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Benign Nonfunctioning Thyroid Adenomas Are Characterized by a Defective Targeting to Cell Membrane or a Reduced Expression of the Sodium Iodide Symporter Protein

Dipartimento di Endocrinologia e Metabolismo (M.T., P.A., G.D.M., A.Pe., C.D.C., M.D.S., F.L., A.Pi., L.C., P.Vit.), Ortopedia e Traumatologia, Medicina del Lavoro; Dipartimento di Oncologia (P.Via., A.G.N.), Sezione Anatomia Patologica; and Dipartimento di Clinica Chirurgica (P.M.), Università di Pisa, 56124 Pisa, Italy

Address all correspondence and requests for reprints to: Massimo Tonacchera, Dipartimento di Endocrinologia, Università degli Studi di Pisa, Via Paradisa 2, 56124, Cisanello, Pisa, Italy.

Nodular thyroid disease is the most common endocrine disorder. Nonfunctioning thyroid nodules are identified by their low radioiodide uptake compared with the normal extranodular tissue, which, at thyroid scintiscan, produces the typical picture of a cold thyroid nodule. Previous in vitro studies demonstrated that the majority of nonfunctioning thyroid nodules have a specific defect in iodide transport that accounts for their failure to accumulate radioactive iodide in vivo. A defect in the expression or structure of the sodium iodide symporter (NIS) gene has been hypothesized as a possible cause of the impaired iodide trapping in nonfunctioning thyroid nodules.

We studied 22 patients who were submitted to surgery for a solitary nonfunctioning thyroid nodule that originated in an otherwise normal gland. Thyroid scintigraphy was performed at 1, 2, 3, 4, 6, and 24 h after the oral administration of a tracer dose of ¹³¹I (iodine). All patients showed absence of ¹³¹I uptake in the nodule, with normal uptake in the extranodular tissue and in the contralateral thyroid lobe. Eight patients with toxic adenomas who underwent lobectomy were also included in the study. We first studied the expression of human NIS (hNIS) protein by immunohistochemistry in paraffin-embedded tissue sections using a specific anti-hNIS monoclonal antibody. Subsequently, we searched for somatic mutations of hNIS gene in nonfunctioning thyroid nodules.

The level of hNIS expression was determined in both the nodules and the normal tissue from the same thyroid gland. In all functioning thyroid nodules (toxic adenomas), a high expression of hNIS protein was detected with respect to normal surrounding tissue. Similar to the normal thyroid tissue, follicular cells of toxic thyroid adenomas showed an exclusive expression of hNIS protein at the cell membrane. Fifty-four percent of benign nonfunctioning thyroid nodules overexpressed hNIS protein compared with the normal surrounding tissue, but in these nodules the hNIS protein failed to target the cell membrane, being mostly localized inside the cytoplasm. hNIS protein was not detected by immunohistochemistry in 46% of nonfunctioning nodules, whereas it was expressed in the surrounding unaffected thyroid tissue. Direct sequencing of the hNIS gene in all of the nonfunctioning nodules did not reveal major genetic alterations. A silent polymorphism (GCC/GCG codon 544, exon 13) was found in one nodule.

In conclusion, the results obtained in this study show that two mechanisms contribute to the reduced radioiodide uptake typical of benign nonfunctioning thyroid nodules: 1) reduced expression of the hNIS protein, and 2) defective targeting of hNIS to the cell membrane.

This work was supported by the following grants: Ministero dell’Università e della Ricerca Scientifica (MURST) Programma di Ricerca, Meccanismi molecolari nella patogenesi del nodulo tiroideo; MURST Programma di Ricerca, Strategie per la valutazione degli effetti disruptivi dei contaminanti ambientali sul sistema endocrino degli animali e dell’uomo; and Consiglio Nazionale delle Richerche Progetto Biotecnologie CTB 99.00.224. PF 31, Basi molecolari delle neoplasie benigne e maligne della tiroide.

Abbreviations: hNIS, Human NIS; NIS, sodium iodide symporter.

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