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Over 50% of newly diagnosed thyroid nodules are either cytologically benign or presumed to be benign on the basis of low-suspicion sonographic findings. The strategies used for their long-term surveillance are based mainly on the estimated residual risk of malignancy calculated with various ultrasonographic classification systems (e.g., Thyroid Image Reporting and Data Systems [TIRADS]). We conducted a longitudinal study to evaluate the temporal stability of the initial risk estimates computed with five widely used systems and to determine whether risk class increases during follow-up are indeed predictive of malignancy.We re-analyzed data prospectively collected at a single academic referral center on 232 patients (age: 54.1 ± 13.7 years) with 432 asymptomatic, sonographically or cytologically benign thyroid nodules at baseline (T0) and 122 new nodules that were present five years later (T5). At both time points, the sonographically estimated risk of malignancy was calculated as recommended by the American Association of Clinical Endocrinologists/American College of Endocrinology/Associazione Medici Endocrinologi, the American College of Radiologists' TIRADS, the American Thyroid Association's 2015 practice guidelines, the European Thyroid Association's TIRADS (EU-TIRADS), and the TIRADS of the Korean Society of Thyroid Radiology (K-TIRADS).For 57 to 127 (13.2-29.4%) of the original nodules, depending on the system used, the estimated malignancy risk increased over the 5-year interval. Of the nodules whose baseline risk had not warranted cytological assessment, very few (6.3-8.3%) met the criteria for cytology at the 5-year evaluation. Biopsy was indicated for only 4 to 8 (3.3-6.6%) of the new nodules based on T5 risk estimates. Despite these changes, none of the 232 patients was ever diagnosed with a cancer.Ultrasound-based risk classes of presumably benign thyroid nodules remain fairly stable over time, and changes warranting biopsy are rare indeed. The appearance of new nodules is a frequent event, but very few (5%) are classified as high risk, and only the 3-7% meet the criteria for cytological assessment. Collectively, these findings support the view that patients with presumably benign thyroid nodules can be safely followed with less intensive protocols.

Comprehension of the regulatory mechanism involved in the sodium iodide symporter (NIS) expression is of great relevance for thyroid cancer. In fact, restoration of NIS expression would be a strategy to treat undifferentiated thyroid cancer. Previous in vitro findings suggest that the cyclic AMP-response element (CRE) modulator (CREM) is involved in control of NIS expression. In this work, we examined the expression of CREM in a series of thyroid cancer tissues and its action on NIS promoter in human thyroid cancer cells.Expression of mRNA levels for CREM, PAX8 and NIS was measured by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in 6 normal thyroid tissues, 22 papillary, 12 follicular and 4 anaplastic thyroid cancers. The effect of CREM on transcriptional activity of the NIS promoter was investigated by transient transfection of human thyroid cell lines.Compared to normal tissues, NIS and PAX8 mRNA levels were significantly reduced in all types of thyroid cancer. As expected, the maximal decrease was detected in anaplastic thyroid cancer. Conversely, CREM mRNA levels were increased in all types of thyroid cancer, reaching statistical significance for follicular and anaplastic thyroid carcinoma (p=0.0157 and 0.0045, respectively). Transfection experiments showed an inhibitory effect of CREM on NIS promoter activity in various thyroid cancer cell lines.These data demonstrate that CREM expression is increased in thyroid cancer tissue and may play a role in the downregulation of NIS expression in thyroid cancer acting at the transcriptional level.

Radioactive iodine (131I) is routinely used for the treatment of differentiated thyroid cancers. Attempts have been made to enlarge this therapeutic strategy to nonthyroid tumors by coupling radioactive iodide administration with transfer of the sodium iodide symporter (NIS) gene into target cells, for example with an adenoviral vector (AdNIS). Although efficient iodide uptake was achieved in the tumors treated with AdNIS, no therapeutic effect could be observed with 131I, most probably because the iodide retention time in the target cells was short. To circumvent this problem, we propose to organify the iodide taken up, as it occurs in the thyroid. We constructed a recombinant adenovirus encoding the human thyroperoxidase (TPO) gene under the control of the cytomegalovirus early promoter (AdTPO). Infection of nonthyroid tumor cells with this virus led to production of an enzymatically active protein. A significant increase in iodide organification could be observed in cells coinfected with both AdNIS and AdTPO in the presence of exogenous hydrogen peroxide. However, the levels of iodide organification obtained were too low to significantly increase the iodide retention time in the target cells.

