Hypercalcemia of malignancy
1. What are the two major categories of hypercalcemia of malignancy?
2. What types of cancers are associated with HHM?
Carcinoma of the lung, particularly squamous cell carcinoma, is the most common. Other tumors associated with this disorder are squamous cell carcinomas of the head, neck, and esophagus and adenocarcinomas of the breast, kidney, bladder, pancreas, and ovary.
HHM results when solid malignancies, both solitary and metastatic, secrete into the circulation one or more substances that cause hypercalcemia. The humoral mediator identified in more than 90% of cases is parathyroid hormone–related peptide (PTHrp). Other humoral substances that are occasionally secreted and contribute to the development of hypercalcemia include transforming growth factor-alpha (TGF-α), tumor necrosis factor (TNF), and various interleukins and cytokines.
PTHrp is a protein that has sequence homology with the first 13 amino acids of parathyroid hormone (PTH). Both PTH and PTHrp bind to a common receptor (PTH/PTHrp receptor), resulting in stimulation of bone resorption and inhibition of renal calcium excretion. PTHrp is found in high concentrations in breast milk and amniotic fluid, but it can be detected in almost every tissue in the body; its level is increased in the circulation during pregnancy. The physiologic endocrine function of PTHrp may be to govern the transfer of calcium from the maternal skeleton and bloodstream into the developing fetus and into breast milk. As a generalized paracrine factor, it also regulates growth and development of many tissues, most prominently the skeleton and breast.
5. How does PTHrp cause hypercalcemia in patients with cancer?
Elevated circulating concentrations of PTHrp stimulate generalized bone resorption, flooding the bloodstream with excessive calcium; PTHrp also acts on the kidneys, preventing excretion of the greater calcium load. This combination produces an increase in the serum calcium concentration. Hypercalcemia induces polyuria, which leads to dehydration with impaired renal function, further reducing calcium excretion and leading to a cycle of progressive and eventually life-threatening hypercalcemia.
6. How do you make a diagnosis of HHM?
