Radioiodine-Refractory Differentiated Thyroid Carcinoma in Children and Adolescents: A Retrospective Study
https://doi.org/10.14341/probl13649
Abstract
BACKGROUND: Differentiated thyroid carcinoma (DTC) in children is a rare malignancy characterized by a high propensity for regional and distant metastases yet generally associated with a favorable long-term prognosis. Radioiodine-refractory (RAIR) disease represents a distinct clinical challenge, accounting for approximately 10–30% of pediatric DTC cases, and warrants comprehensive investigation of its clinical course, prognostic factors, and therapeutic options. This study aimed to perform an integrated assessment of treatment outcomes in children undergoing combined therapy for DTC (surgery and radioiodine therapy, RAI), with a particular focus on advanced and RAIR disease.
MATERIALS AND METHODS: We retrospectively analyzed medical records of 278 patients aged 5–18 years who underwent primary surgical treatment between 2008 and 2022, followed by one or more courses of RAI at the Endocrinology Research Centre (Moscow, Russia) from December 2015 to March 2024. The study included patients with advanced disease (high risk of recurrence at diagnosis) fulfilling at least one RAIR criterion, with a median follow-up of 48.0 months [21.5; 62.0].
RESULTS: Among 278 patients, 39 (14%) were diagnosed with advanced disease. Of these, 4 achieved remissions, 29 had stable disease, and 6 experienced biochemical and/or structural progression. Progression-free survival in the RAIR cohort was 85%, while the 5-year overall survival reached 100%.
CONCLUSION: Based on study findings, we propose a novel classification system integrating both the baseline ability of metastases to accumulate ¹³¹I and the dynamic response to RAI (progression vs. stabilization). This framework is designed to optimize treatment and follow-up algorithms. The management of RAIR pediatric DTC should remain balanced: avoiding overtreatment in stable disease, while ensuring timely initiation of modern systemic therapies in patients with risk factors for progression.
About the Authors
K. Yu. SlaschukRussian Federation
Konstantin Yu. Slashchuk - MD, PhD.
Moscow
Competing Interests:
none
M. V. Reinberg
Russian Federation
Maria V. Reinberg
1 Dm. Ulyanova street, 117036 Moscow
Competing Interests:
none
P. O. Rumyantsev
Russian Federation
Pavel O. Rumyantsev – PhD, MD.
Moscow
Competing Interests:
none
P. A. Nikiforovich
Russian Federation
Petr A. Nikiforovich - MD.
Moscow
Competing Interests:
none
A. P. Konokikhina
Russian Federation
Anastasia P. Kononykhina – MD.
Moscow
Competing Interests:
none
A. P. Pershina-Milyutina
Russian Federation
Anastasiia P. Pershina-Miliutina – MD.
Moscow
Competing Interests:
none
A. V. Aredov
Russian Federation
Aleksey V. Aredov
Moscow
Competing Interests:
none
M. S. Sheremeta
Russian Federation
Marina S. Sheremeta – MD, PhD.
Moscow
Competing Interests:
none
M. V. Degtyarev
Russian Federation
Mikhail V. Degtyarev – MD.
Moscow
Competing Interests:
none
A. A. Trukhin
Russian Federation
Alexey A. Trukhin - PhD.
Moscow
Competing Interests:
none
O. A. Chikulaeva
Russian Federation
Olga A. Chikulaeva - .MD, PhD
Moscow
Competing Interests:
none
E. V. Nagaeva
Russian Federation
Elena V. Nagaeva - MD, PhD.
Moscow
Competing Interests:
none
D. N. Brovin
Russian Federation
Dmitriy N. Brovin - MD, PhD.
Moscow
Competing Interests:
none
R. A. Chernikov
Russian Federation
Roman A. Chernikov - MD, PhD, surgeon.
Saint Petersburg
Competing Interests:
none
O. B. Bezlepkina
Russian Federation
Olga B. Bezlepkina - .MD, PhD, Professor.
Moscow
Competing Interests:
none
V. A. Peterkova
Russian Federation
Valentina A. Peterkova - PhD, professor, academician of RAS.
Moscow
Competing Interests:
none
N. G. Mokrysheva
Russian Federation
Natalia G. Mokrysheva - .MD, PhD, Professor.
Moscow
Competing Interests:
none
I. I. Dedov
Russian Federation
Ivan I. Dedov - MD, PhD, Professor, Academician of the RAS.
Moscow
Competing Interests:
none
References
1. Detskaya onkologiya. Nacional'noe rukovodstvo / pod red. MD Alieva, VG Polyakova, GL Mentkevicha, SA Mayakovoj. M.: Izdatel'skaya gruppa RONC. Prakticheskaya medicina, 2012 (In Russ.)]
