Mechanisms of Humoral Hypercalcemia of Malignancy in Leukemia/Lymphoma

Hypercalcemia is one of the most common paraneoplastic syndromes. The incidence of hypercalcemia is 50-90% in adult T-cell leukemia/lymphoma (ATLL), 27-35% in lung cancer, 25-30% in breast cancer, 7-30% in multiple myeloma, and less than 10% in other types of cancer patients (Mundy & Martin, 1982; Roodman, 1997). Patients with severe hypercalcemia (>12 mg/dL; > 6.0 mM) usually develop neuromuscular, gastrointestinal and renal symptoms including lethargy, depression, anorexia, nausea, vomiting, polyuria and polydipsia. Patients with serum calcium concentrations >15 mg/dL (7.6 mM) can develop renal failure or cardiovascular abnormalities with arrhythmias and coma (Mundy & Martin, 1982). Depending on the sources of the stimulating factors, hypercalcemia in cancer can be divided into 3 types: (1) humoral hypercalcemia of malignancy (HHM) in which humoral factors secreted by tumor cells directly or indirectly affect cells in the target organs including bone, kidney and intestine that regulate calcium homeostasis; (2) local osteolytic hypercalcemia in which factors secreted by either primary or metastatic tumor cells locally in the bone microenvironment stimulate osteoclastic bone resorption; and (3) primary hyperparathyroidism that coexists with the malignancy (Stewart, 2005). This review will focus on HHM, although some types of cancers may induce both HHM and local osteolytic hypercalcemia, since several factors can function both systemically and locally.