Neoplasia is the leading cause of hypercalcemia in dogs and the third most common cause in cats.3,4 T-cell lymphoma and apocrine gland adenocarcinoma of the anal sac are the most common cancerous causes of hypercalcemia in dogs,3,5 and lymphoma and carcinoma are the most common cancerous causes in cats.6,7 Hypercalcemia, however, is also possible with other tumor types, including multiple myeloma, parathyroid tumors, thymoma, melanoma, primary lung carcinomas, and acute and chronic lymphocytic leukemia.3,5
Hypercalcemia of malignancy is often caused by tumor production of parathyroid hormone-related protein (PTHrp), which activates osteoclasts, inducing bone resorption and calcium release. Other mechanisms are also possible via cytokine release or through direct release from bone secondary to widespread osteolysis.8 Absence of detectable PTHrp does not therefore rule out hypercalcemia of malignancy.8
Common clinical signs include polyuria/polydipsia, vomiting, inappetence, bradycardia, and weakness.8,9 In cats, anorexia and lethargy are the most common clinical signs, whereas polyuria/polydipsia and GI upset occur less frequently.6 Minimum database should include CBC, serum chemistry profile, and urinalysis. A rectal examination should also be performed in all patients with hypercalcemia. A high total calcium concentration warrants analysis of ionized calcium (iCa), as iCa is a more accurate reflection of physiologically active calcium.10
Several diagnostic laboratories offer a malignancy panel that includes iCa, PTH, and PTHrp and is helpful in diagnosing hypercalcemia of malignancy and primary hyperparathyroidism.11 Additional screening (eg, thoracic radiography, abdominal ultrasonography, cervical ultrasonography) may be required to identify a primary tumor and/or adequately stage a patient. More advanced diagnostics (eg, bone marrow aspiration, CT scan) can also be considered.
PTHrp and iCa levels (and, consequently, clinical signs) generally improve with successful treatment of the primary tumor.5,10 For critical patients, fluid therapy with 0.9% sodium chloride promotes volume expansion and diuresis, effectively diluting calcium concentrations acutely. Bisphosphonates (eg, zoledronate, pamidronate) induce osteoclast apoptosis, thereby inhibiting release of calcium from bone and temporarily reducing calcium levels in patients with hypercalcemia of malignancy.4,9,12 Loop diuretics are used for their calciuretic effect; however, these should only be used in patients that are well-hydrated and under close medical supervision.9
After a definitive diagnosis is determined, glucocorticoids are useful in decreasing absorption and promoting excretion of calcium through multiple physiologic mechanisms.9 In patients with steroid-responsive cancers (eg, lymphoma, multiple myeloma), glucocorticoids may impede future staging tests or, when used in advance of chemotherapy, increase resistance to some chemotherapy drugs. In these patients, steroids should be reserved for palliative treatment or withheld until all staging diagnostics have been performed and a chemotherapy plan has been instituted.