Expression of the Na+/I- symporter (NIS) gene was investigated by RT-PCR in a selected series of 26 primary thyroid carcinomas (19 papillary, 5 follicular, and 2 anaplastic). Fifteen follicular adenomas (11 "cold" and 4 "hot" adenomas) were also studied. Five of 19 papillary thyroid cancer did not express NIS messenger ribonucleic acid (mRNA). In all but 1 follicular cancer, NIS transcript was fully detected. In anaplastic tissue, NIS mRNA was only barely detected in 1 case. All of the follicular thyroid adenomas except 1 expressed the NIS gene. In contrast, all tumors studied excluding the anaplastic histotype fully expressed thyroglobulin and thyroid peroxidase mRNA transcripts. In 2 patients, a lower expression (3- to 5-fold) of NIS mRNA was found in metastasis by dot blot analysis compared with those in both normal and primary neoplastic thyroid tissue. Four of 8 differentiated thyroid cancer patients selected for the presence of metastases with negative posttherapy 131I total body scan showed the lack of NIS gene expression in their primary cancer. This defect, at least in these cases, is a somatic and intrinsic lesion of the primary cancer cells and is not due to a dedifferentiation process in the metastatic tissue. The early detection of the loss of NIS gene expression in the primary cancer, therefore, may provide useful information for the management of differentiated thyroid cancer patients.