Loss of Parafibromin Immunoreactivity Is a Distinguishing Feature of Parathyroid Carcinoma
Tan, MH and Morrison, C and Wang, PF and Yang, XM and Haven, CJ and Zhang, C and Zhao, P and Tretiakova, MS and Korpi-Hyovalti, E and Burgess, JR and Soo, KC and Cheah, WK and Cao, B and Resau, J and Morreau, H and Teh, BT, Loss of Parafibromin Immunoreactivity Is a Distinguishing Feature of Parathyroid Carcinoma, Clinical Cancer Research, 10, (19) pp. 6629-6637. ISSN 1078-0432 (2004) [Refereed Article]
Purpose: A reliable method for diagnosing parathyroid carcinoma has remained elusive over the years, resulting in its under-recognition and suboptimal therapy. Obtaining an accurate diagnosis has become an even more pressing matter with recent evidence that germline HRPT2 gene mutations are found in patients with apparently sporadic parathyroid carcinoma. There is a high prevalence of HRPT2 gene mutations and biallelic inactivation in parathyroid carcinoma. We hypothesize that loss of parafibromin, the protein product of the HRPT2 gene, would distinguish carcinoma from benign tissue. Experimental Design: We generated a novel antiparafibromin monoclonal antibody and performed immunostaining on 52 definite carcinoma specimens, 6 equivocal carcinoma specimens, 88 benign specimens, and 9 hyperparathyroidism-jaw tumor (HPT-JT) syndrome-related adenomas from patients with primary hyperparathyroidism from nine worldwide centers and one national database. Results: We report that the loss of parafibromin nuclear immunoreactivity has 96% sensitivity [95% confidence interval (CI), 85-99%] and 99% specificity (95% CI, 92-100%) in diagnosing definite carcinoma. Inter-observer agreement for evaluation of parafibromin loss was excellent, with unweighted kappa of 0.89 (95% CI, 0.79-0.98). Two equivocal carcinomas misclassified as adenomas were high-lighted by parafibromin immunostaining. One of these tumors has since recurred, satisfying criteria for a definite carcinoma. Similarly, eight of nine HPT-JT syndrome-related adenomas showed absent nuclear immunoreactivity. Conclusions: Parafibromin is a promising molecular marker for diagnosing parathyroid carcinoma. The similar loss of parafibromin immunoreactivity in HPT-JT syndrome-related adenomas suggests that this is a pivotal step in parathyroid temorigenesis.