Parafibromin-deficient (HPT-JT Type, CDC73 Mutated) Parathyroid Tumors Demonstrate Distinctive Morphologic Features

Abstract

The gene CDC73 (previously known as HRPT2) encodes the protein parafibromin. Biallelic mutation of CDC73 is strongly associated with malignancy in parathyroid tumors. Heterozygous germline mutations cause hyperparathyroidism jaw tumor syndrome,which is associated with a high life-time risk of parathyroid carcinoma. Therefore loss of parafibromin expression by immunohistochemistry may triage genetic testing for hyperparathyroidism jaw tumor syndrome and be associated with malignant behavior in atypical parathyroid tumors. We share our experience that parafibromin-negative parathyroid tumors show distinctive morphology. We searched our institutional database for parathyroid tumors demonstrating complete loss of nuclear expression of parafibromin with internal positive controls. Forty-three parafibromin-negative tumors from 40 (5.1%) of 789 patients undergoing immunohistochemistry were identified. Thirty-three (77%) were external consultation cases; the estimated incidence in unselected tumors was 0.19%. Sixteen (37.2%) fulfilled World Health Organization 2017 criteria for parathyroid carcinoma and 63% had serum calcium greater than 3mmol/L. One of 27 (3.7%) noninvasive but parafibromin-negative tumors subsequently metastasized. Parafibromin-negative patients were younger (mean, 36 vs. 63 y; P<0.001) and had larger tumors (mean, 3.04 vs. 0.62 g; P<0.001). Not all patients had full testing, but 26 patients had pathogenic CDC73 mutation/deletions confirmed in tumor (n=23) and/or germline (n=16). Parafibromin-negative tumors demonstrated distinctive morphology including extensive sheet-like rather than acinar growth, eosinophilic cytoplasm, nuclear enlargement with distinctive coarse chromatin, perinuclear cytoplasmic clearing, a prominent arborizing vasculature, and, frequently, a thick capsule. Microcystic change was found in 21 (48.8%). In conclusion, there are previously unrecognized morphologic clues to parafibromin loss/CDC73 mutation in parathyroid tumors which, given the association with malignancy and syndromic disease, are important to recognize.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0/.

Prognostic role of parafibromin staining and CDC73 mutation in patients with parathyroid carcinoma: A systematic review and meta‐analysis based on individual patient data

“…A total of 770 records were identified from Medline/PubMed, EMBASE, Cochrane and Scopus after excluding duplications. Among these records, a total of 9 articles were selected and data from 193 patients were extracted for this survival analysis . The characteristics of the included articles are listed in Table .…”

“…Among the nine studies, eight provided parafibromin staining data, while five studies provided gene sequencing data and utilized Sanger sequencing to identify CDC73 mutations. One study performed multiplex ligation‐dependent probe amplification (MLPA) when no CDC73 mutations were identified by sequencing . Moreover, a commercial parafibromin primary antibody sc‐33638 (Santa Cruz Biotechnology), a monoclonal antibody of parafibromin targeting amino acid residues 87‐100, was used in seven studies, while one homemade monoclonal antibody and one commercial parafibromin primary antibody ab223840 (Abcam) were used in the other two studies, respectively.…”

“…Various criteria have been applied for the interpretation of the results of parafibromin staining in the different studies. A complete loss of nuclear expression in all tumour cells with the presence of an inner positive control was defined as a negative staining for parafibromin in six studies . To ensure consistent results, focal negative or weak positive staining was not considered a negative result in two studies during analysis .…”

“…Among these records, a total of 9 articles were selected and data from 193 patients were extracted for this survival analysis. 12,16,18,20,[22][23][24][25][26] The characteristics of the included articles are listed in Table 1. Three studies were conducted in Asia, four in Europe were used in the other two studies, respectively.…”

“…the presence of an inner positive control was defined as a negative staining for parafibromin in six studies. 12,16,18,23,24,26 To ensure consistent results, focal negative or weak positive staining was not considered a negative result in two studies during analysis. 20,25 According to the parafibromin staining results, the patients enrolled in these studies were divided into two groups.…”