Cancer-associated hypercalcemia is the #1 cause for hypercalcemia in the inpatient setting (in the outpatient setting, the main cause is primary hyperparathyroidism). In general, hypercalcemia of malignancy portends a poor prognosis, and there are three main mechanisms by which hypercalcemia can occur:
1. PTHrP (PTH-related peptide): this is the most common cause of hypercalcemia of malignancy, and is sometimes referred to as "humoral hypercalcemia of malignancy." The PTHrP essentially mimics the effects of PTH by virtue of its interaction with the PTH receptor, though since PTHrP is not detected by standard PTH assays the measured PTH level is typically very low. Sending a PTHrP level may be helpful, though in my experience it often takes several days to come back. PTHrP is most commonly secreted by solid tumors, such as breast cancer.
2. osteolytic metastases: this is the 2nd most common mechanism of hypercalcemia of malignancy, and is due to osteoclast-mediated bone breakdown. It occurs in characteristic tumor types, which can be recalled by this nifty mnemonic, "BLT with a Kosher Pickle, Mustard & Mayo":
B = breast cancer
L = lymphoma, lung cancer
T = thyroid cancer
K = kidney cancer
P = prostate cancer
M & M = multiple myeloma
3. tumor production of calcitrol: the mechanism is here is similar to that of granulomatous disease: tumor cells provide enzymatic synthesis of 1,25 OH-vitamin D, the active form of vitamin D, leading to unregulated GI uptake of calcium. It is most commonly seen in Hodgkin's lymphoma and some cases of NHL as well. It can be diagnosed by finding an elevated 1,25 OH vitamin D level in the presence of malignancy.
Very, very rarely one can observe ectopic PTH secretion as a mechanism for hypercalcemia of malignancy.