Thyroid Cancer: Pathogenesis, Clinicopathology, Diagnosis, and Management

Abstract

Thyroid cancer is the most common endocrine malignancy, with incidence rising steadily worldwide. Although most cases are differentiated thyroid carcinomas with excellent prognosis, a small subset, such as anaplastic thyroid cancer, demonstrates aggressive behavior and poor survival outcomes. Recent decades have witnessed a transformation in thyroid cancer diagnostics and management, driven by improvements in high-resolution ultrasound, fine-needle aspiration biopsy, molecular profiling, and standardized risk stratification systems such as the Thyroid Imaging Reporting and Data System. Despite these advances, overdiagnosis and overtreatment remain key clinical challenges. Accurate risk stratification and management strategies are critical, especially for distinguishing indolent nodules from aggressive subtypes. This review provides a comprehensive overview of thyroid cancer pathogenesis, clinicopathological classification, diagnostic approaches, and evolving therapeutic strategies, ranging from active surveillance to targeted and immunotherapy-based treatments. By integrating molecular diagnostics with conventional parameters, the article underscores how precision medicine can reduce treatment burden, improve outcomes, and guide personalized care. This review offers valuable insight into the biological complexity of thyroid cancer and highlights the need for continued refinement of diagnostic criteria and therapeutic frameworks in clinical practice.

Keywords

thyroid cancer / differentiated thyroid cancer / medullary thyroid cancer / anaplastic thyroid cancer / thyroid-stimulating hormone / ultrasound

References

[1] F. Bray, M. Laversanne, H. Sung, et al., “Global Cancer Statistics 2022: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries,” CA: A Cancer Journal for Clinicians 74, no. 3 (2024): 229-263.

[2] C. D. Seib and J. A. Sosa, “Evolving Understanding of the Epidemiology of Thyroid Cancer,” Endocrinology and Metabolism Clinics of North America 48, no. 1 (2019): 23-35.

[3] D. V. P. Araque, A. Bleyer, and J. P. Brito, “Thyroid Cancer in Adolescents and Young Adults,” Future Oncology 13, no. 14 (2017): 1253-1261.

[4] L. Boucai, M. Zafereo, and M. E. Cabanillas, “Thyroid Cancer: A Review,” Jama 331, no. 5 (2024): 425-435.

[5] W. Chen, R. Zheng, and P. D. Baade, “Cancer Statistics in China, 2015,” CA: A Cancer Journal for Clinicians 66, no. 2 (2016): 115-132.

[6] M. Li, R. Zheng, and L. Dal Maso, “Mapping Overdiagnosis of Thyroid Cancer in China,” The Lancet Diabetes & Endocrinology 9, no. 6 (2021): 330-332.

[7] J. Lortet-Tieulent, S. Franceschi, and L. Dal Maso, “Thyroid Cancer “Epidemic” Also Occurs in Low- and Middle-income Countries,” International Journal of Cancer 144, no. 9 (2019): 2082-2087.

[8] M. Li, J. P. Brito, and S. Vaccarella, “Long-Term Declines of Thyroid Cancer Mortality: An International Age-Period-Cohort Analysis,” Thyroid: Official Journal of the American Thyroid Association 30, no. 6 (2020): 838-846.

[9] F. Borson-Chazot, I. Borget, and M. Mathonnet, “SFE-AFCE-SFMN 2022 Consensus on the Management of Thyroid Nodules: Epidemiology and Challenges in the Management of Thyroid Nodules,” Annales D Endocrinologie 83, no. 6 (2022): 378-379.

[10] C. Durante, L. Hegedus, A. Czarniecka, et al., “2023 European Thyroid Association Clinical Practice Guidelines for Thyroid Nodule Management,” European Thyroid Journal 12, no. 5 (2023): e230067.

[11] N. Uppal, R. Collins, and B. James, “Thyroid Nodules: Global, Economic, and Personal Burdens,” Front Endocrinol (Lausanne) 14 (2023): 1113977.

[12] G. Grani, M. Sponziello, and V. Pecce, “Contemporary Thyroid Nodule Evaluation and Management,” Journal of Clinical Endocrinology and Metabolism 105, no. 9 (2020): 2869-2883.

[13] G. Grani, M. Sponziello, and S. Filetti, “Thyroid Nodules: Diagnosis and Management,” Nature Reviews Endocrinology 20, no. 12 (2024): 715-728.

[14] G. Grani, M. C. Zatelli, and M. Alfo, “Real-World Performance of the American Thyroid Association Risk Estimates in Predicting 1-Year Differentiated Thyroid Cancer Outcomes: A Prospective Multicenter Study of 2000 Patients,” Thyroid: Official Journal of the American Thyroid Association 31, no. 2 (2021): 264-271.

[15] N. Uppal, C. Cunningham Nee Lubitz, and B. James, “The Cost and Financial Burden of Thyroid Cancer on Patients in the US: A Review and Directions for Future Research,” JAMA Otolaryngol Head Neck Surg 148, no. 6 (2022): 568-575.

[16] R. Wong, S. G. Farrell, and M. Grossmann, “Thyroid Nodules: Diagnosis and Management,” Medical Journal of Australia 209, no. 2 (2018): 92-98.

[17] B. H. Kim, “Comparison of Thyroid Imaging Reporting and Data Systems in Malignancy Risk Stratification of Indeterminate Thyroid Nodules,” Endocrinol Metab (Seoul) 36, no. 5 (2021): 974-976.

[18] Y. P. Sych, V. V. Fadeev, and E. P. Fisenko, “Reproducibility and Interobserver Agreement of Different Thyroid Imaging and Reporting Data Systems (TIRADS),” European Thyroid Journal 10, no. 2 (2021): 161-167.

[19] J. Li, C. Li, and X. Zhou, “US Risk Stratification System for Follicular Thyroid Neoplasms,” Radiology 309, no. 2 (2023): e230949.

[20] F. N. Tessler, W. D. Middleton, and E. G. Grant, “Thyroid Imaging Reporting and Data System (TI-RADS): A User's Guide,” Radiology 287, no. 1 (2018): 29-36.

[21] T. Xu, Y. Wu, and R. X. Wu, “Validation and Comparison of Three Newly-released Thyroid Imaging Reporting and Data Systems for Cancer Risk Determination,” Endocrine 64, no. 2 (2019): 299-307.

[22] R. P. Tufano, P. Pace-Asciak, and J. O. Russell, “Update of Radiofrequency Ablation for Treating Benign and Malignant Thyroid Nodules. The Future Is Now,” Front Endocrinol (Lausanne) 12 (2021): 698689.

[23] I. Sugitani, “Active Surveillance of Low-risk Papillary Thyroid Microcarcinoma,” Best Practice & Research Clinical Endocrinology & Metabolism 37, no. 1 (2023): 101630.

[24] T. Ledesma-Leon, P. Solis-Pazmino, and E. P. Lincango, “Ablation Techniques or Active Surveillance Compared to Surgical Resection in Patients with Low-risk Papillary Thyroid Cancer: A Systematic Review and Meta-analysis,” Endocrine 83, no. 2 (2024): 330-341.

[25] D. W. Chen, B. H. H. Lang, and D. S. A. McLeod, “Thyroid Cancer,” Lancet 401, no. 10387 (2023): 1531-1544.

[26] D. Laha, N. Nilubol, and M. Boufraqech, “New Therapies for Advanced Thyroid Cancer,” Front Endocrinol (Lausanne) 11 (2020): 82.

[27] K. Czene, P. Lichtenstein, and K. Hemminki, “Environmental and Heritable Causes of Cancer among 9.6 Million Individuals in the Swedish Family-Cancer Database,” International Journal of Cancer 99, no. 2 (2002): 260-266.

[28] S. A. Wells, F. Pacini, and B. G. Robinson, “Multiple Endocrine Neoplasia Type 2 and Familial Medullary Thyroid Carcinoma: An Update,” Journal of Clinical Endocrinology and Metabolism 98, no. 8 (2013): 3149-3164.

[29] T. Bogovic Crncic, M. Ilic Tomas, and N. Girotto, “Risk Factors for Thyroid Cancer: What Do We Know So Far?,” Acta Clinica Croatica 59, no. Suppl 1 (2020): 66-72.

[30] J. A. Fagin, G. P. Krishnamoorthy, and I. Landa, “Pathogenesis of Cancers Derived from Thyroid Follicular Cells,” Nature Reviews Cancer 23, no. 9 (2023): 631-650.

[31] J. Gudmundsson, G. Thorleifsson, and J. K. Sigurdsson, “A Genome-wide Association Study Yields Five Novel Thyroid Cancer Risk Loci,” Nature Communications 8 (2017): 14517.

[32] S. Liyanarachchi, J. Gudmundsson, and E. Ferkingstad, “Assessing Thyroid Cancer Risk Using Polygenic Risk Scores,” PNAS 117, no. 11 (2020): 5997-6002.

