PTHrP-associated hypercalcemia in gynecologic malignancies: a scoping review

Parathyroid hormone-related peptide (PTHrP) is a peptide hormone that shares structural similarity with parathyroid hormone (PTH) and binds to the same receptor, leading to increased calcium levels. Humoral hypercalcemia of malignancy (HHM) is typically mediated by tumor-derived PTHrP and accounts for the majority of cases of malignancy-associated hypercalcemia, whereas it is rarely observed in benign conditions. The purpose of this study was to systematically review the literature to map and provide a structured and transparent overview of reported cases of HHM in malignant gynecologic tumors.

A systematic literature search was conducted in PubMed/MEDLINE and Web of Science, complemented by manual reference screening and additional searches using Google Scholar, identifying relevant articles published between 1973 and 2025. Clinical and biochemical characteristics were extracted and analyzed descriptively.

A total of 51 reported cases were identified, including 29 ovarian, 12 uterine, 5 vulvar, and 5 cervical tumors. Among the 29 cases in which serum PTHrP was measured, levels were elevated in 28 patients. In the remaining cases, suppressed PTH levels, exclusion of alternative causes, or indirect evidence from tissue immunohistochemistry (IHC) supported PTHrP involvement. Preoperative calcium levels ranged from 10.5 to 21.3 mg/dL. Following tumor resection, both PTHrP and calcium levels declined and normalized in most patients.

These findings suggest that although rare, PTHrP-mediated hypercalcemia represents a clinically relevant paraneoplastic phenomenon in gynecologic malignancies. Prospective studies with standardized biochemical and tissue-based assessment are needed to clarify its epidemiology and clinical significance.