Abstract
Objective
This study aimed to investigate immunohistochemical staining of sodium iodide symporter (NIS) and its effect on response to I-131 therapy in differentiated thyroid carcinoma patients.
Methods
We evaluated NIS expression, the intracellular distribution of NIS, iodine-131 uptake in residual tissues on post-ablation I-131 whole body scan, and the ablation status after 100 mCi I-131 therapy. We also investigated NIS expression and localization in tumoral paraffin-embedded tissues.
Results
In this retrospective study, 35 patients (mean age 44.17 ± 12.9 years, 27 female, 8 male) were studied. Twenty-one of these patients responded to radioiodine therapy, and 14 did not. NIS expression and iodine-131 uptake in residual tissues post-ablation I-131 whole body scan were not statistically significant. When we compared the patients who responded to radioiodine therapy and the poor responder group, NIS expression and iodine-131 uptake in residual tissues did not demonstrate statistically significant difference [(p = 0.308) (p = 0.985) respectively]. 47.6% of the patients in the successful ablation group and 85.7% in the unsuccessful ablation group had intracellular NIS immunostaining. The difference was not statistically significant (p = 0.139). 52.4% of the patients in the successful ablation group and 7% in the unsuccessful ablation group had NIS immunostaining at the basolateral membrane. The difference was statistically significant (p < 0.05).
Conclusions
In conclusion, we did not find any significant difference between successful and unsuccessful ablation groups in terms of NIS expression; however, we concluded that the intracellular (cytoplasmic) localization of NIS is one of the leading causes of ablation failure regardless of NIS expression in DTC patients.
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References
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.
Weetman AP, Jameson JL. In: Braunwald E, Fauci AS, Kasper DL, Hauser SL, Longo DL, Jameson JL, editors. Disorders of the thyroid gland Harrison’s Principles of Internal Medicine. 15th ed. New York: The McGraw Hill Companies; 2001. p. 2060–84.
Hussain HK, Britton KE, Grossman AB, Reznek RH. In: Husband JE, Reznek RH, editors. Thyroid cancer. Imaging in Oncology. 2nd ed. London: Taylor and Francis; 2004. p. 669–709.
Amdur RJ, Mazzaferri EL. İncidence, prevalence, recurrence, and mortality of differentiated thyroid cancer. In: Amdur RJ, Mazzaferri EL, editors. Essentials of Thyroid Cancer Management. New York: Springer Science; 2005. p. 123–30.
Spitzweg C, Morris JC. The sodium iodide symporter: its pathophysiological and therapeutic implications. Clin Endocrinol. 2002;57:559–74.
Mazzaferri EL, Amdur RJ. Thyroid and parathyroid physiology. In: Amdur RJ, Mazzaferri EL, editors. Essentials of Thyroid Cancer Management. New York: Springer Science; 2005. p. 7–17.
Caillou B, Troalen F, Baudin E, Talbot M, Filetti S, Schlumberger M, et al. Na+/I- symporter distribution in human thyroid tissues: an immunohistochemical study. J Clin Endocrinol Metab. 1998;83:4102–6.
Peyrottes I, Navarro V, Ondo-Mendez A, Marcellin D, Bellanger L, Marsault R, et al. Immunoanalysis indicates that the sodium iodide symporter is not overexpressed in intracellular compartments in thyroid and breast cancers. Eur J Endocrinol. 2009;160:215–25.
Shen DH, Kloos RT, Mazzaferri EL, Jhiang SM. Sodium iodide symporter in health and disease. Thyroid. 2001;11:415–25.
Filetti S, Bidart JM, Arturi F, Caillou B, Russo D, Schlumberger M. Sodium/iodide symporter: a key transport system in thyroid cancer cell metabolism. Eur J Endocrinol. 1999;141:443–57.
Jhiang SM, Sipos JA. Na+/I- symporter expression, function, and regulation in non-thyroidal tissues and impact on thyroid cancer therapy. Endocr Relat Cancer. 2021;28(10):T167–77.
Mazzaferri EL, Kloos RT. Current approaches to primary therapy for papillary and follicular thyroid cancer. J Clin Endocrinol Metab. 2001;86(4):1447–63.
Kogai T, Brent GA. The sodium iodide symporter (NIS): regulation and approaches to targetting for cancer therapeutics. Pharmacol Ther. 2012;135:355–70.
Cai X, Wang R, Tan J, Meng Z, Li N. Mechanisms of regulating NIS transport to the cell membrane and redifferentiation therapy in thyroid cancer. Clin Transl Oncol. 2021;23(12):2403–14.
