Loss of Parafibromin Immunoreactivity Is a Distinguishing Feature of Parathyroid Carcinoma

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 highlighted by parafibromin immunostaining. One of these tumors has since recurred, satisfying criteria for a definite carcinoma. Similarly, eight of nine HPT-JT syndromerelated 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.

Parafibromin is a nuclear protein with a functional monopartite nuclear localization signal

“…The nuclear localization of parafibromin is in agreement with the results of three other studies (Tan et al, 2004;Hahn and Marsh, 2005;Rozenblatt-Rosen et al, 2005). Parafibromin is a 61 kDa protein, and it has been reported that proteins with a molecular mass >45 kDa cannot diffuse freely across the nuclear envelope and require to be actively transported through the nuclear pore complex via a process that involves recognition by the importins of NLSs in the proteins (Quadrini and Bieker, 2002;Vandenbroucke et al, 2004).…”

“…Thus, as part of this protein complex, parafibromin may regulate posttranscriptional events and histone modification. In keeping with such roles parafibromin has been reported to be a nuclear protein by two studies (Tan et al, 2004;Rozenblatt-Rosen et al, 2005), although one other study has reported that parafibromin may also be in the cytoplasm (Woodard et al, 2004).…”

Parathyroid carcinoma

“…Most parathyroid carcinomas also exhibit aberrant immunohistochemical staining for parafibromin, the protein product of CDC73; complete loss of parafibromin expression is the most common staining pattern. As the large majority of benign parathyroid tumors (except in the setting of germline CDC73 mutation) display normal parafibromin staining, parafibromin immunohistochemistry may be considered as a diagnostic adjunct for parathyroid cancer in otherwise equivocal cases [22][23][24] but aberrant parafibromin staining alone is insufficient as a diagnostic marker of parathyroid carcinoma [25] .…”

Molecular Diagnosis in Head and Neck: What a Surgical Pathologist Must Know

“…Expression of parafibromin is lost in between 70 and 90% of both syndromic and sporadic parathyroid carcinomas [43][44][45]. Parafibromin is almost always preserved in histologically and clinically benign parathyroid adenomas [46].…”