[33] L. Huang, X. Feng, and W. Yang, “Appraising the Effect of Potential Risk Factors on Thyroid Cancer: A Mendelian Randomization Study,” Journal of Clinical Endocrinology and Metabolism 107, no. 7 (2022): e2783-e2791.

[34] V. Saenko and N. Mitsutake, “Radiation-Related Thyroid Cancer,” Endocrine Reviews 45, no. 1 (2024): 1-29.

[35] B. J. Duffy and P. J. Fitzgerald, “Thyroid Cancer in Childhood and Adolescence; a Report on 28 Cases,” Cancer 3, no. 6 (1950): 1018-1032.

[36] T. I. Bogdanova, L. Y. Zurnadzhy, and E. Greenebaum, “A Cohort Study of Thyroid Cancer and Other Thyroid Diseases after the Chornobyl Accident: Pathology Analysis of Thyroid Cancer Cases in Ukraine Detected during the First Screening (1998-2000),” Cancer 107, no. 11 (2006): 2559-2566.

[37] P. Bhatti, L. H. Veiga, and C. M. Ronckers, “Risk of Second Primary Thyroid Cancer After Radiotherapy for a Childhood Cancer in a Large Cohort Study: An Update from the Childhood Cancer Survivor Study,” Radiation Research 174, no. 6 (2010): 741-752.

[38] F. de Vathaire, N. Haddy, and R. S. Allodji, “Thyroid Radiation Dose and Other Risk Factors of Thyroid Carcinoma Following Childhood Cancer,” Journal of Clinical Endocrinology and Metabolism 100, no. 11 (2015): 4282-4290.

[39] X. Feng, F. Wang, and W. Yang, “Association between Genetic Risk, Adherence to Healthy Lifestyle Behavior, and Thyroid Cancer Risk,” JAMA Network Open 5, no. 12 (2022): e2246311.

[40] D. Schmid, C. Ricci, and G. Behrens, “Adiposity and Risk of Thyroid Cancer: A Systematic Review and Meta-analysis,” Obesity Reviews 16, no. 12 (2015): 1042-1054.

[41] Y. Shen, X. Wang, and L. Wang, “Modifiable Risk Factors for Thyroid Cancer: Lifestyle and Residence Environment,” Endokrynologia Polska 75, no. 2 (2024): 119-129.

[42] C. M. Kitahara, D. KRF, and J. O. L. Jorgensen, “Benign Thyroid Diseases and Risk of Thyroid Cancer: A Nationwide Cohort Study,” Journal of Clinical Endocrinology and Metabolism 103, no. 6 (2018): 2216-2224.

[43] H. K. Kim, J. H. Yoon, and S. J. Kim, “Higher TSH Level Is a Risk Factor for Differentiated Thyroid Cancer,” Clinical Endocrinology 78, no. 3 (2013): 472-477.

[44] S. S. Moon, Y. S. Lee, and I. K. Lee, “Serum Thyrotropin as a Risk Factor for Thyroid Malignancy in Euthyroid Subjects with Thyroid Micronodule,” Head & Neck 34, no. 7 (2012): 949-952.

[45] H. Huang, J. Rusiecki, and N. Zhao, “Thyroid-Stimulating Hormone, Thyroid Hormones, and Risk of Papillary Thyroid Cancer: A Nested Case-Control Study,” Cancer Epidemiology and Prevention Biomarkers 26, no. 8 (2017): 1209-1218.

[46] S. Rinaldi, M. Plummer, and C. Biessy, “Thyroid-stimulating Hormone, Thyroglobulin, and Thyroid Hormones and Risk of Differentiated Thyroid Carcinoma: The EPIC Study,” JNCI: Journal of the National Cancer Institute 106, no. 6 (2014): dju097.

[47] R. D. Paparodis, D. Bantouna, and E. Karvounis, “Higher TSH Is Not Associated with Thyroid Cancer Risk in the Presence of Thyroid Autoimmunity,” Journal of Clinical Endocrinology and Metabolism 105, no. 7 (2020).

[48] H. Lim, S. S. Devesa, and J. A. Sosa, “Trends in Thyroid Cancer Incidence and Mortality in the United States, 1974-2013,” Jama 317, no. 13 (2017): 1338-1348.

[49] S. T. Rahman, D. S. A. McLeod, and N. Pandeya, “Understanding Pathways to the Diagnosis of Thyroid Cancer: Are There Ways We Can Reduce Over-Diagnosis?,” Thyroid: Official Journal of the American Thyroid Association 29, no. 3 (2019): 341-348.

[50] C. Kahn, L. Simonella, and M. Sywak, “Pathways to the Diagnosis of Thyroid Cancer in New South Wales: A Population-based Cross-sectional Study,” Cancer Causes & Control 23, no. 1 (2012): 35-44.

[51] R. M. Tuttle, S. Ahuja, and A. M. Avram, “Controversies, Consensus, and Collaboration in the Use of (131)I 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: Official Journal of the American Thyroid Association 29, no. 4 (2019): 461-470.

[52] S. B. Fisher and N. D. Perrier, “The Incidental Thyroid Nodule,” CA: A Cancer Journal for Clinicians 68, no. 2 (2018): 97-105.

[53] J. K. Hoang, J. E. Langer, and W. D. Middleton, “Managing Incidental Thyroid Nodules Detected on Imaging: White Paper of the ACR Incidental Thyroid Findings Committee,” Journal of the American College of Radiology 12, no. 2 (2015): 143-150.

[54] L. F. Starker, P. A. Prieto, and J. S. Liles, “Endocrine Incidentalomas,” Current Problems in Surgery 53, no. 5 (2016): 219-246.

[55] P. Shie, R. Cardarelli, and K. Sprawls, “Systematic Review: Prevalence of Malignant Incidental Thyroid Nodules Identified on Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography,” Nuclear Medicine Communications 30, no. 9 (2009): 742-748.

[56] M. Melany and S. Chen, “Thyroid Cancer: Ultrasound Imaging and Fine-Needle Aspiration Biopsy,” Endocrinology and Metabolism Clinics of North America 46, no. 3 (2017): 691-711.

[57] T. Solymosi, L. Hegedus, and S. J. Bonnema, “Considerable Interobserver Variation Calls for Unambiguous Definitions of Thyroid Nodule Ultrasound Characteristics,” European Thyroid Journal 12, no. 2 (2023): e220134.

[58] F. N. Tessler, W. D. Middleton, and E. G. Grant, “ACR Thyroid Imaging, Reporting and Data System (TI-RADS): White Paper of the ACR TI-RADS Committee,” Journal of the American College of Radiology 14, no. 5 (2017): 587-595.

[59] J. Y. Kwak, K. H. Han, and J. H. Yoon, “Thyroid Imaging Reporting and Data System for US Features of Nodules: A Step in Establishing Better Stratification of Cancer Risk,” Radiology 260, no. 3 (2011): 892-899.

[60] J. Zhou, L. Yin, X. Wei, et al., “2020 Chinese Guidelines for Ultrasound Malignancy Risk Stratification of Thyroid Nodules: The C-TIRADS,” Endocrine 70, no. 2 (2020): 256-279.

[61] G. Russ, S. J. Bonnema, and M. F. Erdogan, “European Thyroid Association Guidelines for Ultrasound Malignancy Risk Stratification of Thyroid Nodules in Adults: The EU-TIRADS,” European Thyroid Journal 6, no. 5 (2017): 225-237.

[62] B. R. Haugen, E. K. Alexander, K. C. Bible, et al., “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: Official Journal of the American Thyroid Association 26, no. 1 (2016): 1-133.

[63] H. Gharib, E. Papini, and J. R. Garber, “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,” Endocrine Practice 22, no. 5 (2016): 622-639.

[64] J. H. Shin, J. H. Baek, and J. Chung, “Ultrasonography Diagnosis and Imaging-Based Management of Thyroid Nodules: Revised Korean Society of Thyroid Radiology Consensus Statement and Recommendations,” Korean Journal of Radiology 17, no. 3 (2016): 370-395.

[65] D. H. Kim, S. W. Kim, and M. A. Basurrah, “Diagnostic Performance of Six Ultrasound Risk Stratification Systems for Thyroid Nodules: A Systematic Review and Network Meta-Analysis,” Ajr American Journal of Roentgenology 220, no. 6 (2023): 791-803.

[66] Q. Li, L. Yang, and L. Yang, “Utility of Six Ultrasound-Based Risk Stratification Systems in the Diagnosis of AUS/FLUS Thyroid Nodules,” Academic Radiology 31, no. 1 (2024): 131-141.

[67] G. Grani, M. Gentili, and F. Siciliano, “A Data-Driven Approach to Refine Predictions of Differentiated Thyroid Cancer Outcomes: A Prospective Multicenter Study,” Journal of Clinical Endocrinology and Metabolism 108, no. 8 (2023): 1921-1928.

[68] C. Durante, L. Hegedus, and D. G. Na, “International Expert Consensus on US Lexicon for Thyroid Nodules,” Radiology 309, no. 1 (2023): e231481.

