MEDULLARY THYROID CARCINOMA (MTC): A CURRENT REVIEW OF EPIDEMIOLOGY, DIAGNOSIS, AND THERAPY
Abstract
Background: Medullary Thyroid Carcinoma (MTC) is a rare neuroendocrine tumor (1–5% of all thyroid cancers) characterized by disproportionately high mortality (13%), often complicated by advanced-stage diagnosis and early metastasis. This malignancy is uniquely driven by RET proto-oncogene mutations.
Aim: This review aims to comprehensively analyze contemporary MTC management strategies, focusing on advancements in precision diagnostics, targeted therapies, and identifying critical challenges related to therapeutic resistance and clinical guideline standardization.
Materials and Methods: An extensive synthesis of the current literature, prioritizing comprehensive review articles and meta-analyses published within the last five years, was conducted using multiple electronic databases (PubMed, Scopus).
Results: Recent breakthroughs include the highly effective and well-tolerated selective RET inhibitors (selpercatinib, pralsetinib), which offer improved outcomes compared to older multikinase inhibitors (MKIs). Diagnostic modalities are enhanced by advanced functional imaging (e.g. [18F]F-DOPA-PET/CT). Despite improved overall survival, the major clinical hurdle remains acquired drug resistance, mediated by RET kinase domain mutations and activation of bypass signaling pathways (MET, EGFR). Furthermore, substantial variability persists across international guidelines regarding optimal prophylactic surgery timing and criteria for initiating systemic treatment.
Conclusion: Future efforts must concentrate on establishing unified, dynamic risk stratification protocols, standardizing advanced imaging utilization, and implementing liquid biopsy (ctDNA) guided sequential therapy to effectively overcome acquired resistance and ensure durable long-term disease control.
References
Amin, M. B., Greene, F. L., Edge, S. B., Compton, C. C., Gershenwald, J. E., Brookland, R. K., Meyer, L., Gress, D. M., Byrd, D. R., & Winchester, D. P. (2017). The Eighth Edition AJCC Cancer Staging Manual: Continuing to build a bridge from a population-based to a more "personalized" approach to cancer staging. CA: A Cancer Journal for Clinicians, 67(2), 93–99. https://doi.org/10.3322/caac.21388
Asa, S., Sonmezoglu, K., Uslu-Besli, L., Sahin, O. E., Karayel, E., Pehlivanoglu, H., Sager, S., Kabasakal, L., Ocak, M., & Sayman, H. B. (2021). Evaluation of F-18 DOPA PET/CT in the detection of recurrent or metastatic medullary thyroid carcinoma: comparison with GA-68 DOTA-TATE PET/CT. Annals of Nuclear Medicine, 35(8), 900–915. https://doi.org/10.1007/s12149-021-01627-2
Balinisteanu, I., Panzaru, M.-C., Caba, L., Ungureanu, M.-C., Florea, A., Grigore, A. M., & Gorduza, E. V. (2023). Cancer Predisposition Syndromes and Thyroid Cancer: Keys for a Short Two-Way Street. Biomedicines, 11(8), 2143. https://doi.org/10.3390/biomedicines11082143
Califano, I., Pitoia, F., Chirico, R., De Salazar, A., & Bastianello, M. J. (2022). Prospective study on the clinical relevance of 18F-DOPA positron emission tomography/computed tomography in patients with medullary thyroid carcinoma. Endocrine, 77(1), 143–150. https://doi.org/10.1007/s12020-022-03062-3