2. Zlokachestvennye novoobrazovaniya v Rossii v 2021 godu (zabolevaemost' i smertnost') / pod red. AD Kaprina, VV Starinskogo, AO Shahzadovoj. Moskva: MNIOI im. P.A. Gercena − filial FGBU «NMIC radiologii» Minzdrava Rossii, 2022 (In Russ.)
3. Waguespack S, Wells S, Ross J, Bleyer A. Thyroid Cancer. National Cancer Institute, Bethesda, MD. 2006
4. Nikiforov YE, Nikiforova MN. Molecular genetics and diagnosis of thyroid cancer. Nature Reviews Endocrinology. 2011;7:569–580
5. Alzahrani AS, Murugan AK, Qasem E, Alswailem M, Al-Hindi H, Shi Y. Single Point Mutations in Pediatric Differentiated Thyroid Cancer. Thyroid. 2017 Feb;27(2):189-196. doi: https://doi.org/10.1089/thy.2016.0339
6. Prasad, M.L., Vyas, M., Horne, M.J., et al. NTRK fusion oncogenes in pediatric papillary thyroid carcinoma in northeast United States. Cancer. 2016;122:1097-1107. doi: https://doi.org/10.1002/cncr.29887
7. Vassilopoulou-Sellin R, Goepfert H, Raney B, Schultz PN. Differentiated thyroid cancer in children and adolescents: clinical outcome and mortality after long-term follow-up. Head Neck. 1998;20(6):549-55. doi: https://doi.org/10.1002/(sici)1097-0347(199809)20:6<549::aid-hed10>3.0.co;2-r
8. Zimmerman D, Hay ID, Gough IR, Goellner JR, Ryan JJ, Grant CS, McConahey WM. Papillary thyroid carcinoma in children and adults: long-term follow-up of 1039 patients conservatively treated at one institution during three decades. Surgery. 1988;104(6):1157-66
9. Brink JS, van Heerden JA, McIver B, Salomao DR, Farley DR, Grant CS, Thompson GB, Zimmerman D, Hay ID. Papillary thyroid cancer with pulmonary metastases in children: long-term prognosis. Surgery. 2000;128(6):881-6; discussion 886-7. doi: https://doi.org/10.1067/msy.2000.109728
10. Prasad PK, Mahajan P, Hawkins DS, Mostoufi-Moab S, Venkatramani R. Management of pediatric differentiated thyroid cancer: An overview for the pediatric oncologist. Pediatr Blood Cancer. 2020;67(6):e28141. doi: https://doi.org/10.1002/pbc.28141
11. Stosic A, Fuligni F, Anderson ND, et al. Diverse oncogenic fusions and distinct gene expression patterns define the genomic landscape of pediatric papillary thyroid carcinoma. Cancer Research. 2021;81(22):5625e37
12. Penko K, Livezey J, Fenton C, et al. BRAF mutations are uncommon in papillary thyroid cancer of young patients. Thyroid. 2005;15:320–325
13. Rosenbaum E, Hosler G, Zahurak M, Cohen Y, Sidransky D, Westra WH. Mutational activation of BRAF is not a major event in sporadic childhood papillary thyroid carcinoma. Mod Pathol. 2005;18(7):898-902. doi: https://doi.org/10.1038/modpathol.3800252
14. Van Nostrand D. Radioiodine Refractory Differentiated Thyroid Cancer: Time to Update the Classifications. Thyroid. 2018;28(9):1083-1093. doi: https://doi.org/10.1089/thy.2018.0048
15. Tian T., Shuhui H., Hongyuan D., Mengfang Q., Bin L., Rui H., Radioactive Iodine-Refractory Pulmonary Metastases of Papillary Thyroid Cancer in Children, Adolescents, and Young Adults. // The Journal of Clinical Endocrinology & Metabolism. 2023. Vol. 108, Iss. 2. P. 306–314 doi:10.1210/clinem/dgac600
16. de Sousa MSA, Nunes IN, Christiano YP, Sisdelli L, Cerutti JM. Genetic alterations landscape in pediatric thyroid tumours and/or differentiated thyroid cancer: Systematic review. Review Endocrinology Metabolism Disorders. 2023
17. Christine EC,, et al. Pediatric thyroid cancer: Recent developments. Research Clinical Endocrinology & Metabolism. 2022;37(1):101715
18. Gallant J.N., Chen S.C., Ortega C.A., et al. Evaluation of the molecular landscape of pediatric thyroid nodules and use of a multigene genomic classifier in children. // JAMA Oncol. 2022;8(9):1323-1327. doi:10.1001/jamaoncol.2022.1655
19. Hess JR, Newbern DK, Beebe KL, et al. High prevalence of gene fusions and copy number alterations in pediatric radiation therapy-induced papillary and follicular thyroid carcinomas. Thyroid 2022;32(4):411e20