Min JJ, Chung JK, Lee YJ, Jeong JM, Lee DS, Jang JJ, et al. Relationship between expression of the sodium/iodide symporter and 131I uptake in recurrent lesions of differentiated thyroid carcinoma. Eur J Nucl Med. 2001;28:639–45.
Morari EC, Marcello MA, Guilhen ACT, Cunha LL, Latuff P, Soares FA, et al. Use of sodium iodide symporter expression in differentiated thyroid carcinomas. Clin Endocrinol. 2011;75:247–54.
Ward LS, Santarosa PL, Granja F, Assumpção LVM, Savoldi M, Goldman GH. Low expression of sodium iodide symporter identifies aggressive thyroid tumors. Cancer Lett. 2003;200:85–91.
Castro MR, Bergert ER, Goellner JR, Hay ID, Morris JC. Immunohistochemical analysis of sodium iodide symporter expression in metastatic differentiated thyroid cancer: correlation with radioiodine uptake. J Clin Endocrinol Metab. 2001;86(11):5627–32.
Buffet C, Wassermann J, Hecht F, Leenhardt L, Dupuy C, Groussin L, et al. Redifferentiation of radioiodine-refractory thyroid cancers. Endocr Relat Cancer. 2020;27(5):R113–32.
Sodré AKMB, Rubio IGS, Galrão ALR, Knobel M, Tomimori EK, Alves VAF, et al. Association of low sodium-iodide symporter messenger ribonucleic acid expression in malignant thyroid nodules with increased intracellular protein staining. J Clin Endocrinol Metab. 2008;93:4141–5.
Dohan O, Carrasco N. Advances in Na+/I− symporter (NIS) research in the thyroid and beyond. Mol Cell Endocrinol. 2003;213:59–70.
Dohán O, Baloch Z, Bánrévi Z, Livolsi V, Carrasco N. Predominant intracellular overexpression of the Na+/I- Symporter (NIS) in a large sampling of thyroid cancer cases. J Clin Endocrinol Metab. 2001;86(6):2697–700.
Kogai T, Endo T, Saito T, Miyazakia A, Kawaguchia A, Onaya T. Regulation by thyroid-stimulating hormone of sodium/iodide symporter gene expression and protein levels in FRTL-5 cells. Endocrinology. 1997;138:2227–32.
Riedel C, Levy O, Carrasco N. Post-transcriptional regulation of the sodium/iodide symporter by thyrotropin. J Biol Chem. 2001;276(24):21458–63.
Anekpuritanang T, Uataya M, Claimon A, Laokulrath N, Pongsapich W, Pithuksurachai P. The association between radioiodine refractory in papillary thyroid carcinoma, sodium/iodide symporter expression, and BRAFV600E mutation. Onco Targets Ther. 2021;14:3959–69.
Doi SA, Woodhouse NJ. Ablation of the thyroid remnant and 131I dose in differentiated thyroid cancer. Clin Endocrinol (Oxf). 2000;52(6):765–73.
Smith VE, Sharma N, Watkins RJ, Read ML, Ryan GA, Kwan PP, et al. Manipulation of PBF/PTTG1IP phosphorylation status; a potential new therapeutic strategy for improving radioiodine uptake in thyroid and other tumors. J Clin Endocrinol Metab. 2013;98(7):2876–86.
Zhao Z, Huang R, Cai H, Liu B, Zeng Y, Kuang A. Improved radioiodine-131 imaging of prostatic carcinoma using the sodium iodide symporter gene under control of the survivin promoter. Int J Clin Exp Pathol. 2018;11(8):4067–72.
Son SH, Gangadaran P, Ahn BC. A novel strategy of transferring NIS protein to cells using extracellular vesicles leads to increase in iodine uptake and cytotoxicity. Int J Nanomedicine. 2019;14:1779–87.
Schmohl KA, Dolp P, Schug C, Knoop K, Klutz K, Schwenk N, et al. Reintroducing the sodium-iodide symporter to anaplastic thyroid carcinoma. Thyroid. 2017;27(12):1534–43.
Spitzweg C, Nelson PJ, Wagner E, Bartenstein P, Weber WA, Schwaiger M, et al. The sodium iodide symporter (NIS) novel applications for radionuclide imaging and treatment. Endocr Relat Cancer. 2021;28:193–213.
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mutevelızade, G., Kocer, N.E. & Reyhan, M. The effect of sodium iodide symporter protein on ablation success in patients with differentiated thyroid cancer. Ann Nucl Med 36, 1050–1058 (2022). https://doi.org/10.1007/s12149-022-01794-w
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DOI: https://doi.org/10.1007/s12149-022-01794-w