[69] G. Grani, V. Del Gatto, and V. Cantisani, “A Reappraisal of Suspicious Sonographic Features of Thyroid Nodules: Shape Is Not an Independent Predictor of Malignancy,” Journal of Clinical Endocrinology and Metabolism 108, no. 9 (2023): e816-e822.

[70] A. M. Avram, “Radioiodine Scintigraphy with SPECT/CT: An Important Diagnostic Tool for Thyroid Cancer Staging and Risk Stratification,” Journal of Nuclear Medicine 53, no. 5 (2012): 754-764.

[71] X. J. Wang, X. Li, and Y. Ren, “Radionuclide Imaging and Treatment of Thyroid Cancer,” Front Biosci (Landmark Ed) 21, no. 6 (2016): 1187-1193.

[72] I. Iakovou, E. Giannoula, and C. Sachpekidis, “Imaging and Imaging-Based Management of Pediatric Thyroid Nodules,” Journal of Clinical Medicine 9, no. 2 (2020): 384.

[73] L. Giovanella, A. M. Avram, and I. Iakovou, “EANM Practice Guideline/SNMMI Procedure Standard for RAIU and Thyroid Scintigraphy,” European Journal of Nuclear Medicine and Molecular Imaging 46, no. 12 (2019): 2514-2525.

[74] T. J. Musholt, T. Clerici, and H. Dralle, “German Association of Endocrine Surgeons Practice Guidelines for the Surgical Treatment of Benign Thyroid Disease,” Langenbecks Archives of Surgery 396, no. 5 (2011): 639-649.

[75] P. W. Rosario, M. C. S. Cortes, and G. Franco Mourao, “Follow-up of Patients with Thyroid Cancer and Antithyroglobulin Antibodies: A Review for Clinicians,” Endocrine-Related Cancer 28, no. 4 (2021): R111-R119.

[76] S. Filetti, C. Durante, and D. Hartl, “Thyroid Cancer: ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-updagger,” Annals of Oncology 30, no. 12 (2019): 1856-1883.

[77] L. F. Zavala, M. I. Barra, and R. Olmos, “In Properly Selected Patients with Differentiated Thyroid Cancer, Antithyroglobulin Antibodies Decline After Thyroidectomy and Their Sole Presence Should Not be an Indication for Radioiodine Ablation,” Arch Endocrinol Metab 63, no. 3 (2019): 293-299.

[78] H. O. Zahra, G. A. Omran, and A. G. Gewely, “Prognostic Value of Serum Thyroglobulin and Anti-Thyroglobulin Antibody in Thyroid Carcinoma Patients Following Thyroidectomy,” Diagnostics (Basel) 11, no. 11 (2021): 2080.

[79] Z. Chen, M. L. Guo, and Y. Y. Li, “Immune Profiling Identifies CD8(+) T-cell Subset Signatures as Prognostic Markers for Recurrence in Papillary Thyroid Cancer,” Frontiers in immunology 13 (2022): 894919.

[80] M. L. Gild, R. J. Clifton-Bligh, and L. J. Wirth, “Medullary Thyroid Cancer: Updates and Challenges,” Endocrine Reviews 44, no. 5 (2023): 934-946.

[81] P. Trimboli, C. Mian, and A. Piccardo, “Diagnostic Tests for Medullary Thyroid Carcinoma: An Umbrella Review,” Endocrine 81, no. 2 (2023): 183-193.

[82] H. H. Verbeek, J. W. B. de Groot, and W. J. Sluiter, “Calcitonin Testing for Detection of Medullary Thyroid Cancer in People with Thyroid Nodules,” Cochrane Database of Systematic Reviews (Online) 3, no. 3 (2020): CD010159.

[83] A. Machens, J. Ukkat, and S. Hauptmann, “Abnormal Carcinoembryonic Antigen Levels and Medullary Thyroid Cancer Progression: A Multivariate Analysis,” Archives of Surgery 142, no. 3 (2007): 289-293. discussion 294.

[84] A. Machens and H. Dralle, “Biomarker-based Risk Stratification for Previously Untreated Medullary Thyroid Cancer,” Journal of Clinical Endocrinology and Metabolism 95, no. 6 (2010): 2655-2663.

[85] S. Milman, K. D. Whitney, and N. Fleischer, “Metastatic Medullary Thyroid Cancer Presenting with Elevated Levels of CA 19-9 and CA 125,” Thyroid: Official Journal of the American Thyroid Association 21, no. 8 (2011): 913-916.

[86] P. Trimboli, R. Lauretta, and A. Barnabei, “Procalcitonin as a Postoperative Marker in the Follow-up of Patients Affected by Medullary Thyroid Carcinoma,” International Journal of Biological Markers 33, no. 2 (2018): 156-160.

[87] P. Trimboli, E. Seregni, and G. Treglia, “Procalcitonin for Detecting Medullary Thyroid Carcinoma: A Systematic Review,” Endocrine-Related Cancer 22, no. 3 (2015): R157-164.

[88] A. A. Wijewardene, M. Chehade, and M. L. Gild, “Translational Utility of Liquid Biopsies in Thyroid Cancer Management,” Cancers (Basel) 13, no. 14 (2021): 3443.

[89] S. Ghafouri-Fard, Z. Shirvani-Farsani, and M. Taheri, “The Role of microRNAs in the Pathogenesis of Thyroid Cancer,” Non-coding RNA Research 5, no. 3 (2020): 88-98.

[90] M. F. Mosele, C. B. Westphalen, and A. Stenzinger, “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,” Annals of Oncology 35, no. 7 (2024): 588-606.

[91] S. Z. Ali, Z. W. Baloch, and B. Cochand-Priollet, “The 2023 Bethesda System for Reporting Thyroid Cytopathology,” Journal of the American Society of Cytopathology 12, no. 5 (2023): 319-325.

[92] I. Pradeep, A. L. Joshi, and A. Rath, “Overview of Updates in New the Bethesda System for Reporting of Thyroid Cytopathology Using the Latest World Health Organization Thyroid Tumor Classification Terminology,” Endocrine Practice 29, no. 12 (2023): 1020-1022.

[93] F. Nardi, F. Basolo, and A. Crescenzi, “Italian Consensus for the Classification and Reporting of Thyroid Cytology,” Journal of Endocrinological Investigation 37, no. 6 (2014): 593-599.

[94] M. Hirokawa, A. Suzuki, and M. Higuchi, “The Japanese Reporting System for Thyroid Aspiration Cytology 2019 (JRSTAC2019),” Gland Surg 9, no. 5 (2020): 1653-1662.

[95] M. A. Schumm, M. L. Shu, and E. G. Hughes, “Prognostic Value of Preoperative Molecular Testing and Implications for Initial Surgical Management in Thyroid Nodules Harboring Suspected (Bethesda V) or Known (Bethesda VI) Papillary Thyroid Cancer,” JAMA Otolaryngol Head Neck Surg 149, no. 8 (2023): 735-742.

[96] Z. W. Baloch, S. L. Asa, and J. A. Barletta, “Overview of the 2022 WHO Classification of Thyroid Neoplasms,” Endocrine Pathology 33, no. 1 (2022): 27-63.

[97] WHO Classifcation of Tumours of Endocrine Organs, France: WHO/IARC Press (Vol 10. 4th ed. Lyon,).

[98] O. Mete and S. L. Asa, “Pitfalls in the Diagnosis of Follicular Epithelial Proliferations of the Thyroid,” Advances in Anatomic Pathology 19, no. 6 (2012): 363-373.

[99] H. I. Gozu, R. Bircan, and K. Krohn, “Similar Prevalence of Somatic TSH Receptor and Gsalpha Mutations in Toxic Thyroid Nodules in Geographical Regions with Different Iodine Supply in Turkey,” European Journal of Endocrinology 155, no. 4 (2006): 535-545.

[100] B. Trulzsch, K. Krohn, and P. Wonerow, “Detection of Thyroid-stimulating Hormone Receptor and Gsalpha Mutations: In 75 Toxic Thyroid Nodules by Denaturing Gradient Gel Electrophoresis,” Journal of Molecular Medicine (Berlin,) 78, no. 12 (2001): 684-691.

[101] J. Parma, L. Duprez, and J. Van Sande, “Somatic Mutations in the Thyrotropin Receptor Gene Cause Hyperfunctioning Thyroid Adenomas,” Nature 365, no. 6447 (1993): 649-651.

[102] J. M. Cameselle-Teijeiro, C. Eloy, and M. Sobrinho-Simoes, “Pitfalls in Challenging Thyroid Tumors: Emphasis on Differential Diagnosis and Ancillary Biomarkers,” Endocrine Pathology 31, no. 3 (2020): 197-217.

[103] D. Calebiro, E. S. Grassi, and M. Eszlinger, “Recurrent EZH1 Mutations Are a Second Hit in Autonomous Thyroid Adenomas,” Journal of Clinical Investigation 126, no. 9 (2016): 3383-3388.