20. Wasserman JD, Sabbaghian N, Fahiminiya S, et al. DICER1 mutations are frequent in adolescent-onset papillary thyroid carcinoma. Journal of Clinical Endocrinology and Metabolism. 2018;103(5):2009e15
21. Chernock RD, Rivera B, Borrelli N, et al. Poorly differentiated thyroid carcinoma of childhood and adolescence: a distinct entity characterized by DICER1 mutations. Modern Pathology. 2020;33(7):1264e74
22. Marcia SB, Christopher N, Barbara J, Rossella E, Salvatore S, Lars B. Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer: The phase III DECISION trial. Lancet. 2014;26(384(9940):319-28
23. Mahajan P, Dawrant J, Kheradpour A, et al. Response to Lenvatinib in Children with Papillary Thyroid Carcinoma. Thyroid. 2018;28(11):1450-1454
24. Dadu R, Shah K, Busaidy NL, et al. Efficacy and tolerability of vemurafenib in patients with BRAF (V600E)-positive papillary thyroid cancer: M.D. Anderson Cancer Center off-label experience. Journal of Clinical Endocrinology and Metabolism. 2015;100(1):77
25. Ho AL, Grewal RK, Leboeuf R., et al. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. New English Journal of Medicine. 2013;368(7):623-632
26. Steven GW, Alexander D, Jessica JL, et al. Efficacy and safety of larotrectinib in patients with TRK fusion-positive thyroid carcinoma. European Journal of Endocrinology. 2022;186(Iss.6):631–643
27. Desai AV, Robinson GW, Gauvain K, et al. Entrectinib in children and young adults with solid or primary CNS tumors harboring NTRK, ROS1, or ALK aberrations (STARTRK-NG). Neuro-Oncology. 2022;24(10):1776-1789
28. Wirth LJ, Sherman E, Robinson B, et al. Efficacy of selpercatinib in RET-altered thyroid cancers. The New England Journal of Medicine. 2020;383(9):825e35
29. Subbiah V, Hu MI, Mansfield AS, et al. Pralsetinib in Patients with Advanced/Metastatic Rearranged During Transfection (RET)Altered Thyroid Cancer: Updated Efficacy and Safety Data from the ARROW Study [published correction appears in Thyroid. 2024 Apr 16. doi: 10.1089/thy.2023.0363.correx.]. Thyroid. 2024;34(1):26-40. doi: https://doi.org/10.1089/thy.2023.0363
30. Kieran MW, Geoerger B, Dunkel IJ, Broniscer A, Hargrave D, Hingorani P, Aerts I, et al. A Phase I and Pharmacokinetic Study of Oral Dabrafenib in Children and Adolescent Patients with Recurrent or Refractory BRAF V600 MutationPositive Solid Tumors. Clin Cancer Res. 2019;25(24):7294-7302. doi: https://doi.org/10.1158/1078-0432.CCR-17-3572
31. Tuttle M, Morris LF, Haugen B, Shah J, Sosa JA, Rohren E, Subramaniam RM, Hunt JL & Perrier ND 2017b Thyroid-differentiated and anaplastic carcinoma (Chapter 73). In AJCC Cancer Staging Manual, 8th edition
32. Kakudo K, Bychkov A, Bai Y, Li Y, Liu Z, Jung CK. The new 4th edition World Health Organization classification for thyroid tumors, Asian perspectives. Pathol Int. 2018;68:641-664. doi: https://doi.org/10.1111/pin.12737
33. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). European journal of cancer (Oxford, England: 1990). 2009;45(2):228–247. doi: https://doi.org/10.1016/j.ejca.2008.10.026
34. Tamer F, Güven M, Oral A, Yazici B, Akgün A. Which factors affect treatment success/prognosis in thyroid cancers with pulmonary metastases and what is/how should be the effective cumulative cure/dose as a current approach; a retrospective study. Ann Nucl Med. Published online May 19, 2025. doi: https://doi.org/10.1007/s12149-025-02060-5
35. Durante C, Haddy N, Baudin E, et al. Long-term outcome of 444 patients with distant metastases from papillary and follicular thyroid carcinoma: benefits and limits of radioiodine therapy. J Clin Endocrinol Metab. 2006;91:2892–2899. doi: https://doi.org/10.1210/jc.2005-2838
36. Marotta V, Rocco D, Crocco A, et al. Survival Predictors of Radioiodine-refractory Differentiated Thyroid Cancer Treated With Lenvatinib in Real Life. J Clin Endocrinol Metab. 2024;109(10):2541-2552. doi: https://doi.org/10.1210/clinem/dgae181