Castinetti, F., Waguespack, S. G., Machens, A., Uchino, S., Hasse-Lazar, K., Sanso, G., Else, T., Dvorakova, S., Qi, X. P., Elisei, R., Maia, A. L., Glod, J., Lourenço, D. M., Jr, Valdes, N., Mathiesen, J., Wohllk, N., Bandgar, T. R., Drui, D., Korbonits, M., Druce, M. R., Brain, C., Kurzawinski, T., Patocs, A., Bugalho, M. J., Lacroix, A., Caron, P., Fainstein-Day, P., Borson Chazot, F., Klein, M., Links, T. P., Letizia, C., Fugazzola, L., Chabre, O., Canu, L., Cohen, R., Tabarin, A., Spehar Uroic, A., Maiter, D., Laboureau, L., Mian, C., Peczkowska, M., Sebag, F., Brue, T., Mirebeau-Prunier, D., Leclerc, L., Bausch, B., Berdelou, A., Sukurai, A., Vlcek, P., Krajewska, J., Barontini, M., Vaz Ferreira Vargas, C., Valerio, L., Ceolin, L., Akshintala, S., Hoff, A., Godballe, C., Jarzab, B., Jimenez, C., Eng, C., Imai, T., Schlumberger, M., Grubbs, E., Dralle, H., Neumann, H. P., & Baudin, E. (2019). Natural history, treatment, and long-term follow up of patients with multiple endocrine neoplasia type 2B: an international, multicentre, retrospective study. The Lancet. Diabetes & Endocrinology, 7(3), 213–220. https://doi.org/10.1016/S2213-8587(18)30336-X
Costante, G., & Meringolo, D. (2020). Calcitonin as a biomarker of C cell disease: recent achievements and current challenges. Endocrine, 67(2), 273–280. https://doi.org/10.1007/s12020-019-02183-6
Cupisti, K., Wolf, A., Raffel, A., Schott, M., Miersch, D., Yang, Q., Eisenberger, C. F., Röher, H. D., & Knoefel, W. T. (2007). Long-term clinical and biochemical follow-up in medullary thyroid carcinoma: a single institution's experience over 20 years. Annals of Surgery, 246(5), 815–821. https://doi.org/10.1097/SLA.0b013e31813e66b9
Danila, R., Livadariu, R., & Branisteanu, D. (2019). CALCITONIN REVISITED IN 2020. Acta Endocrinologica (Buchar), 15(4), 544–548. https://doi.org/10.4183/aeb.2019.544
Erickson, T. A., Shih, Y. P., Fass, J., Jang, M., & Tran, E. (2022). T Cells Engineered to Express Immunoreceptors Targeting the Frequently Expressed Medullary Thyroid Cancer Antigens Calcitonin, CEA, and RET M918T. Thyroid, 32(7), 789–798. https://doi.org/10.1089/thy.2022.0020
Filetti, S., Durante, C., Hartl, D., Leboulleux, S., Locati, L. D., Newbold, K., Papotti, M. G., & Berruti, A. (2019). Thyroid cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of Oncology, 30(12), 1856–1883. https://doi.org/10.1093/annonc/mdz400
Fonseca, L., Freitas, C., Caramelo, A., & Eloy, C. (2021). Expression of PD-L1 in medullary thyroid carcinoma—a new therapeutic target? Endocrinology, Diabetes & Metabolism, 4(3), e00241. https://doi.org/10.1002/edm2.241
Forma, A., Kłodnicka, K., Pająk, W., Flieger, J., Teresińska, B., Januszewski, J., & Baj, J. (2025). Thyroid Cancer: Epidemiology, Classification, Risk Factors, Diagnostic and Prognostic Markers, and Current Treatment Strategies. International Journal of Molecular Sciences, 26(11), 5173. https://doi.org/10.3390/ijms26115173
Fuchs, T. L., Nassour, A. J., Glover, A., Sywak, M. S., Sidhu, S. B., Delbridge, L. W., Clifton-Bligh, R. J., Gild, M. L., Tsang, V., Robinson, B. G., Clarkson, A., Sheen, A., Sioson, L., Chou, A., & Gill, A. J. (2020). A Proposed Grading Scheme for Medullary Thyroid Carcinoma Based on Proliferative Activity (Ki-67 and Mitotic Count) and Coagulative Necrosis. American Journal of Surgical Pathology, 44(10), 1419–1428. https://doi.org/10.1097/PAS.0000000000001505
