bologna, Italy

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because the HPTC cells seem to be scarcely responsive to 131I treatment ( Haugen et al . 2016 ). To date, in PTC, the common known mutations are represented by several RET/PTC rearrangements ( Romei & Elisei 2012 ), BRAF p.V600 mutation ( Mathur et

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Christina M Knippler Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University Wexner Medical Center and Arthur G. James Comprehensive Cancer Center, Columbus, Ohio, USA

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Motoyasu Saji Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University Wexner Medical Center and Arthur G. James Comprehensive Cancer Center, Columbus, Ohio, USA

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Neel Rajan College of Arts and Sciences, The Ohio State University, Columbus, Ohio, USA

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Kyle Porter Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio, USA

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Krista M D La Perle Department of Veterinary Biosciences, Comparative Pathology & Mouse Phenotyping Shared Resource, The Ohio State University, Columbus, Ohio, USA

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Matthew D Ringel Division of Endocrinology, Diabetes, and Metabolism, The Ohio State University Wexner Medical Center and Arthur G. James Comprehensive Cancer Center, Columbus, Ohio, USA

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AKT pathways occur frequently in thyroid cancers. The most common form of thyroid cancer, well-differentiated papillary thyroid cancer (PTC), is driven primarily by mutually exclusive mutations that activate MAPK signaling; ~60% have BRAF V600E

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Tae Hyuk Kim Division of Endocrinology and Metabolism, Department of Medicine, Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

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Young-Eun Kim Green Cross Genome, Yongin, Korea

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Soomin Ahn Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

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Ji-Youn Kim Center for Clinical Medicine, Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Korea

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Chang-Seok Ki Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

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Young Lyun Oh Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

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Kyunga Kim Biostatistics and Clinical Epidemiology Center, Research Institute for Future Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

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Jae Won Yun Samsung Genome Institute, Samsung Medical Center, Seoul, Korea
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea

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Woong-Yang Park Samsung Genome Institute, Samsung Medical Center, Seoul, Korea
Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon, Korea

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Jun-Ho Choe Division of Breast and Endocrine Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

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Jung-Han Kim Division of Breast and Endocrine Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

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Jee Soo Kim Division of Breast and Endocrine Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

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Sun Wook Kim Division of Endocrinology and Metabolism, Department of Medicine, Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

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Jae Hoon Chung Division of Endocrinology and Metabolism, Department of Medicine, Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

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sarcoma viral oncogene homolog B ( BRAF ) T1799A mutation has drawn much attention based on its high prevalence, occurring in about 45% of PTC and 25% of ATC cases and its association with PTC recurrence ( Kim et al. 2012 , Xing et al. 2015 ). However

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M Xing Division of Endocrinology and Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, 1830 E. Monument St/Suite 333 Baltimore, MD 21287, USA

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the most common and occurring mainly in PTC and some benign adenomas. The PAX8-PPAR γ occurs both in FTC and benign thyroid adenoma ( Cheung et al. 2003 , Sahin et al. 2005 ). The recently discovered activating mutation in BRAF (the gene for

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Avaniyapuram Kannan Murugan Division of Molecular Endocrinology, Department of Molecular Oncology, King Faisal, Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

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Abeer Al-Amr Department of Microbiology, College of Science, Female Campus, King Saud University, Riyadh, Saudi Arabia

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Mysoon M Al-Ansari Department of Microbiology, College of Science, Female Campus, King Saud University, Riyadh, Saudi Arabia
Department of Molecular Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

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Pulicat S Manogaran Department of Stem Cell Tissue Re-Engineering Program, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

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Hindi Al-Hindi Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

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Ali S Alzahrani Division of Molecular Endocrinology, Department of Molecular Oncology, King Faisal, Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
Department of Medicine, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

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/PTC rearrangements, mutations in BRAF , NRAS , etc., and the PI3K/AKT pathway is activated mostly in poorly differentiated (PDTC) and anaplastic thyroid cancer (ATC) as a result of mutations in ALK , RAS , PIK3CA , AKT , etc. ( Murugan & Xing 2011 , Xing 2013

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Yeon-Sook Choi Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

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Hyemi Kwon Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea

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Mi-Hyeon You Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

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Tae Yong Kim Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

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Won Bae Kim Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

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Young Kee Shong Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

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Min Ji Jeon Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

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Won Gu Kim Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

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. 2005 , Kurata et al. 2016 , Subbiah et al. 2018 , Kim et al. 2020 , Lee & Park 2021 ). The BRAF V600E mutation is one of the common genetic alterations in ATC, accounting for 20–50% of cases ( Xing 2013 , Jeon et al. 2016 , Subbiah et al

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Seo Ki Kim Division of Breast and Endocrine Surgery, Division of Breast and Endocrine Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135‐710, South Korea

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Jung-Woo Woo Division of Breast and Endocrine Surgery, Division of Breast and Endocrine Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135‐710, South Korea

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Jun Ho Lee Division of Breast and Endocrine Surgery, Division of Breast and Endocrine Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135‐710, South Korea

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Inhye Park Division of Breast and Endocrine Surgery, Division of Breast and Endocrine Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135‐710, South Korea

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Jun-Ho Choe Division of Breast and Endocrine Surgery, Division of Breast and Endocrine Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135‐710, South Korea

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Jung-Han Kim Division of Breast and Endocrine Surgery, Division of Breast and Endocrine Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135‐710, South Korea

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Jee Soo Kim Division of Breast and Endocrine Surgery, Division of Breast and Endocrine Surgery, Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 135‐710, South Korea

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Introduction With a rapidly increasing incidence worldwide, papillary thyroid carcinoma (PTC) represents the majority of thyroid cancer cases ( Ahn & Park 2009 , Siegel et al . 2014 ). The recently discovered BRAF V600E mutation (hereafter

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