Loss of parafibromin immunoreactivity is a distinguishing feature of parathyroid carcinoma

Min Han Tan, Carl Morrison, Pengfei Wang, Ximing Yang, Carola J. Haven, Chun Zhang, Ping Zhao, Maria S. Tretiakova, Eeva Korpi-Hyovalti, John M. Burgess, Chee Soo Khee, Wei Keat Cheah, Brian Cao, James Resau, Hans Morreau, Tean Teh Bin*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

174 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)6629-6637
Number of pages9
JournalClinical Cancer Research
Volume10
Issue number19
DOIs
StatePublished - Oct 1 2004

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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