Downregulation of CASR expression and global loss of parafibromin staining are strong negative determinants of prognosis in parathyroid carcinoma

Abstract

Parathyroid carcinoma is associated with mutations in the HRPT2/CDC73 gene and with decreased parafibromin and calcium-sensing receptor (CASR) expression, but in some cases establishing an unequivocal diagnosis remains a challenge. The aim of our study was to evaluate the prognostic value of CASR and parafibromin expression and of HRPT2/CDC73 mutations in patients with an established diagnosis of parathyroid carcinoma. Data on survival and disease-free survival were obtained from hospital records of 23 patients with an established diagnosis of parathyroid carcinoma in whom CASR and parafibromin expression and HRPT2/CDC73 mutation analyses were available from paraffin-embedded pathological specimens. KaplanMeier curves were used for survival analysis. Downregulation of CASR expression, global loss of parafibromin staining and a HRPT2/CDC73 mutation were, respectively, found in 7 (30%), 13 (59%) and 4 (17%) patients, and were associated with, respectively, 16-fold, 4-fold and 7-fold increased risk of developing local or distant metastasis. These findings suggest that although downregulation of CASR expression, global loss of parafibromin staining and mutations in the HRPT2/CDC73 gene are tools of proven value to assist in establishing a diagnosis of parathyroid carcinoma, their absence does not exclude it. Notwithstanding, we demonstrate a significant added value of these markers as strong determinants of increased malignant potential and thus as negative prognostic markers in this malignancy.

Parathyroid Carcinoma

“…54 Wittveen et al have also showed that the loss of parafibromin, either alone or in combination with CDC73 mutations and down-regulation of the calcium sensing receptor expression, has a negative impact on the survival rate in patients with parathyroid cancer. 70 Based on these data, we suggest that abnormalities of the CDC73 gene should be investigated not only for diagnostic purposes in tumors with uncertain diagnosis of malignancy but also in unequivocal cancers, because of their prognostic value. Moreover, the CDC73 mutational analysis would permit the identification of patients carrying a germline mutation and prompt an extension of the genetic analysis to first-degree relatives.…”

“…Diffuse or focal loss of nuclear parafibromin expression by immunohistochemistry has been found in the majority of parathyroid carcinomas but very rarely in parathyroid adenomas. 49,51,52,[64][65][66][67][68][69][70] A recent genome-wide study of DNA methylome from benign and malignant parathyroid tumors identified a number of genes with altered DNA methylation patterns independent of the tumor's nature, suggesting that other genes are involved in parathyroid carcinogenesis. 71 Costa-Guda et al have recently shown that allelic loss at chromosome 11q, the most common alteration in parathyroid adenomas, has never been detected in parathyroid cancers, suggesting that parathyroid malignancy arises de novo, rather than evolving from a pre-existing benign lesion.…”

Novel nonsense CDC73 mutations in Chinese patients with parathyroid tumors

“…Cetani et al [18] has identified germline CDC73 mutations in two patients with sporadic parathyroid cancer. The presence of CDC73 mutations was associated with sevenfold increased risk of developing local or distant metastasis [20]. Identification of CDC73 mutation not only assists in establishing a diagnosis of parathyroid carcinoma, but also has significant prognostic value.…”

A germline mutation of HRPT2/CDC73 (70 G>T) in an adolescent female with parathyroid carcinoma: first case report and a review of the literature

“…In patients with HRPT2/CDC73 mutations, Witteveen et al reported a seven-fold increased risk of developing local or distant metastasis. All four patients with the gene mutation developed local recurrence and/or distant metastasis, which occurred only in 10 of 19 patients without mutations [53]. Wang et al did not find a significant correlation between a mutation in HRPT2/CDC73 and distant metastases but did find a higher incidence of recurrence in patients with HRPT2/CDC73 mutations (100% vs. 50%, p = 0.031), after adjusting for gender, age, initial serum calcium and duration of follow-up [51].…”