Introduction

Hypercalcemia of malignancy and tumor-induced hypercalcemia are the two terms used to describe this common and life-threatening complication of cancer. This paraneoplastic syndrome produces a metabolic emergency. It occurs in 10–20% of patients with cancer.

Etiology

A common misconception of the student is that metastases to bone is required to produce hypercalcemia. Although this “local osteolytic hypercalcemia” does occur, particularly in breast cancer and multiple myeloma, a more important cause overall is that termed “humoral hypercalcemia of malignancy.” This is the paraneoplastic process where humoral and paracrine factors produced by tumor cells stimulate osteoclast activity and proliferation resulting in bone resorption, liberating calcium into the circulation. Even in situations of tumor involving bone, such as in breast cancer and multiple myeloma, this humoral process has been demonstrated. Although many substances have been implicated in this role, it is not surprising that the agent deemed most responsible for this syndrome is a protein produced by the cancer that mimics normal parathyroid hormone (PTH). This peptide, termed parathyroid hormone-related protein (PTHrP), shows considerable homology with the natural PTH at the N-terminal, with 8 of the first 13 amino acids being identical. This protein has been found to interact with the PTH receptor with equal affinity to natural PTH. Therefore it has the same effect as PTH, which causes increased bone resorption by osteoclasts and renal calcium reabsorption. The clinician's level of suspicion for hypercalcemia should be raised in cancers where it occurs commonly (Table 53.1).