Increased thyroid epithelial cell proliferation in toxic thyroid nodules

Most toxic thyroid nodules (TTN) result from clonal expansion of a single c ell 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 TT N with thousands of cells suggests a prolonged increase in proliferation co mpared to nonaffected surrounding cells. To test this hypothesis, we evalua ted cell proliferation in TTN. Tissue from 20 TTN and their surrounding nor mal 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 evalu ated for PCNA immunohistochemistry. In 16 TTN, a significant (p less than o r 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 la beling index compared to the surrounding tissue. Because labeling for KI-67 was much lower, only 16 toxic thyroid nodules were quantified, Twelve of t hese showed significantly (p less than or equal to 0.05%) increased labelin g indices. The increase of the labeling index for both markers was similar for histologically defined adenoma versus adenomatous nodule or nodules wit h or without TSH receptor mutation or clonal versus polyclonal origin of to xic nodules studied. These findings are evidence that an increased thyroid epithelial cell proliferation is a uniform feature common to most TTNs, ind ependent of their histopathological or molecular characteristics. Although increased proliferation in many TTNs is very likely the result of TSH recep tor mutations, the cause of increased proliferation in TTN without a mutati on is unknown.