[104] A. Porcellini, G. Fenzi, and E. V. Avvedimento, “Mutations of Thyrotropin Receptor Gene,” Journal of Molecular Medicine (Berlin) 75, no. 8 (1997): 567-575.

[105] E. Bonora, A. M. Porcelli, and G. Gasparre, “Defective Oxidative Phosphorylation in Thyroid Oncocytic Carcinoma Is Associated with Pathogenic Mitochondrial DNA Mutations Affecting Complexes I and III,” Cancer Research 66, no. 12 (2006): 6087-6096.

[106] R. K. Gopal, K. Kubler, and S. E. Calvo, “Widespread Chromosomal Losses and Mitochondrial DNA Alterations as Genetic Drivers in Hurthle Cell Carcinoma,” Cancer Cell 34, no. 2 (2018): 242-255. e245.

[107] I. Ganly, V. Makarov, and S. Deraje, “Integrated Genomic Analysis of Hurthle Cell Cancer Reveals Oncogenic Drivers, Recurrent Mitochondrial Mutations, and Unique Chromosomal Landscapes,” Cancer Cell 34, no. 2 (2018): 256-270. e255.

[108] V. Maximo, T. Botelho, and J. Capela, “Somatic and Germline Mutation in GRIM-19, a Dual Function Gene Involved in Mitochondrial Metabolism and Cell Death, Is Linked to Mitochondrion-rich (Hurthle cell) Tumours of the Thyroid,” British Journal of Cancer 92, no. 10 (2005): 1892-1898.

[109] M. Correia, A. R. Lima, and R. Batista, “Inherited Thyroid Tumors with Oncocytic Change,” Front Endocrinol (Lausanne) 12 (2021): 691979.

[110] W. R. Doerfler, A. V. Nikitski, and E. M. Morariu, “Molecular Alterations in Hurthle Cell Nodules and Preoperative Cancer Risk,” Endocrine-Related Cancer 28, no. 5 (2021): 301-309.

[111] S. Hodak, R. M. Tuttle, and G. Maytal, “Changing the Cancer Diagnosis: The Case of Follicular Variant of Papillary Thyroid Cancer-Primum Non Nocere and NIFTP,” Thyroid: Official Journal of the American Thyroid Association 26, no. 7 (2016): 869-871.

[112] L. D. Thompson, “Ninety-four Cases of Encapsulated Follicular Variant of Papillary Thyroid Carcinoma: A Name Change to Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features Would Help Prevent Overtreatment,” Modern Pathology 29, no. 7 (2016): 698-707.

[113] J. C. Hernandez-Prera and B. M. Wenig, “RAS-Mutant Follicular Thyroid Tumors: A Continuous Challenge for Pathologists,” Endocrine Pathology 35, no. 3 (2024): 167-184.

[114] I. Tondi Resta, M. A. Gubbiotti, and K. T. Montone, “An Investigation into Noninvasive Follicular Thyroid Neoplasms with Papillary-Like Nuclear Features: Does the Initial Proposal on Noninvasive Follicular Thyroid Neoplasms with Papillary-Like Nuclear Features Behavior Hold True?,” Human Pathology 141 (2023): 139-148.

[115] Y. E. Nikiforov, R. R. Seethala, and G. Tallini, “Nomenclature Revision for Encapsulated Follicular Variant of Papillary Thyroid Carcinoma: A Paradigm Shift to Reduce Overtreatment of Indolent Tumors,” JAMA oncology 2, no. 8 (2016): 1023-1029.

[116] B. Xu, N. Farhat, and J. A. Barletta, “Should Subcentimeter Non-invasive Encapsulated, Follicular Variant of Papillary Thyroid Carcinoma be Included in the Noninvasive Follicular Thyroid Neoplasm With Papillary-Like Nuclear Features Category?,” Endocrine 59, no. 1 (2018): 143-150.

[117] B. Xu and R. A. Ghossein, “Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features (NIFTP): An Update,” Head and Neck Pathology 14, no. 2 (2020): 303-310.

[118] H. Duan, X. Liu, and X. Ren, “Mutation Profiles of Follicular Thyroid Tumors by Targeted Sequencing,” Diagnostic Pathology 14, no. 1 (2019): 39.

[119] L. Lebrun and I. Salmon, “Pathology and New Insights in Thyroid Neoplasms in the 2022 WHO Classification,” Current Opinion in Oncology 36, no. 1 (2024): 13-21.

[120] V. Cracolici, L. L. Ritterhouse, and J. P. Segal, “Follicular Thyroid Neoplasms: Comparison of Clinicopathologic and Molecular Features of Atypical Adenomas and Follicular Thyroid Carcinomas,” American Journal of Surgical Pathology 44, no. 7 (2020): 881-892.

[121] C. C. Juhlin, R. Branstrom, and I. Shabo, “Clear Cell Variant of a Follicular Thyroid Tumor with Uncertain Malignant Potential: A Case Report,” International Journal of Surgical Pathology 27, no. 3 (2019): 290-293.

[122] D. Cabibi, A. Mondello, and A. M. Florena, “A Case of Follicular Tumor of Uncertain Malignant Potential (FT-UMP) with Glomeruloid Features Showing Capsular Mucinous Degeneration,” Case Reports in Pathology 2021 (2021): 1686025.

[123] G. Salvatore, G. Chiappetta, and Y. E. Nikiforov, “Molecular Profile of Hyalinizing Trabecular Tumours of the Thyroid: High Prevalence of RET/PTC Rearrangements and Absence of B-raf and N-ras Point Mutations,” European Journal of Cancer 41, no. 5 (2005): 816-821.

[124] C. Marchio, A. Da Cruz Paula, and R. Gularte-Merida, “PAX8-GLIS3 gene Fusion Is a Pathognomonic Genetic Alteration of Hyalinizing Trabecular Tumors of the Thyroid,” Modern Pathology 32, no. 12 (2019): 1734-1743.

[125] M. N. Nikiforova, A. V. Nikitski, and F. Panebianco, “GLIS Rearrangement Is a Genomic Hallmark of Hyalinizing Trabecular Tumor of the Thyroid Gland,” Thyroid: Official Journal of the American Thyroid Association 29, no. 2 (2019): 161-173.

[126] T. Chiba, “Molecular Pathology of Thyroid Tumors: Essential Points to Comprehend Regarding the Latest WHO Classification,” Biomedicines 12, no. 4 (2024): 712.

[127] C. J. O'Neill, L. Vaughan, and D. L. Learoyd, “Management of Follicular Thyroid Carcinoma Should be Individualised Based on Degree of Capsular and Vascular Invasion,” European Journal of Surgical Oncology 37, no. 2 (2011): 181-185.

[128] N. Cancer Genome Atlas Research, “Integrated Genomic Characterization of Papillary Thyroid Carcinoma,” Cell 159, no. 3 (2014): 676-690.

[129] C. Giani, L. Torregrossa, and T. Ramone, “Whole Tumor Capsule Is Prognostic of Very Good Outcome in the Classical Variant of Papillary Thyroid Cancer,” Journal of Clinical Endocrinology and Metabolism 106, no. 10 (2021): e4072-e4083.

[130] WHO Classification of Tumours Editorial Board, WHO Classification of Tumours Editorial Board: Endocrine and Neuroendocrine Tumours, vol. 8. 5th edn. (International Agency for Research on Cancer, Lyon, France, 2022), 2023.

[131] P. Raman and R. J. Koenig, “Pax-8-PPAR-gamma Fusion Protein in Thyroid Carcinoma,” Nature reviews Endocrinology 10, no. 10 (2014): 616-623.

[132] Y. Wang, P. Hou, and H. Yu, “High Prevalence and Mutual Exclusivity of Genetic Alterations in the Phosphatidylinositol-3-kinase/Akt Pathway in Thyroid Tumors,” Journal of Clinical Endocrinology and Metabolism 92, no. 6 (2007): 2387-2390.

[133] P. Hou, D. Liu, and Y. Shan, “Genetic Alterations and Their Relationship in the Phosphatidylinositol 3-kinase/Akt Pathway in Thyroid Cancer,” Clinical Cancer Research 13, no. 4 (2007): 1161-1170.

[134] S. K. Yoo, S. Lee, and S. J. Kim, “Comprehensive Analysis of the Transcriptional and Mutational Landscape of Follicular and Papillary Thyroid Cancers,” PLos Genet 12, no. 8 (2016): e1006239.

[135] J. S. Bae, S. H. Jung, and M. Hirokawa, “High Prevalence of DICER1 Mutations and Low Frequency of Gene Fusions in Pediatric Follicular-Patterned Tumors of the Thyroid,” Endocrine Pathology 32, no. 3 (2021): 336-346.

[136] J. O. Paulsson, N. Rafati, and S. DiLorenzo, “Whole-genome Sequencing of Follicular Thyroid Carcinomas Reveal Recurrent Mutations in MicroRNA Processing Subunit DGCR8,” Journal of Clinical Endocrinology and Metabolism 106, no. 11 (2021): 3265-3282.

