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Loss of Parafibromin Immunoreactivity Is a Distinguishing Feature of Parathyroid Carcinoma

¹ Laboratories of Cancer Genetics, ² Antibody Technology, and ³ Analytical, Cellular and Molecular Microscopy, Van Andel Research Institute, Grand Rapids, Michigan; ⁴ Department of Pathology, Ohio State University Medical Center, Columbus, Ohio; ⁵ Division of Surgical Pathology, Northwestern University, Chicago, Chicago, Illinois; ⁶ Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands; ⁷ Department of Pathology, University of Chicago, Illinois; ⁸ Department of Internal Medicine, Seinäjoki Central Hospital, Finland; ⁹ Department of Diabetes and Endocrine Services, Royal Hobart Hospital, University of Tasmania, Australia; ¹⁰ Department of General Surgery, Singapore General Hospital, Singapore; ¹¹ Department of Surgery, National University Hospital, Singapore; and ¹² Department of Medicine, Alexandra Hospital, Singapore

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 highlighted 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 tumorigenesis.

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