Characterization of autonomous thyroid adenoma: Metabolism, gene expression, and pathology

Fifty-one in vivo characterized autonomous single adenomas have been studie d for functional parameters in vitro, for gene and protein expression and f or pathology, and have been systematically compared to the corresponding ex tratumoral quiescent tissue. The adenomas were characterized by a high leve l of iodide trapping that corresponds to a high level of Na+/iodide symport er gene expression, a high thyroperoxidase mRNA and protein content, and a low H2O2 generation. This explains the iodide metabolism characteristics de monstrated before, ie, the main cause of the "hot" character of the adenoma s is their increased iodide transport. The adenomas spontaneously secreted higher amounts of thyroid hormone than the quiescent tissue and in agreemen t with previous in vivo data, this secretion could Ire further enhanced by thyrotropin (TSH). Inositol uptake was also increased but there was no spon taneous increase of the generation of inositol phosphates and this metaboli sm could be further activated by TSH. These positive responses to TSH are i n agreement with the properties of TSH-stimulated thyroid cells in vitro an d in vivo. They are compatible with the characteristics of mutated TSH rece ptors whose constitutive activation accounts for the majority of autonomous thyroid adenomas in Europe. The number of cycling cells, as evaluated by M IB-1 immunolabeling was low but increased in comparison with the correspond ing quiescent tissue or normal tissue. The cycling cells are observed mainl y at the periphery; there was very little apoptosis. Both findings account for the slow growth of these established adenomas. On the other hand, by th yroperoxidase immunohistochemistry, the whole lesion appeared hyperfunction al, which demonstrates a dissociation of mitogenic and functional stimulati ons. Thyroglobulin, TSH receptor, and E-cadherin mRNA accumulations were no t modified in a consistent way, which confirms the near-constitutive expres sion of the corresponding genes in normal differentiated tissue. On the con trary, early immediate genes expressions (c-myc, NGF1B, egr 1, genes of the fos and jun families) were decreased. This may be explained by the prolife rative heterogeneity of the lesion and the previously described short, biph asic expression of these genes when induced by mitogenic agents. All the ch aracteristics of the autonomous adenomas can therefore be explained by the effect of the known activating mutations of genes coding for proteins of th e TSH cyclic adenosine monophosphate (cAMP) cascade, all cells being functi onally activated while only those at the periphery multiply. The reason of this heterogeneity is unknown.