Increased thyroid epithelial cell proliferation in toxic thyroid nodules

Most toxic thyroid nodules (TTN) result from clonal expansion of a single cell caused by a somatic mutation in the thyrotropin (TSH) receptor, the G(s alpha) protein, or yet unknown proteins. Expanding a single cell into a TTN with thousands of cells suggests a prolonged increase in proliferation compared to nonaffected surrounding cells. To test this hypothesis, we evaluated cell proliferation in TTN. Tissue from 20 TTN and their surrounding normal thyroid tissue was studied for the occurrence of the proliferating cell nuclear antigen (PCNA) and Ki-67 epitope as markers for cell proliferation. The labeling index (number of labeled cells versus total cell number) for nodular and surrounding tissue was calculated. Nineteen samples were evaluated for PCNA immunohistochemistry. In 16 TTN, a significant (p less than or equal to 0.05%) up to 3-fold increase in the labeling index for PCNA was detectable. In only 3 toxic nodules (2 without a detectable TSH receptor or G(s alpha) protein mutation), we found no significant difference in the labeling index compared to the surrounding tissue. Because labeling for KI-67 was much lower, only 16 toxic thyroid nodules were quantified, Twelve of these showed significantly (p less than or equal to 0.05%) increased labeling indices. The increase of the labeling index for both markers was similar for histologically defined adenoma versus adenomatous nodule or nodules with or without TSH receptor mutation or clonal versus polyclonal origin of toxic nodules studied. These findings are evidence that an increased thyroid epithelial cell proliferation is a uniform feature common to most TTNs, independent of their histopathological or molecular characteristics. Although increased proliferation in many TTNs is very likely the result of TSH receptor mutations, the cause of increased proliferation in TTN without a mutation is unknown.