Expression of the sodium iodide symporter in differentiated thyroid cancer^[*]

Summary

Aim: Molecular analysis of the expression of the sodium iodide symporter (NIS) in 32 patients with differentiated thyroid cancer (DTC) and correlation with scintigraphic findings (¹³¹I,¹²³I) in 19 (59.4%) of them. Patients, methods: NIS expression of 27 primary tumours, 13 lymphnodes and 18 distant metastases was determined by immunostaining using a murine monoclonal anti-NIS-antibody. NIS expression and radionuclide uptake of metastases were analysed by a semiquantitative visual score. Patients were divided into two subgroups: Group 1 (n = 8 patients): indirect correlation of radioiodine uptake (RIU) of subsequent metastases with NIS expression of 7 primary tumours and 3 metastases; Group 2 (n=11 patients): direct correlation of radionuclide uptake with NIS expression of 19 metastases which were excised after imaging. Results: 49 of 58 specimens (84.5%) were NIS-positive. A preserved NIS-expression was found in 12 primary tumours and 8 of 10 (80%) synchrone and 6 of 7 (85.7%) metachrone metastases. Group 1 revealed a 100% positive predictive value (PPV) of a preserved NIS expression in the primary tumour regarding radioiodine uptake in metastases while a lack of NIS expression in the primary tumor did not reliable predict a loss of the metastases’ ability to concentrate radioiodine. In group 2, only 11 of 19 (57.9%) specimens showed a concordant NIS expression and RIU whereas in the remaining 8 cases without visible RIU NIS expression was still present. Conclusions: NIS expression of the primary tumour and metastases in DTC is usually well preserved. We found a positive correlation between NIS expression of the primary and metastatic tissue but could not identify such well correspondence between NIS expression and the RIU of subsequent metastases.

Zusammenfassung

Ziel: Molekulare Untersuchungen der Expression des Natriumiodid- Symporters (NIS) bei 32 Patienten mit differenziertem Schilddrüsenkarzinom und Korrelation mit szintigraphischen Befunden (¹²³I, ¹³¹I) bei 19 (59,4%) dieser Patienten. Patienten, Methoden: 27 Primärtumoren, 13 Lymphknoten- sowie 18 Organmetastasen wurden mittels eines spezifischen murinen monoklonalen anti-NIS-Antikörpers hinsichtlich ihrer NIS-Expression immunhistochemisch analysiert. Sowohl die NIS-Expression als auch der jeweilige Radionuklid-Uptake wurden anhand eines visuellen Scores semiquantitativ evaluiert. Das Patientenkollektiv wurde in zwei Gruppen unterteilt: Gruppe 1 (n = 8 Patienten): indirekte Korrelation des RIU verbliebener, immunhistochemisch nicht untersuchter Metastasen mit der NIS-Expression von 7 Primärtumoren und 3 entnommenen Metastasen; Gruppe 2 (n = 11 Patienten): Direkte Korrelation des präoperativen Uptakes von Radioiod mit der NIS-Expression von 19 entnommenen Metastasen. Ergebnisse: 49 der 58 (84,5%) Gewebeproben waren NIS-positiv. Bei 12 Primärtumoren mit NIS-Expression wiesen 8 von 10 (80%) synchronen sowie 6 von 7 (85,7%) metachronen Metastasen eine NIS-Positivität auf. In Gruppe 1 lag der positiv prädiktive Wert einer NIS-Expression im Primärtumor in Bezug auf den RIU der Metastasen bei 100%. Eine fehlende NIS-Expression im Primärtumor sagte einen Verlust an Radioiodspeicherung in Metastasen allerdings nicht zuverlässig voraus. In Gruppe 2 hatten lediglich 11 von 19 (57,9%) Metastasen eine konkordante NIS-Expression bei nachweisbarem präoperativen RIU, bei 8 NIS-positiven Präparaten blieb der RIU negativ. Schlussfolgerung: Die NIS-Expression bei differenzierten Schilddrüsenkarzinomen und ihren Metastasen ist in der Regel erhalten. Trotz einer guten Korrelation zwischen NIS-Expression des Primärtumors und seiner Metastasen, ist im Einzelfall eine zuverlässige Aussage über den RIU von Metastasen durch den Nachweis der NIS-Expression nicht möglich.

Keywords

Sodium iodide symporter - differentiated thyroid cancer - immunohistochemistry - radioiodine uptake

Schlüsselwörter

Natriumiodid-Symporter - differenziertes Schilddrüsenkarzinom - Immunhistochemie - Radioiod-Uptake

^* Diese Arbeit ist Herrn Prof. Dr. med. W. Becker gewidmet, der tragischerweise am 18. Mai 2002 verstarb. Ohne seine inspirierenden Gedanken wäre diese Arbeit nie entstanden.

