Filamin A and parafibromin expression in parathyroid carcinoma

Abstract

Objective: Parathyroid carcinoma (PC), atypical parathyroid tumors (APT) and parathyroid adenoma (PA) present with hypercalcemia. Diminished calcium-sensing receptor (CaSR) expression is reported in PC but is rare in benign tumours. Filamin A (FLNA) binds to the CaSR and activates the mitogen-activated protein kinase (MAPK) signalling pathway. FLNA is related to tumour aggressiveness in several cancers, but its role in parathyroid neoplasia is unknown. Design: We examined FLNA, CaSR and parafibromin expression in PCs (n = 32), APTs (n = 44) and PAs (n = 77) and investigated their potential as diagnostic and/or prognostic markers. Methods: Tissue microarray slides were immunohistochemically stained with FLNA, CaSR and parafibromin. Staining results were correlated with detailed clinical data. Results: All tumours stained positively for CaSR, with two tumours (one PC and one APT) showing diminished expression. Carcinomas were characterized by increased cytoplasmic FLNA expression compared to APTs and PAs (p = 0.004). FLNA expression was not correlated with Ki-67 proliferation index or loss of parafibromin expression. Cytoplasmic FLNA expression was also associated with higher serum calcium, PTH concentrations and male sex (p = 0.014, p = 0.017 and p = 0.049, respectively). Using a combined marker score, we found that parathyroid tumours with low FLNA expression and positive parafibromin staining were extremely likely to be benign (p < 0.001). Conclusion: Cytoplasmic and membranous FLNA expression is increased in parathyroid carcinomas compared to benign tumours. A combined FLNA and parafibromin expression score shows potential as a prognostic predictor of indolent behaviour in parathyroid neoplasms.

Genetics and Epigenetics of Parathyroid Carcinoma

“…The filamin A (FLNA) gene encodes the homonym filamin A protein, a non-muscle actin filament cross-linking scaffold protein that influences the intracellular localization of numerous proteins. A very recent study by Storvall et al (35) found that PCs were characterized by significantly increased cytoplasmic FLNA expression, compared to both PAs and atypical parathyroid adenomas (aPAs), suggesting that the increased cytoplasmic, and membranous, FLNA expression could be a marker of malignancy, and a potential prognostic predictor of aggressive behavior in parathyroid neoplasms, mostly in combination with parafibromin expression. However, a previous study (36) showed opposite results, reporting a decreased expression of full-length FLNA in the cytoplasm of tumoral parathyroid epithelial cells, both for PAs (50% to 10% of FLNA-positive cells) and PCs (less than 10% or totally absent FLNA-positive cells), with respect to the normal parathyroid counterpart.…”

Immunohistochemical Profile of Parathyroid Tumours: A Comprehensive Review

“…Cytoplasmic expression of filamin A was statistically significantly higher in carcinomas compared to atypical adenomas or adenomas [165]. The expression of filamin A also correlated with the serum levels of calcium and PTH, but was not associated with Ki-67 indicating that filamin A plays significant role in calcium turnover but is not associated with the degree of anaplasia [165]. Indeed, Mingione et al, demonstrated that loss of filamin A reduces CaSR expression in protein and mRNA levels; the CaSR-induced ERK phosphorylation also decreases [169].…”

“…Scaffold protein filamin A binds to calcium-sensing receptor and activates the mitogenactivated protein kinase MAPK pathway. Cytoplasmic expression of filamin A was statistically significantly higher in carcinomas compared to atypical adenomas or adenomas [165]. The expression of filamin A also correlated with the serum levels of calcium and PTH, but was not associated with Ki-67 indicating that filamin A plays significant role in calcium turnover but is not associated with the degree of anaplasia [165].…”

“…More recently, global loss of CaSR has been reported in 5/10 carcinomas while all adenomas (21) showed retained expression (p = 0.001), and only a single atypical adenoma (1/14) yielded global loss of expression [66]. In contrast, Storvall et al observed retained immunohistochemical CaSR expression in all the evaluated parathyroid tumours, including 32 carcinomas, 44 atypical adenomas and 77 adenomas; just a single carcinoma and one atypical adenoma presented weaker expression [165]. CaSR shows negative correlation with Ki-67 both in secondary hyperparathyroidism and adenoma [166][167][168].…”

“…Although tumour weight is strongly associated with calcium and PTH concentration in blood [164], abnormal feedback and/or disturbed sensitivity to blood calcium levels could be expected in the neoplastic cells, and the dysfunction might be more marked in carcinoma. Indeed, diminished calcium-sensing receptor expression has been reported in parathyroid carcinoma but is rare in benign tumours [165]. Thus, 31% of carcinomas showed downregulation of CaSR, contrasting with adenomas and hyperplasia.…”