Defining a molecular phenotype for benign and malignant parathyroid tumors

Abstract

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. © 2009 American Cancer Society.

Parathyroid tumors and related disorders

“…Recent studies indicate that the molecular profiles of parathyromatosis are similar to those of benign parathyroid tumors with respect to expression of parafibromin, Ki-67, RB and galectin-3. 71 …”

Non-functional parathyroid carcinoma: a case report and review of the literature

“…57 Other recurrent genetic aberrations in parathyroid cancer include the abnormal expression of cell cycle regulators, such as retinoblastoma (Rb), breast carcinoma susceptibility (BRCA2), and p53. 58 However, there is no definitive evidence for a primary role of these genes in parathyroid carcinoma, although the altered expression of these gene products may participate in the process of malignant transformation.…”

Diagnosis of parathyroid carcinoma using immunohistochemical staining against hTERT

“…The accelerated cell proliferation in carcinoma was successfully evaluated by displaying the increase in PCNA- (15) or the Ki-67-positive cell population. Ki-67 is the most widely used molecular marker to estimate the activity of cellular proliferation, and typically more than 5% (4-6%) of cells stain positively in parathyroid carcinoma (5,17,29). Ki-67 is a human nuclear proliferation-associated antigen, expressed in all cells that are not in the G0-phase.…”

“…Therefore, it is particularly important to diagnose parathyroid carcinoma correctly during the initial surgical operation for proper treatment. For cases demonstrating typical clinical features such as a palpable neck mass, an extremely high serum calcium level (hypercalcemic crisis) and painful bone lesions (ostelitis fibrosa cystica), a preoperative diagnosis of parathyroid carcinoma is not difficult (5,6). However, some of these clinical features frequently occur in cases of benign adenoma.…”

“…and there have been conflicting results with respect to the potential role of Ki-67 in predicting clinical outcomes (15,17). Since it is not sufficient to use Ki-67 practically as a single diagnostic marker, the combination with several other markers has been recommended (5,16,19).…”