37. Nakanishi K, Kikumori T, Miyajima N, et al. Impact of Patient Age and Histological Type on Radioactive Iodine Avidity of Recurrent Lesions of Differentiated Thyroid Carcinoma. Clin Nucl Med. 2018;43(7):482-485. doi: https://doi.org/10.1097/RLU.0000000000002078
38. Lang BH, Wong KP, Cheung CY, Wan KY, Lo CY. Evaluating the prognostic factors associated with cancer-specific survival of differentiated thyroid carcinoma presenting with distant metastasis. Ann Surg Oncol. 2013;20(4):1329-1335. doi: https://doi.org/10.1245/s10434-012-2711-x
39. Tsai HC, Ho KC, Chen SH, Tseng JR, Yang LY, Lin KJ, Cheng JC, Liou MJ. Feasibility of Recombinant Human TSH as a Preparation for Radioiodine Therapy in Patients with Distant Metastases from Papillary Thyroid Cancer: Comparison of Long-Term Survival Outcomes with Thyroid Hormone Withdrawal. Diagnostics. 2022;12(1):221. doi: https://doi.org/10.3390/diagnostics12010221
40. Zhuanzhuan Mu, Xin Zhang, Di Sun, Yuqing Sun, Cong Shi, Gaoda Ju, et al. Characterizing Genetic Alterations Related to Radioiodine Avidity in Metastatic Thyroid Cancer, The Journal of Clinical Endocrinology & Metabolism. 2024;109(5):1231–1240. doi: https://doi.org/10.1210/clinem/dgad697
41. Seo GH, Kong KA, Kim BS, et al. Radioactive iodine treatment for children and young adults with thyroid cancer in South Korea: a population-based study. The Journal of Clinical Endocrinology & Metabolism. 2021;106(7):e2580e8
42. Pasqual E, Schonfeld S, Morton LM, et al. Association between radioactive iodine treatment for pediatric and young adulthood differentiated thyroid cancer and risk of second primary malignancies. The Journal of Clinical Oncology. 2022;40(13):1439e49
43. Sugino K, Nagahama M, Kitagawa W, et al. Distant metastasis in pediatric and adolescent differentiated thyroid cancer: clinical outcomes and risk factor Analyses. The Journal of Clinical Endocrinology & Metabolism. 2020;105:11
44. Klein HMS, Nies M, Bocca G, et al. Pediatric differentiated thyroid carcinoma in The Netherlands: a nationwide follow-up study. The Journal of Clinical Endocrinology & Metabolism. 2016;101(5):2031e9
45. Hay ID, Johnson TR, Kaggal S, et al. Papillary thyroid carcinoma (PTC) in children and adults: comparison of initial presentation and longterm postoperative outcome in 4432 patients consecutively treated at the mayo clinic during eight decades (1936-2015). World Journal of Surgery. 2018;42(2):329e42
46. Shi C, Sun D, Sun YQ, et al. Less is more: once vs. multiple radioactive iodine (RAI) therapy in patients with RAI-avid pulmonary micrometastatic differentiated thyroid cancer. Eur J Nucl Med Mol Imaging. Published online May 26, 2025. doi: https://doi.org/10.1007/s00259-025-07339-3
47. Seejore K, Mulla O, Gerrard GE, et al. Outcomes of 756 patients with differentiated thyroid cancer and excellent response to treatment: An evidence-based paradigm for long-term surveillance strategies. Clin Endocrinol (Oxf). 2022;96(3):395-401. doi: https://doi.org/10.1111/cen.14549
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1. Figure 1. Graph comparing the duration of follow-up for patients in the groups without and with disease progression. | |
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2. Figure 2. Classification of high-risk patients based on dynamic stratification after combination therapy. | |
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For citations:
Slaschuk K.Yu., Reinberg M.V., Rumyantsev P.O., Nikiforovich P.A., Konokikhina A.P., Pershina-Milyutina A.P., Aredov A.V., Sheremeta M.S., Degtyarev M.V., Trukhin A.A., Chikulaeva O.A., Nagaeva E.V., Brovin D.N., Chernikov R.A., Bezlepkina O.B., Peterkova V.A., Mokrysheva N.G., Dedov I.I. Radioiodine-Refractory Differentiated Thyroid Carcinoma in Children and Adolescents: A Retrospective Study. Problems of Endocrinology. 2026;72(3):66-79. (In Russ.) https://doi.org/10.14341/probl13649
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