Parathyroid Carcinoma: From Molecular Pathogenesis and Diagnostic Biomarkers to Targeted Therapeutics

Parathyroid carcinoma (PC) is a rare endocrine malignancy characterized by aggressive clinical behavior driven primarily by parathyroid hormone (PTH) overproduction. Standard morphological assessments frequently struggle to definitively distinguish true carcinomas from atypical benign lesions, presenting significant diagnostic challenges and a risk of overdiagnosis. Recent advances emphasize the genetic and epigenetic foundations of PC tumor biology. A central oncogenic mechanism involves the CDC73 gene, where the biallelic inactivation of CDC73 and the gain of function of mutant parafibromin—which destabilizes p53 mRNA—facilitate apoptosis evasion. Additionally, alterations in parallel pathways, such as the PI3K/AKT/mTOR cascade, and epigenetic dysregulation further contribute to disease progression. To address morphological limitations, contemporary diagnostic approaches increasingly utilize adjunctive multimarker immunohistochemical panels (including parafibromin, Ki-67, and Galectin-3) and explore emerging non-coding RNA liquid biopsy signatures. Finally, this review discusses the development of preclinical models and the application of genotype-guided targeted therapies, aiming to improve the clinical management and precision medicine strategies for PC.