Thyroid cancer: is the incidence rise abating?

OBJECTIVE: The aim of the present study was to determine recent trends in thyroid cancer incidence rates and to analyze histopathological characteristics and geographical distribution. METHODS: Histologically proven 5367 cases were collected over the period 1998-2006 in France from the Rhône-Alpes thyroid cancer registry. Geographical variations of incidence were analyzed using a mixed Poisson model. RESULTS: The average incidence rates, age standardized to the world population, were 3.9/100,000 in men and 12.3/100,000 in women, higher than those previously reported in France. After an initial increase during the first 3 years, a steady level of incidence was observed for the period 2001-2006. The annual incidence rate of microcarcinomas was correlated with that of all cancers in men and women (r=0.78 and 0.89; P<0.01) respectively. Papillary microcarcinomas represented 38% of tumors and two-thirds of them measured less than 5 mm in diameter. They were fortuitously discovered after thyroidectomy for benign diseases in 64% of cases. Histological marks of aggressiveness differed according to the size of the tumor. Despite recent advances in diagnosis, 13% of tumors were diagnosed at advanced stage especially in men. Geographical distribution of incidence based on subregional administrative entities showed lower incidence rates in rural than in urban zones in men (relative rate: 0.72; 95% CI: 0.62-0.84) and women (relative rate: 0.85; 95% CI: 0.73-0.93). CONCLUSION: The present study suggests that the rise in thyroid cancer incidence is now abating. It could reflect standardization in diagnostic procedures. Further studies, performed on a more prolonged period, are necessary to confirm these data.

Evaluation of gene expression profiles in thyroid nodule biopsy material to diagnose thyroid cancer.

CONTEXT: Detection of thyroid cancer among benign nodules on fine-needle aspiration biopsies (FNAB), which presently relies on cytological examination, is expected to be improved by new diagnostic tests set up from genomic data. OBJECTIVE: The aim of the study was to use a set of genes discriminating benign from malignant tumors, on the basis of their expression levels, to build tumor classifiers and evaluate their capacity to predict malignancy on FNAB. DESIGN: We analyzed the level of expression of 200 potentially informative genes in 56 thyroid tissue samples (benign or malignant tumors and paired normal tissue) using nylon macroarrays. Gene expression data were subjected to a weighted voting algorithm to generate tumor classifiers. The performances of the classifiers were evaluated on a series of 26 sham FNAB, i.e. FNAB carried out on thyroid nodules after surgical resection. RESULTS: A series of 19 genes with a similar expression in follicular adenomas and normal tissue and discriminating follicular adenomas+normal tissue from the following: 1) follicular thyroid carcinomas (FTCs), 2) papillary thyroid carcinomas (PTCs), or 3) both FTCs and PTCs. These were used to generate four classifiers, the FTCs, PTCs, common (FTC+PTCs), and global classifiers. In 23 of the 26 sham FNAB, the four classifiers yielded a diagnosis in agreement with the diagnosis of the pathologist used as reference; in the three other cases, the correct diagnosis was given by three of four classifiers. CONCLUSIONS: We developed a procedure of molecular diagnosis of benign vs. malignant tumors applicable to the material collected by FNAB. The molecular test complied with a preclinical validation stage; it must be now evaluated on ultrasound-guided FNAB in a large-scale prospective study.

Silencing of the tumor suppressor gene SLC5A8 is associated with BRAF mutations in classical papillary thyroid carcinomas.