[137] J. O. Paulsson, J. Zedenius, and C. C. Juhlin, “TERT Promoter Mutated Follicular Thyroid Carcinomas Exhibit a Distinct microRNA Expressional Profile with Potential Implications for Tumor Progression,” Endocrine Pathology 32, no. 4 (2021): 513-516.

[138] M. H. Wu, Y. Y. Lee, and Y. L. Lu, “Risk Factors and Prognosis for Metastatic Follicular Thyroid Cancer,” Front Endocrinol (Lausanne) 13 (2022): 791826.

[139] H. Yamazaki, K. Sugino, and R. Katoh, “Management of Follicular Thyroid Carcinoma,” European Thyroid Journal 13, no. 5 (2024): e240146.

[140] C. Y. Lo, W. F. Chan, and K. Y. Lam, “Follicular Thyroid Carcinoma: The Role of Histology and Staging Systems in Predicting Survival,” Annals of Surgery 242, no. 5 (2005): 708-715.

[141] F. Basolo, E. Macerola, and A. M. Poma, “The 5(th) Edition of WHO Classification of Tumors of Endocrine Organs: Changes in the Diagnosis of Follicular-derived Thyroid Carcinoma,” Endocrine 80, no. 3 (2023): 470-476.

[142] H. G. Vuong, A. M. A. Altibi, and U. N. P. Duong, “Prognostic Implication of BRAF and TERT Promoter Mutation Combination in Papillary Thyroid Carcinoma-A Meta-analysis,” Clinical Endocrinology 87, no. 5 (2017): 411-417.

[143] B. Chen, Y. Shi, and Y. Xu, “The Predictive Value of Coexisting BRAFV600E and TERT Promoter Mutations on Poor Outcomes and High Tumour Aggressiveness in Papillary Thyroid Carcinoma: A Systematic Review and Meta-analysis,” Clinical Endocrinology 94, no. 5 (2021): 731-742.

[144] J. Huang, J. Wang, and J. Xv, “Genetic Alterations and Allele Frequency of BRAF V600E and TERT Mutation in Papillary Thyroid Carcinoma with Intermediate-to-high Recurrence Risk: A Retrospective Study,” Clinical and Experimental Medicine 24, no. 1 (2024): 76.

[145] S. Moon, Y. S. Song, and Y. A. Kim, “Effects of Coexistent BRAF(V600E) and TERT Promoter Mutations on Poor Clinical Outcomes in Papillary Thyroid Cancer: A Meta-Analysis,” Thyroid: Official Journal of the American Thyroid Association 27, no. 5 (2017): 651-660.

[146] R. J. Leeman-Neill, A. V. Brenner, and M. P. Little, “RET/PTC and PAX8/PPARgamma Chromosomal Rearrangements in Post-Chernobyl Thyroid Cancer and Their Association with Iodine-131 Radiation Dose and Other Characteristics,” Cancer 119, no. 10 (2013): 1792-1799.

[147] Q. Gou, X. Gan, and L. Li, “Precious Gene: The Application of RET-Altered Inhibitors,” Molecules (Basel, Switzerland) 27, no. 24 (2022): 8839.

[148] M. Guo, Y. Sun, and Y. Wei, “Advances in Targeted Therapy and Biomarker Research in Thyroid Cancer,” Front Endocrinol (Lausanne) 15 (2024): 1372553.

[149] C. M. Caudill, Z. Zhu, and R. Ciampi, “Dose-dependent Generation of RET/PTC in human Thyroid Cells after in Vitro Exposure to Gamma-radiation: A Model of Carcinogenic Chromosomal Rearrangement Induced by Ionizing Radiation,” Journal of Clinical Endocrinology and Metabolism 90, no. 4 (2005): 2364-2369.

[150] B. Pekova, V. Sykorova, and K. Mastnikova, “NTRK Fusion Genes in Thyroid Carcinomas: Clinicopathological Characteristics and Their Impacts on Prognosis,” Cancers (Basel) 13, no. 8 (2021): 1932.

[151] E. M. Morariu, K. L. McCoy, and S. I. Chiosea, “Clinicopathologic Characteristics of Thyroid Nodules Positive for the THADA-IGF2BP3 Fusion on Preoperative Molecular Analysis,” Thyroid: Official Journal of the American Thyroid Association 31, no. 8 (2021): 1212-1218.

[152] Y. C. Lee, J. Y. Chen, and C. J. Huang, “Detection of NTRK1/3 Rearrangements in Papillary Thyroid Carcinoma Using Immunohistochemistry, Fluorescent in Situ Hybridization, and Next-Generation Sequencing,” Endocrine Pathology 31, no. 4 (2020): 348-358.

[153] B. Pekova, V. Sykorova, and S. Dvorakova, “RET, NTRK, ALK, BRAF, and MET Fusions in a Large Cohort of Pediatric Papillary Thyroid Carcinomas,” Thyroid: Official Journal of the American Thyroid Association 30, no. 12 (2020): 1771-1780.

[154] F. Panebianco, A. V. Nikitski, and M. N. Nikiforova, “Characterization of Thyroid Cancer Driven by Known and Novel ALK Fusions,” Endocrine-Related Cancer 26, no. 11 (2019): 803-814.

[155] C. K. Jung, S. H. Jung, and S. Jeon, “Risk Stratification Using a Novel Genetic Classifier Including PLEKHS1 Promoter Mutations for Differentiated Thyroid Cancer with Distant Metastasis,” Thyroid: Official Journal of the American Thyroid Association 30, no. 11 (2020): 1589-1600.

[156] N. R. Caron and O. H. Clark, “Papillary Thyroid Cancer,” Current Treatment Options in Oncology 7, no. 4 (2006): 309-319.

[157] B. Schmidbauer, K. Menhart, and D. Hellwig, “Differentiated Thyroid Cancer-Treatment: State of the Art,” International Journal of Molecular Sciences 18, no. 6 (2017): 1292.

[158] J. J. Yeh, K. L. Lunetta, and N. J. van Orsouw, “Somatic Mitochondrial DNA (mtDNA) Mutations in Papillary Thyroid Carcinomas and Differential mtDNA Sequence Variants in Cases with Thyroid Tumours,” Oncogene 19, no. 16 (2000): 2060-2066.

[159] G. Gasparre, A. M. Porcelli, and E. Bonora, “Disruptive Mitochondrial DNA Mutations in Complex I Subunits Are Markers of Oncocytic Phenotype in Thyroid Tumors,” PNAS 104, no. 21 (2007): 9001-9006.

[160] L. Lopez-Penabad, A. C. Chiu, and A. O. Hoff, “Prognostic Factors in Patients with Hurthle Cell Neoplasms of the Thyroid,” Cancer 97, no. 5 (2003): 1186-1194.

[161] E. L. Maxwell, C. E. Palme, and J. Freeman, “Hurthle Cell Tumors: Applying Molecular Markers to Define a New Management Algorithm,” Archives of Otolaryngology - Head and Neck Surgery 132, no. 1 (2006): 54-58.

[162] J. A. Bishop, G. Wu, and R. P. Tufano, “Histological Patterns of Locoregional Recurrence in Hurthle Cell Carcinoma of the Thyroid Gland,” Thyroid: Official Journal of the American Thyroid Association 22, no. 7 (2012): 690-694.

[163] S. Kure and R. Ohashi, “Thyroid Hurthle Cell Carcinoma: Clinical, Pathological, and Molecular Features,” Cancers (Basel) 13, no. 1 (2020): 26.

[164] A. M. Chindris, J. D. Casler, and V. J. Bernet, “Clinical and Molecular Features of Hurthle Cell Carcinoma of the Thyroid,” Journal of Clinical Endocrinology and Metabolism 100, no. 1 (2015): 55-62.

[165] K. S. Wong, F. Dong, and M. Telatar, “Papillary Thyroid Carcinoma with High-Grade Features versus Poorly Differentiated Thyroid Carcinoma: An Analysis of Clinicopathologic and Molecular Features and Outcome,” Thyroid: Official Journal of the American Thyroid Association 31, no. 6 (2021): 933-940.

[166] I. Landa, T. Ibrahimpasic, and L. Boucai, “Genomic and Transcriptomic Hallmarks of Poorly Differentiated and Anaplastic Thyroid Cancers,” Journal of Clinical Investigation 126, no. 3 (2016): 1052-1066.

[167] M. Volante, A. K. Lam, and M. Papotti, “Molecular Pathology of Poorly Differentiated and Anaplastic Thyroid Cancer: What Do Pathologists Need to Know?,” Endocrine Pathology 32, no. 1 (2021): 63-76.

[168] R. D. Chernock, B. Rivera, and N. Borrelli, “Poorly Differentiated Thyroid Carcinoma of Childhood and Adolescence: A Distinct Entity Characterized by DICER1 Mutations,” Modern Pathology 33, no. 7 (2020): 1264-1274.

