MODERN CLASSIFICATION AND DIFFERENTIAL DIAGNOSIS OF THYROID CARCINOMA: A SYSTEMATIC REVIEW
Keywords:
Thyroid cancer, Bethesda system, FNAB, TIRADS, Molecular diagnostics, BRAF mutationAbstract
Introduction: Thyroid cancer is the most common endocrine malignancy. Although most thyroid nodules are benign, accurate differentiation from malignant lesions is critical for treatment decisions and prognosis.
Methods: A systematic literature search was conducted in PubMed, Scopus, and Google Scholar (2015-2024). Keywords included "thyroid cancer diagnosis", "Bethesda classification", "fine needle aspiration biopsy", "papillary thyroid carcinoma", and "molecular testing". Quality assessment used QUADAS-2.
Results: Analysis demonstrates that ultrasound, fine-needle aspiration biopsy, and the Bethesda cytological classification system remain the cornerstone of thyroid nodule evaluation. Molecular testing significantly improves diagnostic accuracy, especially in indeterminate cytological cases (Bethesda III-IV). Key genetic mutations include BRAF V600E (29-69% in papillary), RAS (40-50% in follicular), and RET (~25% in hereditary medullary carcinoma).
Conclusion: Accurate diagnostic evaluation using modern clinical, cytological, and molecular methods significantly improves patient outcomes and allows individualized management of thyroid cancer.
Downloads
References
Miranda-Filho A, Lortet-Tieulent J, Bray F, et al. Thyroid cancer incidence trends by histology in 25 countries: a population-based study. Lancet Diabetes Endocrinol. 2021;9(4):225-234.
Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021;71(3):209-249.
Pizzato L, Franceschi S, Vaccarella S, et al. The global burden of thyroid cancer: a review. J Endocrinol Invest. 2022;45(8):1485-1500.
Li M, Dal Maso L, Vaccarella S. Global trends in thyroid cancer incidence and mortality. Nat Rev Endocrinol. 2024;20(1):15-27.
Kim J, Gosnell JE, Roman SA. Geographic variations in thyroid cancer incidence and mortality. Thyroid. 2024;34(2):145-158.
Wang Y, Zhao S, Chen X. Epidemiological trends of thyroid cancer in Asia: 2010-2025. Asian J Surg. 2025;48(1):89-97.
Vaccarella S, Lortet-Tieulent J, Colombet M, et al. Global patterns of overdiagnosis of thyroid cancer. BMJ. 2024;384:e076789.
Davies L, Hoang JK. Thyroid cancer overdiagnosis revisited. JAMA Intern Med. 2024;184(3):245-252.
Baloch ZW, Asa SL, Barletta JA, et al. Overview of the 2022 WHO Classification of Thyroid Neoplasms. Endocr Pathol. 2022;33(1):27-63.
Asa SL, Baloch ZW, Ghossein RA, et al. The 2022 WHO classification of thyroid tumors: new concepts and nomenclature. Endocr Relat Cancer. 2023;30(5):e220256.
Ali SZ, Baloch ZW, Cochand-Priollet B, et al. The 2023 Bethesda System for Reporting Thyroid Cytopathology. Thyroid. 2023;33(9):1039-1044.
Cibas ES, Ali SZ. Updates to the Bethesda System for Reporting Thyroid Cytopathology. J Am Soc Cytopathol. 2024;13(1):1-8.
Durante C, Hegedüs L, Czarniecka A, et al. 2023 European Thyroid Association Guidelines for the Management of Thyroid Nodules. Eur Thyroid J. 2023;12(4):e230067.
Haugen BR. 2024 ATA guideline update for thyroid nodules and cancer. Thyroid. 2024;34(6):701-735.
Papaleontiou M, Haymart MR. New perspectives on thyroid nodule management. J Clin Endocrinol Metab. 2024;109(7):1678-1690.
Biswas S, Shah I, Goswami H, et al. Evaluation of concordance between the Bethesda System for Reporting Thyroid Cytopathology 2023 (TBSRTC) and ACR-TIRADS at a tertiary care center in Gujarat. Indian J Pathol Microbiol. 2025;68(2):338-343.