Gild, M. L., Clifton-Bligh, R. J., Wirth, L. J., & Robinson, B. G. (2023). Medullary Thyroid Cancer: Updates and Challenges. Endocrine Reviews, 44(5), 934–946. https://doi.org/10.1210/endrev/bnad013
Haddad, R. I., Bischoff, L., Applewhite, M., Bernet, V., Blomain, E., Brito, M., Busaidy, N. L., Campbell, M., DeLozier, O., Duh, Q. Y., Ehya, H., Grady, E., Guo, T., Haymart, M., Hunt, J. P., Kandeel, F., Kotwal, A., Lamonica, D. M., Lorch, J., Mandel, S. J., Markovina, S., Mydlarz, W., Nabell, L., Raeburn, C. D., Rezaee, R., Ridge, J. A., Ritter, H., Roth, M. Y., Salgado, S. A., Scheri, R. P., Shah, J. P., Sipos, J. A., Sippel, R., Sturgeon, C., Wirth, L. J., Wong, R. J., Worden, F., Yeh, M. W., Darlow, S., Cassara, C. J., & Sliker, B. (2025). NCCN Guidelines® Insights: Thyroid Carcinoma, Version 1.2025. Journal of the National Comprehensive Cancer Network, 23(7), e250033. https://doi.org/10.6004/jnccn.2025.0033
Ito, Y., Onoda, N., & Okamoto, T. (2020). The revised clinical practice guidelines on the management of thyroid tumors by the Japan Associations of Endocrine Surgeons: Core questions and recommendations for treatments of thyroid cancer. Endocrine Journal, 67(7), 669–717. https://doi.org/10.1507/endocrj.EJ20-0025
Jacob, M., Rowland, D., Lekarev, O., & Ergun-Longmire, B. (2022). Multiple Endocrine Neoplasia in Childhood: An Update on Diagnosis, Screening, Management and Treatment. Endocrines, 3(1), 76–91. https://doi.org/10.3390/endocrines3010007
Jung, K. Y., Kim, S. M., Yoo, W. S., Kim, B. W., Lee, Y. S., Kim, K. W., Lee, K. E., Jeong, J. J., Nam, K. H., Lee, S. H., Hah, J. H., Chung, W. Y., Yi, K. H., Park, D. J., Youn, Y. K., Sung, M. W., Cho, B. Y., Park, C. S., & Park, Y. J. (2016). Postoperative biochemical remission of serum calcitonin is the best predictive factor for recurrence-free survival of medullary thyroid cancer: a large-scale retrospective analysis over 30 years. Clinical Endocrinology, 84(4), 587–597. https://doi.org/10.1111/cen.12852
Kaliszewski, K., Ludwig, M., Ludwig, B., Mikuła, A., Greniuk, M., & Rudnicki, J. (2022). Update on the Diagnosis and Management of Medullary Thyroid Cancer: What Has Changed in Recent Years? Cancers, 14(15), 3643. https://doi.org/10.3390/cancers14153643
Kazakou, P., Simeakis, G., Alevizaki, M., & Saltiki, K. (2021). Medullary thyroid carcinoma (MTC): unusual metastatic sites. Endocrinology, Diabetes & Metabolism Case Reports, 2021(1), 21–0063. https://doi.org/10.1530/EDM-21-0063
Kim, M., & Kim, B. H. (2021). Current Guidelines for Management of Medullary Thyroid Carcinoma. Endocrinology and Metabolism, 36(3), 514–524. https://doi.org/10.3803/EnM.2021.1082
Kurzawinski, T. R., Butler, C. R., & Aziz, T. A. (2025). MEN2: surgical precision in the era of precision medicine. Endocrine-Related Cancer, 32(6), e240251. https://doi.org/10.1530/ERC-24-0251
Lee, C. R., Lee, S., Son, H., Ban, E., Kang, S. W., Lee, J., Jeong, J. J., Nam, K. H., Chung, W. Y., & Park, C. S. (2016). Medullary thyroid carcinoma: a 30-year experience at one institution in Korea. Annals of Surgical Treatment and Research, 91(6), 278–287. https://doi.org/10.4174/astr.2016.91.6.278
