Parathyroid carcinoma: epidemiology and genetics

Primary hyperparathyroidism (PHPT), considered a rare disease almost a century ago, has shown a notable increase in incidence over the past five decades, driven largely by improved diagnostic screening and greater clinical awareness. Following the same trend, the incidence of parathyroid carcinoma (PC), a very rare but aggressive malignancy accounting for approximately 1% of PHPT cases, appears to be rising. This increase parallels the overall rise in PHPT detection, suggesting that enhanced surveillance contributes to identifying more PC cases. PC is mostly characterized by severe hypercalcaemia, due to tumoral parathyroid hormone (PTH) over-secretion and a high rate of local recurrence and metastasis, making early diagnosis and surgical treatment crucial. Recent advances in genetics and epigenetics have profoundly expanded our understanding of PC pathogenesis. Germline and somatic mutations in the tumour suppressor gene CDC73 (encoding parafibromin) are implicated in up to 75% of familial and sporadic PC cases. Additional recurrent mutations in genes such as MEN1 and PRUNE2, alterations in cell cycle regulators such as CCND1 and EZH2, and disruptions in signalling pathways including PI3K/AKT/mTOR have been identified. Epigenetic modifications, including microRNA expression changes and promoter hypermethylation, also play a significant role in tumour development and progression. This mini review synthesizes epidemiological trends demonstrating an increasing incidence of PC following the rise of PHPT and highlights pivotal genetic and epigenetic findings contributing to tumourigenesis. Integrating new molecular insights with advances in clinical surveillance offers promise for improved diagnosis, prognostic stratification, and the development of future targeted therapies for parathyroid carcinoma.