• References

• 1 Arturi F, Russo D, Schlumberger M. et al. Iodide symporter gene expression in human thyroid tumors. J Clin Endocrinol Metab 1998; 83: 2493-6.
• 2 Arturi F, Russo D, Giuffrida D. et al. Sodium-iodide symporter (NIS) gene expression in lymphnode metastases of papillary thyroid carcinomas. Eur J Endocrinol 2000; 134: 623-7.
• 3 Caillou B, Troalen F, Baudin E. et al. Na+/I- symporter distribution in human thyroid tissues : An immunohistochemical study. J Clin Endocrinol Metab 1998; 83: 4102-6.
• 4 Castro MR, Bergert ER, Beito TG. et al. Monoclonal antibodies against the human sodium iodide symporter: utility for immunocytochemistry of thyroid cancer. J Endocrinol 1999; a 163: 495-504.
• 5 Castro MR, Bergert ER, Beito TG. et al. Development of monoclonal antibodies against the human sodium iodide symporter: immunohistochemical characterization of this protein in thyroid cells. J Clin Endocrinol Metab 1999; b 84: 2957-62.
• 6 Castro MR, Bergert ER, Goellner JR. et al. Immunohistochemical analysis of sodium iodide symporter expression in metastatic differentiated thyroid cancer: correlation with radioiodine uptake. J Clin Endocrinol Metab 2001; 86: 5627-32.
• 7 Dai G, Levy O, Carrasco N. Cloning and characterization of the thyroid iodide transporter. Nature 1996; 379: 458-60.
• 8 Dietlein M, Dressler J, Eschner W. et al. Procedure guideline for iodine-131 whole-body scintigraphy for differentiated thyroid cancer (version 2). Nuklearmedizin 2003; 42: 123-5.
• 9 Dietlein M, Dressler J, Farahati J. et al. Procedure guidelines for radioiodine therapy of differentiated thyroid cancer (version 2). Nuklearmedizin 2004; 115-20.
• 10 Dietlein M, Dressler J, Grünwald F. et al. Guideline for in vivo- and in vitro procedures for thyroid diseases (version 2). Nuklearmedizin 2003; 42: 109-15.
• 11 Dohán O, Baloch Z, Banrevi Z. et al. Rapid communication: Predominant intracellular overexpression of the Na+/I- Symporter (NIS) in a large sampling of thyroid cancer cases. J Clin Endocrinol Metab 2001; 86: 2697-700.
• 12 Faggiano A, Coulot J, Bellon N. et al. Age-dependent variation of follicular size and expression of iodine transporters in human thyroid tissue. J Nucl Med 2004; 45: 232-7.
• 13 Hedinger C, Williams ED, Sobin LH. The WHO histological classification of thyroid tumors: a commentary on the second edition. Cancer 1989; 63: 908-11.
• 14 Hermanek P, Hutter RVP, Sobin LH. et al. (eds). TNM Atlas: illustrated guide to the TNM/pTNM classification of malignant tumours/UICC, International Union against Cancer. 4th ed. Berlin, Heidelberg, New York: Springer; 1997
• 15 Koch W, Knesewitsch P, Tatsch K. et al. Stunning effects in radioiodine therapy of thyroid carcinoma: existence, clinical effects and ways out. Nuklearmedizin 2003; 42: 10-4.
• 16 Lazar V, Bidart JM, Caillou B. et al. Expression of the Na+/I- symporter gene in human thyroid tumors: a comparison study with other thyroid-specific genes. J Clin Endocrinol Metab 1999; 84: 3228-34.
• 17 Leitha Th, Staudenherz A. Frequency of diagnostic dilemmas in ¹³¹I whole body scanning. Nuklearmedizin 2003; 42: 55-62.
• 18 Lin JD, Chan EC, Chao TC. et al. Expression of sodium iodide symporter in metastatic and follicular human thyroid tissues. Ann Oncol 2000; 11: 625-9.
• 19 Min JJ, Chung JK, Lee YJ. 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; a 28: 639-45.
• 20 Min JJ, Chung JK, Lee YJ. et al. Relationship between differentiation and expression of sodium/iodide symporter or glucose transporter-1 in differentiated thyroid carcinoma. J Nucl Med 2001; b 42 (suppl): 133P.
• 21 Park HJ, Kim JY, Park KY. et al. Expressions of human sodium iodide symporter mRNA in primary and metastatic papillary thyroid carcinomas. Thyroid 2000; 10: 211-7.
• 22 Petrich T, Knapp WH, Pötter E. Functional activity of human sodium/iodide symporter in tumor cell lines. Nuklearmedizin 2003; 42: 15-8.
• 23 Ringel MD, Anderson J, Souza SL. et al. Expression of the sodium iodide symporter and thyroglobulin genes are reduced in papillary thyroid cancer. Mod Pathol 2001; 14: 289-96.
• 24 Schlumberger M, Challeton C, De Vathaire F. et al. Radioactive iodine treatment and external radiotherapy for lung and bone metastases from thyroid carcinoma. J Nucl Med 1996; 37: 598-605.
• 25 Smanik PA, Liu Q, Furminger TL. et al. Cloning of the human sodium iodide symporter. Biochem Biophys Res Commun 1996; 226: 339-45.
• 26 Wang CY, Zhong WB, Chang TC. et al. Lovastatin, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, induces apoptosis and differentiation in human anaplastic thyroid carcinoma cells. J Clin Endocrinol Metab 2003; 88: 3021-6.
• 27 Waxman A, Ramanna L, Chapman N. et al. The significance of 131-I scan dose in patients with thyroid cancer: Determination of ablation: Concise Communication. J Nucl Med 1981; 22: 861-5.