Matrone, A., Gambale, C., Prete, A., & Elisei, R. (2022). Sporadic Medullary Thyroid Carcinoma: Towards a Precision Medicine. Frontiers in Endocrinology, 13, 864253. https://doi.org/10.3389/fendo.2022.864253
Moley, J. F. (2010). Medullary thyroid carcinoma: management of lymph node metastases. Journal of the National Comprehensive Cancer Network, 8(5), 549–556. https://doi.org/10.6004/jnccn.2010.0042
Oh, M. Y., Jung, K. Y., Choi, H., Chai, Y. J., Cho, S. W., Kim, S. J., Lee, K. E., Chung, E. J., Park, D. J., Park, Y. J., & Yang, H. K. (2024). Distinct Impacts of Clinicopathological and Mutational Profiles on Long-Term Survival and Recurrence in Medullary Thyroid Carcinoma. Endocrinology and Metabolism, 39(6), 877–890. https://doi.org/10.3803/EnM.2024.2027
Parghane, R. V., Naik, C., Talole, S., Desmukh, A., Chaukar, D., Banerjee, S., & Basu, S. (2020). Clinical utility of Lu-DOTATATE PRRT in somatostatin receptor-positive metastatic medullary carcinoma of thyroid patients with assessment of efficacy, survival analysis, prognostic variables, and toxicity. Head & Neck, 42(3), 401–416. https://doi.org/10.1002/hed.26024
Pelizzo, M. R., Mazza, E. I., Mian, C., & Merante Boschin, I. (2023). Medullary thyroid carcinoma. Expert Review of Anticancer Therapy, 23(9), 943–957. https://doi.org/10.1080/14737140.2023.2247566
Raue, F., & Frank-Raue, K. (2018). Update on Multiple Endocrine Neoplasia Type 2: Focus on Medullary Thyroid Carcinoma. Journal of the Endocrine Society, 2(8), 933–943. https://doi.org/10.1210/js.2018-00178
Ramos Santillan, V., Master, S. R., Menon, G., & Burns, B. (2024). Medullary Thyroid Cancer. In StatPearls. StatPearls Publishing.
Román-González, A., Califano, I., Concepción-Zavaleta, M., Pitoia, F., & Salgado, S. A. (2025). Systemic therapies for medullary thyroid carcinoma: state of the art. Therapeutic Advances in Endocrinology and Metabolism, 16, 20420188251336091. https://doi.org/10.1177/20420188251336091
Wells, S. A., Jr, Asa, S. L., Dralle, H., Elisei, R., Evans, D. B., Gagel, R. F., Lee, N., Machens, A., Moley, J. F., Pacini, F., Raue, F., Frank-Raue, K., Robinson, B., Rosenthal, M. S., Santoro, M., Schlumberger, M., Shah, M., & Waguespack, S. G. (2015). Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid, 25(6), 567–610. https://doi.org/10.1089/thy.2014.0335
Wijewardene, A. A., Chehade, M., Gild, M. L., Clifton-Bligh, R. J., & Bullock, M. (2021). Translational Utility of Liquid Biopsies in Thyroid Cancer Management. Cancers, 13(14), 3443. https://doi.org/10.3390/cancers13143443
Yasir, M., Mulji, N. J., & Kasi, A. (2023). Multiple Endocrine Neoplasias Type 2. In StatPearls. StatPearls Publishing.
Zhang, K., Wang, X., Wei, T., Li, Z., Zhu, J., & Chen, Y. W. (2024). Well-defined survival outcome disparity across age cutoffs at 45 and 60 for medullary thyroid carcinoma: a long-term retrospective cohort study of 3601 patients. Frontiers in Endocrinology, 15, 1393904. https://doi.org/10.3389/fendo.2024.1393904
Zhang, Z., Yu, J., Rainer, E., Hargitai, L., Jiang, Z., Karanikas, G., Traub-Weidinger, T., Crevenna, R., Hacker, M., & Li, S. (2024). The role of [18F]F-DOPA PET/CT in diagnostic and prognostic assessment of medullary thyroid cancer: a 15-year experience with 109 patients. European Thyroid Journal, 13(4), e240089. https://doi.org/10.1530/ETJ-24-0089
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