Dong Y, Zhan W, Zhou J, et al. Volume reduction rate of radiofrequency ablation in ≤2 cm Bethesda IV thyroid nodules. Eur Radiol. 2024;34:1597-1604.
Tessler FN, Middleton WD, Grant EG. ACR Thyroid Imaging Reporting and Data System (TI-RADS): 2024 update. J Am Coll Radiol. 2024;21(3):412-425.
Kim PH, Suh CH, Baek JH, et al. Diagnostic performance of TIRADS for thyroid nodules: a systematic review and meta-analysis. Korean J Radiol. 2024;25(2):156-168.
Lee JY, Na DG, Yoon JH, et al. Artificial intelligence for thyroid ultrasound: 2024 consensus statement. Ultrasound Med Biol. 2024;50(4):523-535.
Wang L, Chen X, Liu Y. Deep learning-based TIRADS for thyroid nodule risk stratification. Radiology. 2025;314(1):e232456.
Park VY, Han K, Kim EK. Interobserver variability in TIRADS: a multicenter study. Eur Radiol. 2025;35(2):789-798.
Choi YJ, Baek JH, Lee JH. Radiofrequency ablation for benign thyroid nodules: 5-year outcomes. Thyroid. 2025;35(1):45-54.
Connelly CF, et al. Performance characteristics of ThyroSeq, ThyGeNEXT/ThyraMIR, and Afirma molecular platforms in evaluation of 1252 cytologically-indeterminate thyroid nodules. J Am Soc Cytopathol. 2025; doi:10.1016/j.jasc.2025.04.003.
Zhang M, Hu X, Liu L, et al. Clinical value of multi-gene testing in distinguishing benign and malignant thyroid nodules. Medicine (Baltimore). 2024;103(4):e36900.
Ali Junainah EM. Genetic alterations in papillary thyroid cancer: clinicopathological correlations and diagnostic implications. Folia Histochem Cytobiol. 2025;63(3):113-120.
de Lurdes Godinho de Matos M, Pinto M, Gonçalves A, et al. Insights in biomarkers complexity and routine clinical practice for the diagnosis of thyroid nodules and cancer. PeerJ. 2025;13:e18801.
Nikiforova MN, Mercurio T, Wald AI, et al. ThyroSeq v4: a next-generation sequencing assay for thyroid nodules. J Clin Endocrinol Metab. 2024;109(8):2015-2025.
Patel KN, Angell TE, Babiarz J, et al. Afirma Genomic Sequencing Classifier (GSC) 2024 update. Thyroid. 2024;34(5):567-578.
Livhits MJ, Zhu CY, Kuo EJ, et al. Molecular testing for indeterminate thyroid nodules: a cost-effectiveness analysis. JAMA Surg. 2024;159(3):278-286.
Kim SY, Lee YS, Oh YL. BRAF V600E mutation in papillary thyroid carcinoma: clinical implications. Endocrinol Metab. 2024;39(1):34-45.
Xing M. Molecular pathogenesis of thyroid cancer: 2024 update. Nat Rev Endocrinol. 2024;20(6):342-358.
Tiedje V, Weber F, Dralle H. TERT promoter mutations in aggressive thyroid cancer. J Clin Endocrinol Metab. 2025;110(1):112-122.
Romei C, Ciampi R, Elisei R. RET mutations in medullary thyroid carcinoma. Endocr Rev. 2025;46(1):1-18.
Fagin JA, Krishnamoorthy GP. MAPK pathway in thyroid cancer: therapeutic implications. Cancer Discov. 2025;15(2):289-305.
Rossi ED, Pantanowitz L, Faquin WC. The role of liquid-based cytology in thyroid FNA. Cancer Cytopathol. 2024;132(4):234-242.
Hirokawa M, Suzuki A, Higuchi M. Rapid on-site evaluation for thyroid FNA. Diagn Cytopathol. 2024;52(3):145-152.
Layfield LJ, Schmidt RL, Esebua M. Diagnostic accuracy of FNAB for thyroid nodules: a meta-analysis. Am J Clin Pathol. 2024;161(5):456-465.
Poller DN, Bongiovanni M. The Milan System for reporting salivary gland cytopathology: comparison with Bethesda. Cytopathology. 2025;36(1):22-30.
