Expression of PRAD1 cyclin D1, retinoblastoma gene products, and Ki67 in parathyroid hyperplasia caused by chronic renal failure versus primary adenoma

Background In primary hyperparathyroidism, certain genetic abnormalities re sponsible for parathyroid tumorigenesis are proposed, and it has been repor ted that the overexpression of PRAD1/cyclin D1 induced by a DNA rearrangeme nt of the parathyroid hormone (PTH) gene is one of the genetic disorders in a number of primary parathyroid adenomas. However, in secondary hyperparat hyroidism caused by uremia, the mechanism of monoclonal proliferation in no dular parathyroid hyperplasia is not well understood. To elucidate the mech anism, we examined the expression of PRAD1/cyclin D1, retinoblastoma gene p roducts, and Ki67 in primary adenoma and secondary hyperplasia. Methods. In adenomas (N = 15) and associated glands (N = 7) with normal his tology obtained from patients with primary hyperparathyroidism and in diffu se (N = 14), multinodular (N = 58), and single nodular (N = 28) glands from patients who underwent parathyroidectomy for renal hyperparathyroidism, th e expression of these cell cycle regulators was evaluated by immunohistoche mical technique. A labeling index was used to define the proportion of cell s with positive nuclear staining by each antibody. Results. In 6 out of 15 (40%) primary adenomas, PRAD1/cyclin D1 was overexp ressed (a labeling index of more than 500), possibly because of the PTH gen e rearrangement, but not in secondary hyperplasia, including single nodular glands. Compared with diffuse hyperplasia, nodular hyperplasia showed a si gnificantly higher expression of PRAD1/cyclin D1 (P < 0.05), retinoblastoma gene products (P < 0.05), and Ki67 (P < 0.05). However, no statistically s ignificant correlation between the expression of PRAD1/cyclin D1 and that o f Ki67 was observed in both primary adenoma and secondary hyperplasia. Conclusions. These results suggest that in secondary hyperplasia caused by uremia, at least remarkable overexpression of PRAD1/cyclin D1 induced by PT H gene rearrangement may be not the major genetic abnormality responsible f or tumorigenesis. Heterogenous genetic changes seem to contribute to monocl onal proliferation of parathyroid cells induced by the expression of PRAD1/ cyclin D1 or by some other mechanism independent of the amplification of th e proto-oncogene.