Tumors associated with hypercalcemia of malignancy do not represent a homogeneous group, and there is no single unifying mechanism that can explain all cases of hypercalcemia. However, it is likely that similar mechanisms are responsible in similar types of tumors (1). In the hematologic malignancies (~15-20% of the total), local bone-resorbing factors are responsible for extensive osteolytic bone destruction and hypercalcemia usually occurs in association with impaired glomerular filtration. In a second group, the solid tumors associated with advanced osteolytic metastases, hypercalcemia rarely occurs unless the tumor is widespread and there is extensive local bone destruction. The most common example of this group is breast cancer (~25% of the total). A third group is comprised of solid tumors such as squamous cell carcinoma of the lung, head, and neck, carcinoma of the kidney, and carcinoma of the ovaries, where the primary mechanism is increased bone resorption caused by tumor secretion of a circulating stimulator or stimulators of osteoclast activity. This syndrome is called the humoral hypercalcemia of malignancy (HHM)1 and comprises ~55% of the total. These patients may or may not have metastatic bone disease.
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