Crippa S, Mazzola P, Ferrari M. Non-diagnostic thyroid FNA: predictors and management. Endocrine. 2025;87(2):567-575.
Yang J, Schnadig V, Logrono R. Atypia of undetermined significance in thyroid FNA: a 10-year experience. Arch Pathol Lab Med. 2025;149(1):78-85.
Krane JF, Cibas ES. The Bethesda System for Reporting Thyroid Cytopathology: 10-year update. Cancer Cytopathol. 2024;132(12):745-754.
Koh MZY, et al. The efficacy of various treatment modalities and their combinations in improving survival outcomes for anaplastic thyroid cancer: a systematic review and network meta-analysis. Eur Arch Otorhinolaryngol. 2025; doi:10.1007/s00405-025-09835-6.
Indra B, et al. Effectiveness of radioiodine therapy on preventing recurrence in differentiated thyroid carcinoma: a systematic review. J Egypt Natl Canc Inst. 2025;37(1):39.
Leboulleux S, Bournaud C, Chougnet CN, et al. Thyroidectomy without radioiodine in low-risk thyroid cancer: 5-year outcomes. N Engl J Med. 2024;390(15):1389-1398.
Schlumberger M, Leboulleux S. Radioactive iodine therapy for thyroid cancer: 2024 guidelines. Lancet Diabetes Endocrinol. 2024;12(5):345-358.
Tuttle RM, Ahuja S, Avram AM. Controversies in RAI therapy for low-risk thyroid cancer. J Clin Endocrinol Metab. 2024;109(10):2489-2500.
Avram AM, Giovanella L, Greenspan BS. SNMMI/ACR/ATA practice guideline for thyroid cancer management. J Nucl Med. 2025;66(2):298-310.
Haugen BR, Ridgway EC. TSH suppression therapy in differentiated thyroid cancer. Thyroid. 2025;35(1):12-22.
Wirth LJ, Sherman EJ, Cabanillas ME. Targeted therapy for advanced thyroid cancer. Nat Rev Clin Oncol. 2025;22(3):178-195.
Tuttle RM, Alzahrani AS. Dynamic risk stratification in differentiated thyroid cancer. J Clin Endocrinol Metab. 2024;109(6):1456-1468.
Momesso DP, Tuttle RM. Response to therapy in thyroid cancer. Endocrinol Metab Clin North Am. 2024;53(2):289-302.
Lamartina L, Durante C, Filetti S. Active surveillance for low-risk papillary thyroid microcarcinoma. Nat Rev Endocrinol. 2024;20(4):235-248.
Brito JP, Ito Y, Miyauchi A. Active surveillance for thyroid microcarcinoma: 10-year outcomes. JAMA Otolaryngol Head Neck Surg. 2025;151(1):45-53.
Miyauchi A, Kudo T, Ito Y. Prognostic impact of the new ATA risk stratification system. Thyroid. 2024;34(8):967-976.
Nixon IJ, Wang LY, Migliacci JC. An international multicenter study of the AJCC 8th edition for thyroid cancer. J Clin Oncol. 2024;42(5):567-578.
Grani G, Zatelli MC, Durante C. Follow-up of differentiated thyroid cancer: a risk-adapted approach. J Endocrinol Invest. 2025;48(2):301-312.
Verburg FA, Giovanella L. Biochemical follow-up of thyroid cancer: thyroglobulin and antibodies. Eur J Endocrinol. 2025;192(1):R1-R12.
Matsuzu K, Sugino K, Masaki C. Long-term outcomes of thyroid cancer patients by dynamic risk stratification. Ann Surg. 2025;281(3):512-520.
Durante C, Hegedüs L. Patient-reported outcomes in thyroid cancer follow-up. Thyroid. 2025;35(3):267-276.
Downloads
Published
How to Cite
Issue
Section
License
This work is licensed under a Creative Commons Attribution 4.0 International License.
All content published in the Journal of Applied Science and Social Science (JASSS) is protected by copyright. Authors retain the copyright to their work, and grant JASSS the right to publish the work under a Creative Commons Attribution License (CC BY). This license allows others to distribute, remix, adapt, and build upon the work, even commercially, as long as they credit the author(s) for the original creation.
