Defining a molecular phenotype for benign and malignant parathyroid tumors

BACKGROUND: It is frequently difficult to establish histologically whether a parathyroid tumor is a parathyroid carcinoma, parathyromatosis, or an atypical adenoma. The authors asked whether these tumors have a distinctive molecular profile, whether benign tumors could be distinguished from malignant tumors, and whether parathyromatosis is a low-grade parathyroid carcinoma or is benign tissue that can invade other organs. METHODS: Samples of parathyroid carcinoma, atypical adenoma, parathyromatosis, parathyroid adenoma, and hyperplasia were obtained for tissue microarray studies. The molecular expression of genes involved in parathyroid tumor progression (HRPT2 ["parafibromin"], galectin-3, Ki-67, Rb, p27, and mdm-2) was investigated by immunohistochemistry. RESULTS: Complete loss of parafibromin expression was seen in 5 of 16 (31.3%) parathyroid carcinomas; all parathyromatosis, atypical adenomas, adenomas, and hyperplasia stained positive for parafibromin. Loss of Rb expression was seen in 5 (33.3%) of 15 parathyroid carcinomas and 1 (7.1%) of 14 parathyroid hyperplasias; all parathyromatosis, atypical adenomas, and adenomas stained positive. Galectin-3 stained strongly positive in 14 (93.3%) of 15 parathyroid carcinomas, and positive in 3 (18.7%) of 16 cases of parathyromatosis, 2 (100%) of 2 atypical adenomas, 1 (5.6%) of 18 adenomas, and 2 (14.3%) of 14 hyperplasias. The Ki-67 proliferative index was high in 9 (60%) of 15 parathyroid carcinomas, 1 (6.7%) of 15 cases of parathyromatosis, 1 (5.6%) of 18 adenomas, and no atypical adenomas or hyperplasia. P27 and mdm-2 protein expression did not differ appreciably among the tumor types. CONCLUSIONS: No single diagnostic marker currently determines whether a parathyroid tumor is a parathyroid carcinoma, but loss of parafibromin and Rb expression, and overexpression of galectin-3, generally distinguish parathyroid carcinoma from other parathyroid tumors. Parathyromatosis does not appear to be a low-grade parathyroid carcinoma. Cancer 2009;115:334-44.