[169] J. L. Song, L. R. Li, and Z. L. Xu, “Long-Term Survival in Patients with Papillary Thyroid Cancer Who Did Not Undergo Prophylactic Central Lymph Node Dissection: A SEER-Based Study,” World Journal of Oncology 13, no. 3 (2022): 136-144.

[170] B. Xu, T. Fuchs, and S. Dogan, “Dissecting Anaplastic Thyroid Carcinoma: A Comprehensive Clinical, Histologic, Immunophenotypic, and Molecular Study of 360 Cases,” Thyroid: Official Journal of the American Thyroid Association 30, no. 10 (2020): 1505-1517.

[171] J. W. Kunstman, C. C. Juhlin, and G. Goh, “Characterization of the Mutational Landscape of Anaplastic Thyroid Cancer Via Whole-exome Sequencing,” Human Molecular Genetics 24, no. 8 (2015): 2318-2329.

[172] K. S. Wong, J. H. Lorch, and E. K. Alexander, “Clinicopathologic Features of Mismatch Repair-Deficient Anaplastic Thyroid Carcinomas,” Thyroid: Official Journal of the American Thyroid Association 29, no. 5 (2019): 666-673.

[173] S. S. Wu, E. D. Lamarre, and A. Yalamanchali, “Association of Treatment Strategies and Tumor Characteristics with Overall Survival among Patients with Anaplastic Thyroid Cancer: A Single-Institution 21-Year Experience,” JAMA Otolaryngol Head Neck Surg 149, no. 4 (2023): 300-309.

[174] A. Jannin, A. Escande, and A. Al Ghuzlan, “Anaplastic Thyroid Carcinoma: An Update,” Cancers (Basel) 14, no. 4 (2022): 1061.

[175] R. L. Siegel, K. D. Miller, and A. Jemal, “Cancer Statistics, 2020,” CA: A Cancer Journal for Clinicians 70, no. 1 (2020): 7-30.

[176] B. Saravana-Bawan, A. Bajwa, and J. Paterson, “Active Surveillance of Low-risk Papillary Thyroid Cancer: A Meta-analysis,” Surgery 167, no. 1 (2020): 46-55.

[177] J. Zhang and S. Xu, “High Aggressiveness of Papillary Thyroid Cancer: From Clinical Evidence to Regulatory Cellular Networks,” Cell Death Discovery 10, no. 1 (2024): 378.

[178] D. Uno, K. Endo, and T. Yoshikawa, “Correlation between Gene Mutations and Clinical Characteristics in Papillary Thyroid Cancer: A Retrospective Analysis of BRAF Mutations and RET Rearrangements,” Thyroid Research 17, no. 1 (2024): 21.

[179] C. Nylen, R. Mechera, and I. Marechal-Ross, “Molecular Markers Guiding Thyroid Cancer Management,” Cancers (Basel) 12, no. 8 (2020).

[180] L. Yip and J. A. Sosa, “Molecular-Directed Treatment of Differentiated Thyroid Cancer: Advances in Diagnosis and Treatment,” JAMA Surgery 151, no. 7 (2016): 663-670.

[181] J. A. Fagin and S. A. Wells, “Biologic and Clinical Perspectives on Thyroid Cancer,” New England Journal of Medicine 375, no. 11 (2016): 1054-1067.

[182] E. T. Kimura, M. N. Nikiforova, and Z. Zhu, “High Prevalence of BRAF Mutations in Thyroid Cancer: Genetic Evidence for Constitutive Activation of the RET/PTC-RAS-BRAF Signaling Pathway in Papillary Thyroid Carcinoma,” Cancer Research 63, no. 7 (2003): 1454-1457.

[183] D. G. McFadden and P. M. Sadow Genetics, “Diagnosis, and Management of Hurthle Cell Thyroid Neoplasms,” Frontiers in Endocrinology (Lausanne) 12 (2021): 696386.

[184] P. Goffredo, S. A. Roman, and J. A. Sosa, “Hurthle Cell Carcinoma: A Population-level Analysis of 3311 Patients,” Cancer 119, no. 3 (2013): 504-511.

[185] S. L. Asa and O. Mete, “Oncocytic Change in Thyroid Pathology,” Front Endocrinol (Lausanne) 12 (2021): 678119.

[186] J. B. Jalaly and Z. W. Baloch, “Hurthle-cell Neoplasms of the Thyroid: An Algorithmic Approach to Pathologic Diagnosis in Light of Molecular Advances,” Seminars in Diagnostic Pathology 37, no. 5 (2020): 234-242.

[187] A. R. Frank, V. Li, and S. D. Shelton, “Mitochondrial-Encoded Complex I Impairment Induces a Targetable Dependency on Aerobic Fermentation in Hurthle Cell Carcinoma of the Thyroid,” Cancer Discovery 13, no. 8 (2023): 1884-1903.

[188] M. Volante, P. Collini, and Y. E. Nikiforov, “Poorly Differentiated Thyroid Carcinoma: The Turin Proposal for the Use of Uniform Diagnostic Criteria and an Algorithmic Diagnostic Approach,” American Journal of Surgical Pathology 31, no. 8 (2007): 1256-1264.

[189] K. Y. Lam, C. Y. Lo, and M. C. Liu, “Primary Squamous Cell Carcinoma of the Thyroid Gland: An Entity with Aggressive Clinical Behaviour and Distinctive Cytokeratin Expression Profiles,” Histopathology 39, no. 3 (2001): 279-286.

[190] J. Wendler, M. Kroiss, and K. Gast, “Clinical Presentation, Treatment and Outcome of Anaplastic Thyroid Carcinoma: Results of a Multicenter Study in Germany,” European Journal of Endocrinology 175, no. 6 (2016): 521-529.

[191] S. De Leo, M. Trevisan, and L. Fugazzola, “Recent Advances in the Management of Anaplastic Thyroid Cancer,” Thyroid Research 13, no. 1 (2020): 17.

[192] S. A. Wells, S. L. Asa, and H. Dralle, “Revised American Thyroid Association Guidelines for the Management of Medullary Thyroid Carcinoma,” Thyroid: Official Journal of the American Thyroid Association 25, no. 6 (2015): 567-610.

[193] S. A. Wells, D. E. Haagensen,, and W. M. Linehan, “The Detection of Elevated Plasma Levels of Carcinoembryonic Antigen in Patients with Suspected or Established Medullary Thyroid Carcinoma,” Cancer 42 (1978): 1498-1503. Suppl.

[194] D. Viola and R. Elisei, “Management of Medullary Thyroid Cancer,” Endocrinology and Metabolism Clinics of North America 48, no. 1 (2019): 285-301.

[195] J. F. Moley, “Medullary Thyroid Carcinoma: Management of Lymph Node Metastases,” Journal of the National Comprehensive Cancer Network: JNCCN 8, no. 5 (2010): 549-556.

[196] F. American, R. T. Kloos, C. Eng, et al., “Medullary Thyroid Cancer: Management Guidelines of the American Thyroid Association,” Thyroid: Official Journal of the American Thyroid Association 19, no. 6 (2009): 565-612.

[197] M. R. Pelizzo, E. I. Mazza, and C. Mian, “Medullary Thyroid Carcinoma,” Expert Review of Anticancer Therapy 23, no. 9 (2023): 943-957.

[198] D. Rusinek, E. Chmielik, and J. Krajewska, “Current Advances in Thyroid Cancer Management. Are We Ready for the Epidemic Rise of Diagnoses?,” International Journal of Molecular Sciences 18, no. 8 (2017): 1817.

[199] C. Romei, R. Ciampi, and R. Elisei, “A Comprehensive Overview of the Role of the RET Proto-oncogene in Thyroid Carcinoma,” Nature reviews Endocrinology 12, no. 4 (2016): 192-202.

[200] R. Ciampi, C. Mian, and L. Fugazzola, “Evidence of a Low Prevalence of RAS Mutations in a Large Medullary Thyroid Cancer Series,” Thyroid: Official Journal of the American Thyroid Association 23, no. 1 (2013): 50-57.

[201] A. Boichard, L. Croux, and A. Al Ghuzlan, “Somatic RAS Mutations Occur in a Large Proportion of Sporadic RET-negative Medullary Thyroid Carcinomas and Extend to a Previously Unidentified Exon,” Journal of Clinical Endocrinology and Metabolism 97, no. 10 (2012): E2031-2035.

[202] M. M. Moura, B. M. Cavaco, and A. E. Pinto, “High Prevalence of RAS Mutations in RET-negative Sporadic Medullary Thyroid Carcinomas,” Journal of Clinical Endocrinology and Metabolism 96, no. 5 (2011): E863-868.

[203] F. Najdawi, S. Ahmadi, and M. Capelletti, “Evaluation of Grade in a Genotyped Cohort of Sporadic Medullary Thyroid Carcinomas,” Histopathology 79, no. 3 (2021): 427-436.

