Hypercalcemia of Malignancy: Epidemiology and Pathogenesis

Humoral hypercalcemia of malignancy due to bipartite squamous cell/small cell carcinoma of the esophagus immunoreactive for parathyroid hormone related protein*

“…6 PHRP was extracted from various malignant tumors and increased blood levels of PHRP were demonstrated in patients with malignant tumors associated with humoral hypercalcemia. 1 In our case, the immunohistochemical demonstration of PHRP in the tumor provided conclusive evidence that PHRP secretion by the tumor accounted for the hypercalcemia. The tumor consisted of two parts: a squamous cell and a pleomorphic small cell component.…”

“…It was an intriguing finding that PHRP immunoreactivity was apparent only in the pleomorphic small cell component and not in the squamous epithelial cells. It is known that PHRP is expressed in the stratum spinosum of the normal epidermis and in many squamous cell carcinomas 1 . Thus, it was an unexpected observation that in our case, PHRP immunopositivity was detected only in the pleomorphic small cell component and not in the squamous cells of the tumor.…”

“…PHRP was localized in various tumor types by immunohistochemistry, Northern blot analysis and in‐situ hybridization and is the cause of ‘humoral hypercalcemia of malignancy’, a term introduced by Martin and Atkins (1979) 6 . PHRP was extracted from various malignant tumors and increased blood levels of PHRP were demonstrated in patients with malignant tumors associated with humoral hypercalcemia 1 …”

“…In more recent studies, it has been established that the cause of the hypercalcemia is not PTH itself secreted by the parathyroid gland, but a similar protein called PHRP released from the tumor cells. 1,[6][7][8] Except for the significant homology in the first 13 amino acids of the N-terminal end of the molecules, PHRP differs from PTH in its amino acid composition. Molecular cloning demonstrated that the PHRP molecule is longer than the PTH molecule.…”

“…Hypercalcemia, a common finding in patients with various types of malignant tumors, results from increased bone resorption. 1 Enhanced release of calcium from the bones to the blood is due either to widespread bone metastases or the secretion of humoral substances, primarily parathyroid hormone related protein (PHRP) by the tumor cells. Humoral hypercalcemia of malignancy which is unrelated to the parathyroid gland can be caused by a wide variety of tumor types.…”