SLC5A8, proposed as a thyroid apical iodide transporter, was recently defined as a Na+-coupled transporter of short-chain fatty acid. To document the expression pattern of SLC5A8 in the thyroid, we analyzed the regulation of its expression in normal human thyrocytes in culture and in tissues with distinct functional activity. To determine whether SLC5A8 expression is altered in all thyroid carcinomas or only in particular subtypes, we investigated the level of its expression in a series of 50 hypofunctioning tumors. SLC5A8 expression was studied at the transcript level and compared with that of SLC26A4 or Pendrin and SLC5A5 or Na+/iodide symporter. SLC5A8 expression, unlike that of SLC5A5 and SLC26A4, was not regulated by TSH in normal human thyrocytes in culture and was not related to the functional state of thyroid tissue; toxic adenomas and adjacent resting tissues exhibited the same SLC5A8 transcript content. SLC5A8 expression was selectively down-regulated (40-fold) in papillary thyroid carcinomas of classical form (PTC-cf.). Methylation-specific PCR analyses showed that SLC5A8 was methylated in 90% of PTC-cf. and in about 20% of other papillary thyroid carcinomas. In a series of 52 PTC-cf., a low SLC5A8 expression was highly significantly associated with the presence of BRAF T1796A mutation. These data identify a relationship between the methylation-associated silencing of the tumor-suppressor gene SLC5A8 and the T1796A point mutation of the BRAF gene in the PTC-cf. subtype of thyroid carcinomas.

Evidence for transcriptional and posttranscriptional alterations of the sodium/iodide symporter expression in hypofunctioning benign and malignant thyroid tumors.

The uptake of iodide by epithelial thyroid cells requires the expression of a specific transporter, the Na(+)/I(-) symporter, NIS. Benign and malignant thyroid tumors of epithelial origin show a decrease up to a loss of iodide uptake activity. Previous studies of the human NIS (hNIS) gene expression in these tumors, based on the amplification of transcripts and/or immunohistochemical detection of the protein, have yielded divergent data; hNIS expression was found either increased or decreased. To get a new and integrated view of the alterations of hNIS expression in hypofunctioning thyroid tumors, we performed investigations of hNIS transcript and hNIS protein levels on the same tumors and paired normal tissue samples. HNIS, identified as a 75- to 80-kd species, was present in all normal tissue samples from euthyroid patients, but was undetectable, even at high membrane protein input, in all benign and malignant hypofunctioning thyroid tumors. By contrast, approximately 50% of tumors contained hNIS transcripts. This dissociation between transcript and protein levels was not found for the transcript and protein encoded by the PDS gene assayed in the same tumors. The hNIS transcript-positive tumors contained small amounts of low-molecular mass hNIS-immunoreactive species identified as nonglycosylated hNIS. Tumors containing the nonmature form of hNIS exhibited a predominant intracellular immunolabeling. In conclusion, our data show that benign and malignant hypofunctioning thyroid tumors either no longer express hNIS protein or express only a very low amount of nonglycosylated hNIS and indicate that the impairment of hNIS gene expression might result from alterations at both transcriptional and posttranscriptional levels.

Characterization and semiquantitative analyses of pendrin expressed in normal and tumoral human thyroid tissues.

The gene mutated in Pendred syndrome (PDS), the PDS gene, is expressed in the inner ear, kidney, and thyroid. It encodes a membrane protein named pendrin that is endowed with the function of anion transporter or exchanger. It has been postulated that in the thyroid pendrin could participate in the transport of iodide from the cell to the lumen of follicles. We generated antipeptide antibodies directed against the C- terminal sequence of human pendrin 1) to characterize the protein expressed in the human thyroid, and 2) to analyze its expression level in relation to the functional activity of thyroid tissue. In denaturing conditions, a single molecular species of 110-115 kDa was identified in human thyroid membrane fractions. After treatment of thyroid membranes with N-glycosidase F, pendrin had an apparent molecular mass of 85 kDa. Analyzed by ultracentrifugation on sucrose gradient in nondenaturing conditions, pendrin sedimented as a main 120- to 140-kDa component. Pendrin was assayed by semiquantitative Western blot in thyroid membrane fractions from 25 hyper- or hypofunctioning tumors and paired normal tissue samples. Pendrin was increased 2-fold in toxic adenomas, was not significantly altered in follicular adenoma, and was decreased, on the average, by 35% in papillary carcinomas compared with levels in paired normal tissue. The variations in the pendrin tissue content and PDS transcript levels, assayed by RT-PCR on duplicate samples of the same tumors, were similar. In conclusion, we show that pendrin expressed by the human thyroid gland is a mainly monomeric glycoprotein and that the level of expression of pendrin, although somewhat related, only moderately varied with the functional status of the thyroid tissue.