Intratumor heterogeneity in human parathyroid tumors

Parathyroid tumors are the second most common endocrine neoplasia after thyroid neoplasia. They are mostly associated with impaired parathormone (PTH) synthesis and release determining the metabolic and clinical condition of primary hyperparathyroidism (PHPT). PHPT is the third most prevalent endocrine disorder, mainly affecting postmenopausal women. Parathyroid benign tumors, both adenomas of a single gland or hyperplasia involving all the glands, are the main histotypes, occurring in more than 95% of PHPT cases. The differential diagnosis between benign and malignant parathyroid lesions is a challenge for clinicians. It relies on histologic features, which display significant overlap between the histotypes with different clinical outcomes. Parathyroid adenomas and hyperplasia have been considered so far as a unique monoclonal/polyclonal entity, while accumulating evidence suggest great heterogeneity. Intratumor parathyroid heterogeneity involves tumor cell type, as well as tumor cell function, in terms of PTH synthesis and secretion, and of expression patterns of membrane and nuclear receptors (calcium sensing receptor, vitamin D receptor, α-klotho receptor and others). Intratumor heterogeneity can also interfere with cell molecular biology, in regard to clonality, oncosuppressor gene expression (such as MEN1 and HRPT2/CDC73), transcription factors (GCM2, TBX1) and microRNA expression. Such heterogeneity is likely involved in the phenotypic variability of the parathyroid tumors, and it should be considered in the clinical management, though at present target therapies are not available, with the exception of the calcium sensing receptor agonists.