Diagnosing the silent: the molecular landscape of non-functional parathyroid carcinoma

Non-functional parathyroid carcinoma (NFPC) is an exceptionally rare malignancy, with approximately 50 cases reported since the parathyroid glands were first described in the late nineteenth century. Unlike functional parathyroid carcinomas (PC), which typically present with severe hyperparathyroidism (HPT) and are monitored via serum calcium and parathyroid hormone (PTH) levels, NFPC lacks biochemical markers and is monitored solely through imaging. In this study, we present two new cases of primary NFPC and provide a comprehensive review of the literature, including a detailed analysis of immunohistochemical and molecular testing. We also explore potential mechanisms underlying the non-functional state in PC. In one case, the tumor lacked PTH expression by immunohistochemistry, yet low levels of PTH mRNA expression were consistently detected. Differential diagnoses-including medullary and non-medullary thyroid carcinoma, paraganglioma, and other head and neck tumors-were excluded. The second case demonstrated patchy residual PTH immunostaining. Both tumors exhibited extensive whole chromosome losses resulting in a near-haploid genome, with (NFPC 2) or without (NFPC 1) subsequent endoreduplication/genome doubling. The mutational landscape differed between the two, with neither showing CDC73 mutations or loss of parafibromin expression. Diagnosing primary non-functional parathyroid carcinoma can be especially challenging in cases with negative PTH immunohistochemistry.