[204] H. Khandakar, S. Agarwal, and M. C. Sharma, “Amphicrine Medullary Thyroid Carcinoma—A Case-Based Review Expanding on Its MUC Expression Profile,” Endocrine Pathology 33, no. 3 (2022): 378-387.

[205] M. K. Le, M. Kawai, and T. Odate, “Metastatic Risk Stratification of 2526 Medullary Thyroid Carcinoma Patients: A Study Based on Surveillance, Epidemiology, and End Results Database,” Endocrine Pathology 33, no. 3 (2022): 348-358.

[206] G. Tonon, S. Modi, and L. Wu, “t(11;19)(q21;p13) Translocation in Mucoepidermoid Carcinoma Creates a Novel Fusion Product That Disrupts a Notch Signaling Pathway,” Nature Genetics 33, no. 2 (2003): 208-213.

[207] J. Wang, Q. R. Guli, and X. C. Ming, “Primary Mucinous Carcinoma of Thyroid Gland with Prominent Signet-ring-cell Differentiation: A Case Report and Review of the Literature,” OncoTargets and Therapy 11 (2018): 1521-1528.

[208] E. Y. Wu, J. Lebastchi, and E. Marqusee, “A Case of Primary Secretory Carcinoma of the Thyroid with High-grade Features,” Histopathology 71, no. 4 (2017): 665-669.

[209] N. S. Huang, Y. M. Cao, and Z. W. Lu, “Mammary Analog Secretory Carcinoma of the Thyroid Gland: A Rare Cancer Harboring TRK Fusion,” Oral Oncology 115 (2021): 105092.

[210] F. Pitoia, F. Jerkovich, and C. Urciuoli, “Implementing the Modified 2009 American Thyroid Association Risk Stratification System in Thyroid Cancer Patients with Low and Intermediate Risk of Recurrence,” Thyroid: Official Journal of the American Thyroid Association 25, no. 11 (2015): 1235-1242.

[211] M. Saliba, A. S. Mohanty, and A. L. Ho, “Secretory Carcinoma of the Thyroid in a 49-Year-Old Man Treated with Larotrectinib: Protracted Clinical Course of Disease Despite the High-Grade Histologic Features,” Head and Neck Pathology 16, no. 2 (2022): 612-620.

[212] M. Chambers, V. Nose, and P. M. Sadow, “Salivary-Like Tumors of the Thyroid: A Comprehensive Review of Three Rare Carcinomas,” Head and Neck Pathology 15, no. 1 (2021): 212-224.

[213] M. A. Desai, M. Mehrad, and K. A. Ely, “Secretory Carcinoma of the Thyroid Gland: Report of a Highly Aggressive Case Clinically Mimicking Undifferentiated Carcinoma and Review of the Literature,” Head and Neck Pathology 13, no. 4 (2019): 562-572.

[214] I. Tahara, N. Oishi, and K. Mochizuki, “Identification of Recurrent TERT Promoter Mutations in Intrathyroid Thymic Carcinomas,” Endocrine Pathology 31, no. 3 (2020): 274-282.

[215] B. Boyraz, P. M. Sadow, and S. L. Asa, “Cribriform-Morular Thyroid Carcinoma Is a Distinct Thyroid Malignancy of Uncertain Cytogenesis,” Endocrine Pathology 32, no. 3 (2021): 327-335.

[216] S. Cameselle-Garcia, I. Abdulkader-Nallib, and M. Sanchez-Ares, “Cribriform Morular Thyroid Carcinoma: Clinicopathological and Molecular Basis for both a Preventive and Therapeutic Approach for a Rare Tumor (Review),” Oncology Reports 52, no. 3 (2024): 119.

[217] M. D. Aydemirli, K. van der Tuin, and F. J. Hes, “A Unique Case of Two Somatic APC Mutations in an Early Onset Cribriform-morular Variant of Papillary Thyroid Carcinoma and Overview of the Literature,” Familial Cancer 19, no. 1 (2020): 15-21.

[218] J. Corean, L. V. Furtado, and S. Kadri, “Cribriform-Morular Variant of Papillary Thyroid Carcinoma with Poorly Differentiated Features: A Case Report with Immunohistochemical and Molecular Genetic Analysis,” International Journal of Surgical Pathology 27, no. 3 (2019): 294-304.

[219] D. Schuetze, A. P. Hoschar, and R. R. Seethala, “The T1799A BRAF Mutation Is Absent in Cribriform-morular Variant of Papillary Carcinoma,” Archives of Pathology & Laboratory Medicine 133, no. 5 (2009): 803-805.

[220] C. Christofer Juhlin, O. Mete, and Z. W. Baloch, “The 2022 WHO Classification of Thyroid Tumors: Novel Concepts in Nomenclature and Grading,” Endocrine-Related Cancer 30, no. 2 (2023): e220293.

[221] J. L. Hunt, V. A. LiVolsi, and E. L. Barnes, “p63 expression in Sclerosing Mucoepidermoid Carcinomas with Eosinophilia Arising in the Thyroid,” Modern Pathology 17, no. 5 (2004): 526-529.

[222] S. Leboulleux, L. Lamartina, and E. Lecornet Sokol, “SFE-AFCE-SFMN 2022 Consensus on the Management of Thyroid Nodules: Follow-up: How and How Long?,” Annales D endocrinologie 83, no. 6 (2022): 407-414.

[223] M. J. Kim, J. H. Moon, and E. K. Lee, “Active Surveillance for Low-Risk Thyroid Cancers: A Review of Current Practice Guidelines,” Endocrinology and Metabolism (Seoul) 39, no. 1 (2024): 47-60.

[224] M. Grussendorf, I. Ruschenburg, and G. Brabant, “Malignancy Rates in Thyroid Nodules: A Long-term Cohort Study of 17,592 Patients,” European Thyroid Journal 11, no. 4 (2022): e220027.

[225] Y. Ito, A. Miyauchi, and H. Inoue, “An Observational Trial for Papillary Thyroid Microcarcinoma in Japanese Patients,” World Journal of Surgery 34, no. 1 (2010): 28-35.

[226] Y. Ito, A. Miyauchi, and M. Kihara, “Patient Age Is Significantly Related to the Progression of Papillary Microcarcinoma of the Thyroid Under Observation,” Thyroid: Official Journal of the American Thyroid Association 24, no. 1 (2014): 27-34.

[227] R. M. Tuttle, J. A. Fagin, and G. Minkowitz, “Natural History and Tumor Volume Kinetics of Papillary Thyroid Cancers during Active Surveillance,” JAMA Otolaryngology - Head & Neck Surgery 143, no. 10 (2017): 1015-1020.

[228] E. H. Benaim, C. Nieri, and M. Mamidala, “High-intensity Focused Ultrasound for Benign Thyroid Nodules: Systemic Review and Meta-analysis,” American Journal of Otolaryngology 44, no. 6 (2023): 103999.

[229] J. Ding, D. Wang, and W. Zhang, “Ultrasound-Guided Radiofrequency and Microwave Ablation for the Management of Patients with Benign Thyroid Nodules: Systematic Review and Meta-Analysis,” Ultrasound Quarterly 39, no. 1 (2023): 61-68.

[230] S. Jasim, K. N. Patel, and G. Randolph, “American Association of Clinical Endocrinology Disease State Clinical Review: The Clinical Utility of Minimally Invasive Interventional Procedures in the Management of Benign and Malignant Thyroid Lesions,” Endocrine Practice 28, no. 4 (2022): 433-448.

[231] C. F. Sinclair, J. H. Baek, and K. E. Hands, “General Principles for the Safe Performance, Training, and Adoption of Ablation Techniques for Benign Thyroid Nodules: An American Thyroid Association Statement,” Thyroid: Official Journal of the American Thyroid Association 33, no. 10 (2023): 1150-1170.

[232] E. Papini, H. Monpeyssen, A. Frasoldati, et al., “2020 European Thyroid Association Clinical Practice Guideline for the Use of Image-Guided Ablation in Benign Thyroid Nodules,” European Thyroid Journal 9, no. 4 (2020): 172-185.

[233] L. A. Orloff, J. E. Noel, B. C. Stack, et al., “Radiofrequency Ablation and Related Ultrasound-guided Ablation Technologies for Treatment of Benign and Malignant Thyroid Disease: An International Multidisciplinary Consensus Statement of the American Head and Neck Society Endocrine Surgery Section with the Asia Pacific Society of Thyroid Surgery, Associazione Medici Endocrinologi, British Association of Endocrine and Thyroid Surgeons, European Thyroid Association, Italian Society of Endocrine Surgery Units, Korean Society of Thyroid Radiology, Latin American Thyroid Society, and Thyroid Nodules Therapies Association,” Head & Neck 44, no. 3 (2022): 633-660.

[234] K. N. Patel, L. Yip, and C. C. Lubitz, “The American Association of Endocrine Surgeons Guidelines for the Definitive Surgical Management of Thyroid Disease in Adults,” Annals of Surgery 271, no. 3 (2020): e21-e93.