Decrease or loss of the sodium iodide (Na+/I-) symporter (NIS) activity influences the suitability of using radioiodine to detect and treat metastatic thyroid tissues. In previous studies, the presence of the NIS transcript, albeit at lower expression levels, has been shown in most thyroid differentiated carcinomas. In this study we searched for point mutations or other genetic alterations that may be responsible for an altered function of the NIS protein in tumors that still express NIS transcripts. Tumoral cDNAs derived from seven differentiated thyroid carcinomas (DTC), five papillary and two follicular, were analyzed by direct sequencing after polymerase chain reaction (PCR) amplification of the structural gene of the Na+/I- symporter. Neither mutations nor other genetic abnormalities were detected in any tumor sample examined. The data indicate that mutations or other genetic alterations of the NIS structural gene are not a major cause of the reduced iodide uptake in DTC.

Hepatocyte nuclear factor (HNF)-1alpha and HNF-1beta are related transcription factors that are mainly expressed in liver cells. Our previous study showed that HNF-1beta was highly expressed in papillary thyroid cancer cell lines and tumors. HNF-1alpha mRNA, however, was not detected in differentiated thyroid cancer cell lines. The objective of this study was to determine whether HNF-1alpha is expressed in dedifferentiated anaplastic thyroid cancer cells.Total RNA isolated from six anaplastic thyroid cancer cell lines and 38 surgical samples was analyzed for HNF-1alpha mRNA by conventional reverse-transcription polymerase chain reaction (RT-PCR) or real-time RT-PCR. HNF-1alpha DNA binding activity was measured by gel retardation assay and HNF-1alpha protein was identified by Western blotting.HNF-1alpha mRNA was expressed in four of the six anaplastic cell lines. The presence of HNF-1alpha protein and DNA binding activity was detected in three lines with higher HNF-1alpha mRNA level. Three cell lines also expressed HNF-1beta. HNF-1alpha transcripts were also detected in five out of six anaplastic tumors, but not in the papillary tumors except one with weak PCR signal.HNF-1alpha mRNA was detected in high frequency in anaplastic thyroid cancer cell lines and tumors. HNF-1alpha might play a role in the pathogenesis of anaplastic thyroid cancer.

OBJECTIVE: Nonfunctioning thyroid nodules (NFTNs) display a diminished iodide-concentrating ability, owing to defective expression and cell membrane targeting of the sodium-iodide symporter (NIS). Since NIS expression is primarily modulated by thyroid iodine content in vitro and in animal models, we attempted to determine whether iodine supply influences the expression and localization of human NIS (hNIS) in NFTNs. DESIGN: Using immunohistochemistry, we analyzed cold hyperplastic nodules and nonnodular thyroid samples (controls) from patients living in iodine-sufficient (n = 19) or severely iodine-deficient (n = 15) areas. MAIN OUTCOME: Nodules from the iodine-sufficient area exhibited weak or absent hNIS immunostaining whereas almost all nodules from the iodine-deficient area were hNIS positive. Heterogeneous hNIS staining was common among the iodine-deficient samples (p = 0.028). hNIS was localized on membrane in all nodular samples from the iodine-deficient area and in less than 40% in the iodine-sufficient area. CONCLUSIONS: hNIS is adequately expressed and appropriately localized in NFTNs cell membrane from iodine-deficient areas and its expression in vivo is modulated by iodine supply.

Immunohistochemistry provides insights in the expression of functional proteins and of their localization in normal thyroid tissue and in thyroid diseases. In hyperfunctional thyroid tissues, staining for sodium/iodide symporter (NIS), pendrin, thyroid peroxidase (TPO), and thyroglobulin (Tg) is increased. In hypofunctioning thyroid tissues, NIS staining is markedly decreased; in benign hypofunctioning adenomas, the expression of the other functional proteins is unmodified or slightly decreased, whereas their expression is profoundly decreased or absent in differentiated thyroid carcinoma.