HRPT2 gene analysis and the diagnosis of parathyroid carcinoma

Parathyroid carcinoma is an uncommon cause of primary hyperparathyroidism (PHPT) and is usually associated with more severe clinical manifestations than its much more common benign counterpart, the parathyroid adenomas. The histopathological distinction between benign and malignant parathyroid tumors is difficult. Currently, pathological diagnosis of parathyroid carcinoma is restricted to lesions showing unequivocal growth, as evidenced by perineural invasion, full-thickness capsular invasion with growth into adjacent tissues, or metastasis. Major advances in the molecular pathogenesis of parathyroid carcinoma have been made by the cloning of the HRPT2 gene, which encodes parafibromin, a 531-amino acid putative tumor-suppressor protein. Germline mutations of HRPT2 confer susceptibility to the hyperparathyroidism–jaw tumor syndrome (HPT-JT), an autosomal dominant syndrome with high but incomplete penetrance. Somatic inactivating mutations of the HRPT2 gene have been reported in the majority of apparently sporadic parathyroid carcinomas but, unexpectedly, germline HRPT2 mutation have been found in up to 30% of these patients. Several studies have been performed to evaluate whether parafibromin immunostaining might have some diagnostic utility. Loss of parafibromin immunoreactivity has been found in the majority of parathyroid carcinomas, in 50% of equivocal carcinomas and, very rarely, in benign adenomas. On the other hand, with the exception of HPT-JT-related tumors, loss of parafibromin associated with HRPT2 mutations strongly predicts parathyroid malignancy. In clinical practice, parafibromin immunostaining and HRPT2 gene analysis could be particularly useful in the subset of parathyroid tumors with equivocal histology.