[235] C. Schvartz, F. Bonnetain, and S. Dabakuyo, “Impact on Overall Survival of Radioactive Iodine in Low-risk Differentiated Thyroid Cancer Patients,” Journal of Clinical Endocrinology and Metabolism 97, no. 5 (2012): 1526-1535.

[236] I. D. Hay, M. E. Hutchinson, and T. Gonzalez-Losada, “Papillary Thyroid Microcarcinoma: A Study of 900 Cases Observed in a 60-year Period,” Surgery 144, no. 6 (2008): 980-987. discussion 987-988.

[237] J. Jonklaas, D. S. Cooper, and K. B. Ain, “Radioiodine Therapy in Patients with Stage I Differentiated Thyroid Cancer,” Thyroid: Official Journal of the American Thyroid Association 20, no. 12 (2010): 1423-1424.

[238] S. Leboulleux, C. Bournaud, and C. N. Chougnet, “Thyroidectomy without Radioiodine in Patients with Low-Risk Thyroid Cancer,” New England Journal of Medicine 386, no. 10 (2022): 923-932.

[239] J. Jonklaas, N. J. Sarlis, and D. Litofsky, “Outcomes of Patients with Differentiated Thyroid Carcinoma Following Initial Therapy,” Thyroid: Official Journal of the American Thyroid Association 16, no. 12 (2006): 1229-1242.

[240] L. Lamartina, C. Durante, and S. Filetti, “Low-risk Differentiated Thyroid Cancer and Radioiodine Remnant Ablation: A Systematic Review of the Literature,” Journal of Clinical Endocrinology and Metabolism 100, no. 5 (2015): 1748-1761.

[241] D. Chakravarty, E. Santos, and M. Ryder, “Small-molecule MAPK Inhibitors Restore Radioiodine Incorporation in Mouse Thyroid Cancers with Conditional BRAF Activation,” Journal of Clinical Investigation 121, no. 12 (2011): 4700-4711.

[242] X. Zhang, L. Tian, and D. Teng, “The Relationship between Thyrotropin Serum Concentrations and Thyroid Carcinoma,” Cancers (Basel) 15, no. 20 (2023): 5017.

[243] B. Biondi, “TSH Suppression in Differentiated Thyroid Cancer Patients. Still More Questions than Answers after 30 Years,” Thyroid: Official Journal of the American Thyroid Association 34, no. 6 (2024): 671-673.

[244] B. Biondi and D. S. Cooper, “Thyroid Hormone Suppression Therapy,” Endocrinology and Metabolism Clinics of North America 48, no. 1 (2019): 227-237.

[245] B. Biondi and D. S. Cooper, “Benefits of Thyrotropin Suppression versus the Risks of Adverse Effects in Differentiated Thyroid Cancer,” Thyroid: Official Journal of the American Thyroid Association 20, no. 2 (2010): 135-146.

[246] L. Fugazzola, R. Elisei, D. Fuhrer, et al., “2019 European Thyroid Association Guidelines for the Treatment and Follow-Up of Advanced Radioiodine-Refractory Thyroid Cancer,” European Thyroid Journal 8, no. 5 (2019): 227-245.

[247] L. J. Wirth, C. Durante, and D. J. Topliss, “Lenvatinib for the Treatment of Radioiodine-Refractory Differentiated Thyroid Cancer: Treatment Optimization for Maximum Clinical Benefit,” The Oncologist 27, no. 7 (2022): 565-572.

[248] F. Volpe, C. Nappi, and E. Zampella, “Current Advances in Radioactive Iodine-Refractory Differentiated Thyroid Cancer,” Current Oncology 31, no. 7 (2024): 3870-3884.

[249] M. S. Brose, C. M. Nutting, and B. Jarzab, “Sorafenib in Radioactive Iodine-refractory, Locally Advanced or Metastatic Differentiated Thyroid Cancer: A Randomised, Double-blind, Phase 3 Trial,” Lancet 384, no. 9940 (2014): 319-328.

[250] M. Schlumberger, M. Tahara, and L. J. Wirth, “Lenvatinib versus Placebo in Radioiodine-refractory Thyroid Cancer,” New England Journal of Medicine 372, no. 7 (2015): 621-630.

[251] S. A. Wells, B. G. Robinson, and R. F. Gagel, “Vandetanib in Patients with Locally Advanced or Metastatic Medullary Thyroid Cancer: A Randomized, Double-blind Phase III Trial,” Journal of Clinical Oncology 30, no. 2 (2012): 134-141.

[252] M. Schlumberger, R. Elisei, and S. Muller, “Overall Survival Analysis of EXAM, a Phase III Trial of cabozantinib in Patients with Radiographically Progressive Medullary Thyroid Carcinoma,” Annals of Oncology 28, no. 11 (2017): 2813-2819.

[253] M. S. Brose, B. Robinson, and S. I. Sherman, “Cabozantinib for Radioiodine-refractory Differentiated Thyroid Cancer (COSMIC-311): A Randomised, Double-blind, Placebo-controlled, Phase 3 Trial,” The Lancet Oncology 22, no. 8 (2021): 1126-1138.

[254] V. Subbiah, R. J. Kreitman, and Z. A. Wainberg, “Dabrafenib plus Trametinib in Patients with BRAF V600E-mutant Anaplastic Thyroid Cancer: Updated Analysis from the Phase II ROAR Basket Study,” Annals of Oncology 33, no. 4 (2022): 406-415.

[255] N. L. Busaidy, B. Konda, and L. Wei, “Dabrafenib versus Dabrafenib + Trametinib in BRAF-Mutated Radioactive Iodine Refractory Differentiated Thyroid Cancer: Results of a Randomized, Phase 2, Open-Label Multicenter Trial,” Thyroid: Official Journal of the American Thyroid Association 32, no. 10 (2022): 1184-1192.

[256] S. G. Waguespack, A. Drilon, and J. J. Lin, “Efficacy and Safety of Larotrectinib in Patients with TRK Fusion-positive Thyroid Carcinoma,” European Journal of Endocrinology 186, no. 6 (2022): 631-643.

[257] G. D. Demetri, F. De Braud, and A. Drilon, “Updated Integrated Analysis of the Efficacy and Safety of Entrectinib in Patients with NTRK Fusion-Positive Solid Tumors,” Clinical Cancer Research 28, no. 7 (2022): 1302-1312.

[258] J. Hadoux, R. Elisei, and M. S. Brose, “Phase 3 Trial of Selpercatinib in Advanced RET-Mutant Medullary Thyroid Cancer,” New England Journal of Medicine 389, no. 20 (2023): 1851-1861.

[259] L. J. Wirth, E. Sherman, and B. Robinson, “Efficacy of Selpercatinib in RET-Altered Thyroid Cancers,” New England Journal of Medicine 383, no. 9 (2020): 825-835.

[260] V. Subbiah, M. I. Hu, and L. J. Wirth, “Pralsetinib for Patients with Advanced or Metastatic RET-altered Thyroid Cancer (ARROW): A Multi-cohort, Open-label, Registrational, Phase 1/2 Study,” The Lancet Diabetes & Endocrinology 9, no. 8 (2021): 491-501.

[261] S. Hamidi, R. Dadu, and M. E. Zafereo, “Initial Management of BRAF V600E-Variant Anaplastic Thyroid Cancer: The FAST Multidisciplinary Group Consensus Statement,” JAMA Oncology 10, no. 9 (2024): 1264-1271.

[262] Y. J. Lee-Saxton, C. E. Egan, and B. A. Bratton, “Low Mitotic Activity in Papillary Thyroid Cancer: A Marker for Aggressive Features and Recurrence,” Journal of Clinical Endocrinology and Metabolism (2024).

[263] X. Li, S. Zhang, and Q. Zhang, “Diagnosis of Thyroid Cancer Using Deep Convolutional Neural Network Models Applied to Sonographic Images: A Retrospective, Multicohort, Diagnostic Study,” The Lancet Oncology 20, no. 2 (2019): 193-201.

[264] H. S. Ahn, H. J. Kim, and H. G. Welch, “Korea's Thyroid-cancer “Epidemic”-screening and Overdiagnosis,” New England Journal of Medicine 371, no. 19 (2014): 1765-1767.

[265] S. Vaccarella, S. Franceschi, F. Bray, et al., “Worldwide Thyroid-Cancer Epidemic? The Increasing Impact of Overdiagnosis,” New England Journal of Medicine 375, no. 7 (2016): 614-617.

[266] R. Chou, T. Dana, and M. Haymart, “Active Surveillance versus Thyroid Surgery for Differentiated Thyroid Cancer: A Systematic Review,” Thyroid: Official Journal of the American Thyroid Association 32, no. 4 (2022): 351-367.

[267] K. A. Zanocco, J. M. Hershman, and A. M. Leung, “Active Surveillance of Low-Risk Thyroid Cancer,” Jama 321, no. 20 (2019): 2020-2021.

RIGHTS & PERMISSIONS

2025 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.