Hypercalcemia of Malignancy - The Merck Veterinary Manual

Hypercalcemia of Malignancy

Adenocarcinoma of the Apocrine Glands of the Anal Sac

Malignancy is the most common cause of persistent hypercalcemia in dogs and is a common cause in cats. In hypercalcemia of malignancy, the hypercalcemia primarily results from increased osteoclastic bone resorption, but increased renal tubular resorption and increased intestinal absorption may also play a role. Factors that may be produced by tumors and result in humoral hypercalcemia of malignancy include PTH, PTH-related protein, transforming growth factor, 1,25-dihydroxyvitamin D, prostaglandin E₂, osteoclast-activating factor, and other cytokines (interleukin-1, interleukin-2, and g-interferon). Although many tumors have been associated with hypercalcemia in humans, in dogs malignancy-associated hypercalcemia has been most commonly linked to lymphoma, adenocarcinoma of the apocrine glands of the anal sac, and multiple myeloma. Other tumors (thymoma, squamous cell carcinoma, nasal carcinoma, hemangiosarcoma, and undifferentiated adenocarcinoma) have also been associated with hypercalcemia in dogs. In cats, humoral hypercalcemia of malignancy occurs less frequently than in dogs but has been reported with squamous cell carcinoma, multiple myeloma, and lymphoproliferative diseases.

Lymphoma (Lymphosarcoma):

The most common tumor associated with hypercalcemia in dogs, lymphoma is also one of the tumors associated with hypercalcemia in cats. The pathogenesis of the hypercalcemia may involve 2 general mechanisms. One is local elaboration of an osteolytic factor that induces resorption of bone and mobilization of calcium when the bone marrow is infiltrated by tumors cells. The other, probably more important, is humoral hypercalcemia in which neoplastic cells produce a humoral factor that acts at a distance from the tumor. As evidence for secretion of a humoral substance by tumor cells, increased bone resorption, phosphaturia, and urinary excretion of cyclic adenosine monophosphate (cAMP) have been documented in dogs with lymphoma. Serum concentrations of both PTH and 1,25-dihydroxyvitamin D are generally low in these dogs, but a peptide related to PTH (PTH-related peptide) has been detected in dogs with lymphoma (Table: Characteristic Laboratory Abnormalities of Common Causes of Hypercalcemia).

Of dogs with lymphoma, 10-40% have concurrent hypercalcemia, and a large number of these cases also have the mediastinal form of lymphoma. Although detectable lymphadenopathy is usually present, hypercalcemia may be the first abnormality noted. A thorough physical examination, together with thoracic chest and abdominal radiographs, abdominal ultrasonography, multiple lymph node aspirates or biopsies, and multiple bone marrow aspirates may be necessary to make the diagnosis. Treatment with glucocorticoids (eg, prednisone) will lower the serum calcium concentrations; however, steroids are lympholytic and will make identification of lymphoma difficult. Although remission rates in dogs with lymphoma and hypercalcemia are not statistically different from those without hypercalcemia, survival times are considerably less, indicating that hypercalcemic lymphomas have a poorer prognosis. (See also canine malignant lymphoma, Canine Malignant Lymphoma: Introduction, and feline leukemia virus and related diseases, Feline Leukemia Virus and Related Diseases: Introduction.)

Adenocarcinoma of the Apocrine Glands of the Anal Sac:

This tumor usually occurs in older female dogs, with hypercalcemia developing in ~90% of cases. Humoral mechanisms are most likely responsible for the hypercalcemia as a PTH-like protein has been identified from tumor tissue in dogs. This tumor is usually malignant and has metastasized to regional lymph nodes by the time of diagnosis. Surgical resection is associated with reduction of serum calcium. Failure to remove all of the tumor or recurrence of the tumor usually results in recurrence of hypercalcemia. Despite surgical excision, radiation, and various chemotherapy protocols, the tumor usually recurs within a few months, and prognosis is poor.

Multiple Myeloma:

This malignancy in dogs and cats has been associated with hypercalcemia in 10-15% of cases. The pathogenesis of the hypercalcemia is most likely multifactorial. Myeloma cells are known to produce osteoclast-activating factor in humans, which may partially account for the hypercalcemia. The presence of extensive bony lysis may also contribute to the increased serum calcium. Although serum protein concentration is usually increased in multiple myeloma, increased protein binding of calcium rarely accounts for the hypercalcemia. Treatment of multiple myeloma with chemotherapy has been associated with longterm survival, but the presence of associated hypercalcemia, light chain proteinuria, and extensive bony lesions is associated with a shorter survival time.