ACTIVATING THYROTROPIN RECEPTOR MUTATIONS IN HISTOLOGICALLY HETEROGENEOUS HYPERFUNCTIONING NODULES OF MULTINODULAR GOITER

Activating thyrotropin (TSH) receptor mutations have been found in tox ic adenomas and in hot nodules contained in toxic multinodular goiter. The typical feature of multinodular goiter is the heterogeneity in mo rphology and function of different follicles within the same enlarged gland. In this report we describe a patient with a huge multinodular g oiter, normal free triiodothyronine (FT3) and free thyroxine (FT4) ser um values, and subnormal TSH serum concentration. Thyroid scintiscan s howed two hot areas corresponding to the basal and apical nodules of t he left lobe. The right lobe was poorly visualized by the radioisotope . The patient underwent thyroidectomy, and histological examination of the tissue was performed. Genomic DNA was extracted from the tissue s pecimen and direct sequencing of the TSH receptor and Gs alpha genes w as done. At histology, one hyperfunctioning nodule had the typical mic roscopic structure of thyroid adenomas, and the other contained multip le macrofollicular areas not confined by a capsule. In spite of this h istological difference, both hyperfunctioning nodules harbored a mutat ion of the thyrotropin receptor (TSHr) gene: an isoleucine instead of a threonine in position 632 (TG32I) in the first nodule and a methioni ne instead of an isoleucine in position 486 (I486M) in the second nodu le. In conclusion, our findings show for the first time that gain-of-f unction TSHr mutations are not only present in hyperfunctioning thyroi d nodules with the histological features of the true thyroid adenomas, but also in hyperfunctioning hyperplastic nodules contained in the sa me multinodular goiter.