CYCLIN D1 PRAD1 EXPRESSION IN PARATHYROID ADENOMAS - AN IMMUNOHISTOCHEMICAL STUDY/

The cyclin D1 (PRAD1) oncogene is rearranged with the PTH gene and is transcriptionally activated in a subset of parathyroid adenomas. Becau se of heterogeneity in rearrangement breakpoints, the true percentage of adenomas with cyclin D1 deregulation is unknown. Overexpression of the cyclin D1 protein in parathyroid adenomas appears to be a unifying consequence of all cyclin D1 gene rearrangements and can, therefore, be examined to more comprehensively identify adenomas in which cyclin D1 is pathogenetically important. We studied cyclin D1 expression in 6 5 parathyroid adenomas (from 64 patients), 51 normal parathyroid gland s (from the same patients), and 4 parathyroid carcinoma specimens (fro m 3 patients) using a microwave-enhanced immunohistochemical method an d affinity-purified cyclin D1 polyclonal antiserum. When available, da ta on adenoma mass, intact PTH level, and concurrent serum calcium lev el were also collected. Twelve of the 65 adenomas (18%) showed diffuse nuclear staining of approximately 30-70% of the tumor cells. All 51 n ormal glands were negative, except 1 gland that showed scattered cells (<10%) with positive nuclear staining. In addition, scattered positiv e cells were seen in the compressed rim of histologically normal parat hyroid tissue surrounding 2 adenomas that were cyclin D1 negative. No significant differences in adenoma mass, intact PTH levels, or concurr ent calcium levels were found between positive and negative tumors. Tw o of 4 parathyroid carcinoma specimens from 2 of 3 patients showed str ong nuclear staining for cyclin D1. Overexpression of the cyclin D1 on cogene in 18% of our cases, due to the cyclin D1/PTH translocation and /or other mechanisms, suggests that overexpressed cyclin D1 plays a ro le in the pathogenesis of a much larger proportion of parathyroid aden omas than previously appreciated. Cyclin D1 overexpression is a featur e of typical parathyroid adenomas and is not confined to unusually lar ge, symptom-causing adenomas as had been suggested by early DNA studie s. Although only three patients with parathyroid carcinoma were studie d, two of the patients' tumors stained for cyclin D1, raising the poss ibility that; the frequency of cyclin D1 overexpression may be even gr eater in carcinomas. Cyclin D1 overexpression appears to highlight a c entral pathway in parathyroid neoplasia.