Humoral hypercalcemia of malignancy
Humoral hypercalcemia of malignancy may involve the malignant secretion of PTHrP, a polypeptide structurally similar to intact
PTH, as well as the liberation of cytokines such as interleukin-1, interleukin-6, or tumor necrosis factor.3-5,7,8,15,19 The production and secretion of these humoral mediators lead to pathologic increases in osteoclastic resorption, often without
visible radiographic bone lesions. The most common cancers associated with humoral hypercalcemia of malignancy in dogs are
T-cell lymphoma (see boxed text titled "Canine T-cell lymphoma: The most common cause of hypercalcemia of malignancy in dogs") and apocrine gland anal sac adenocarcinoma (see boxed text titled "Apocrine gland anal sac adenocarcinoma: The second most common cause of hypercalcemia of malignancy
in dogs")8 ; while in cats lymphoma, bronchogenic carcinoma, and squamous cell carcinoma are most commonly reported.7,10,28,29 Other tumors such as leukemias,30,31 thymoma,32,33 malignant melanoma,34 acanthomatous ameloblastoma,35 and various carcinomas have been sporadically reported to secrete PTHrP in dogs.36-40
Like its physiologic counterpart, PTHrP binds to PTH1 receptors on osteoblasts and renal tubular cells to exert its hypercalcemic
effects.9,15,16,22 Some growth factors, such as epidermal growth factor and transforming growth factor-beta, increase PTHrP expression.15,22,41 Animals with hypercalcemia due to elevated PTHrP concentrations typically exhibit moderate to marked hypercalcemia, hypophosphatemia,
and hypercalciuria with decreased fractional calcium excretion and increased fractional phosphorus excretion. For a supportive
diagnosis of humoral hypercalcemia of malignancy, circulating PTHrP concentrations may be assessed by sending EDTA plasma
samples to commercial laboratories.8
While it may seem at first that PTHrP is an abnormal hormone produced only by certain cancer cells, this hormone is produced
by normal tissues in certain conditions and participates in calcium homeostasis and metabolism. For example, PTHrP is known
to function in an endocrine manner in the fetus and is produced by the fetal parathyroid glands and the placenta, permitting
ionized calcium uptake by the fetus.15 It is also produced by the mammary gland in lactating dams to facilitate calcium mobilization from maternal bones and may
play a role in the transport of calcium into the milk.15 Finally, although the circulating blood concentrations are low in normal adults, PTHrP has been demonstrated in some epithelial
tissues, endocrine glands, muscles, bone, brain, and lymphocytes.15
Local osteolytic tumors
Metastatic carcinomas are commonly associated with malignant osteolysis in people and can lead to hypercalcemia both through
humoral hypercalcemia of malignancy or direct osteolytic mechanisms. These tumors express osteotropism, or the affinity and
ability to grow within bone; the exact mechanisms behind this phenomenon have yet to be fully characterized.
Tumor cells' presence within the bone microenvironment can increase the number and activity of local osteoclasts through the
paracrine release of factors such as interleukin-1, interleukin-6, tumor necrosis factor-alpha and tumor necrosis factor-beta,
receptor activator of nuclear factor kappa-B ligand (RANKL), and prostaglandins, leading to localized bone resorption.15 Excessive focal bone resorption can cause bone pain, predispose patients to pathologic fracture, and induce hypercalcemia.
These malignant clinical consequences occur most typically in companion animals with multiple myeloma and metastatic carcinomas
of urinary bladder, prostate, and mammary gland origins and occasionally with lymphoma and leukemias.19,42-44 In cats, squamous cell carcinoma and osteosarcoma have been associated with hypercalcemia, possibly resulting from local
osteolysis.10
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