Maria Rendon

May 1, 2007

Treating paraneoplastic hypercalcemia in dogs and cats

Various tumor-related factors may lead to elevated calcium concentrations that can greatly contribute to acancer patient's morbidity. Here's how to help alleviate the suffering associated with this commonparaneoplastic syndrome.

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The links: Hypercalcemia is one of the most common paraneoplastic syndromes, and cancer is the most common causeof hypercalcemia in companion animals. Hypercalcemia of malignancy is usually associated with T-cell lymphoma andapocrine gland anal sac adenocarcinoma in dogs and lymphoma, bronchogenic carcinoma, and squamous cell carcinomain cats.The signs: Clinical signs of hypercalcemia include polyuria, polydipsia, lethargy, weakness, nausea, anorexia, vomiting,constipation, diarrhea, and weight loss.The tests: The main diagnostic tests include a CBC, a serum chemistry profile, urinalysis, a radiographic orultrasonographic examination, a rectal examination (in dogs), and ionized calcium, PTH, and PTHrP measurements.The treatment: In addition to addressing the primary tumor, supportive treatment consists chiefly of fluid therapy andfurosemide, as well as, in some cases, glucocorticoids and aminobisphosphonates.

Cancer accounts for about 50% of all deaths in companion animals more than 10 years of age.1 Cancer-related morbidity andmortality can result not only from neoplastic invasion of vital organs such as the pulmonary parenchyma or liver but also fromneoplasm-associated alterations in bodily structure or function that occur distant to the primary tumor and any metastaticlesions. These alterations are classically referred to as paraneoplastic syndromes. Hypercalcemia is a common paraneoplasticsyndrome in people and companion animals that frequently contributes to morbidity.2-6 Various tumor-related factors may lead toparaneoplastic hypercalcemia, including the release of humoral peptides, the abnormal expression of membrane-bound ligands,and dysregulated enzymatic pathways responsible for calcium homeostasis.7-9

The most common cause of hypercalcemia in companion animals is cancer, with about 45% to 65% of hypercalcemic dogs and10% to 30% of hypercalcemic cats having underlying neoplasia.7,10-13 The cancers that most frequently lead to paraneoplastichypercalcemia are T-cell lymphoma and apocrine gland anal sac adenocarcinoma in dogs and lymphoma, bronchogeniccarcinoma, and squamous cell carcinoma in cats.7,10,14 Given the prevalence of cancer in geriatric pets and the morbidityassociated with hypercalcemia, this review focuses on the diagnosis and treatment of paraneoplastic hypercalcemia in dogsand cats.

CALCIUM HOMEOSTASIS

Calcium homeostasis is a tightly regulated physiologic process whereby the body maintainssteady-state concentrations of ionized calcium, the biologically active fraction of total calcium, in theplasma and extracellular fluid through a dynamic interaction among key hormones and vitamins andtheir respective target organs. Three principal soluble mediators balance whole body calciumconcentrations: parathyroid hormone (PTH), calcitonin, and calcitriol (the biologically active form ofvitamin D). PTH and calcitriol are the master regulators of calcium homeostasis, with calcitonin playinga lesser, yet essential role.

These mediators exert their biologic activities on three target organs: the kidneys, intestines, andbone matrix. If serum calcium concentrations are decreased, the parathyroid glands secrete PTH toact on 1) the distal renal tubules, causing calcium reabsorption and phosphorus excretion from thekidney; 2) the intestines indirectly through the conversion of calcidiol to highly active calcitriol in the proximal renal tubules,which will increase intestinal absorption of calcium and phosphate; and 3) the bones, either by stimulating the activity of existingbone cells (early effect) or by increasing the number of osteoclasts and their bone resorption activities (late effect) via PTH'seffect on osteoblasts.

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Conversely, if serum calcium concentrations are elevated, PTH secretion is down-regulated, leading to 1) a net calcium lossthrough the distal tubules, 2) a reduction in intestinal calcium absorption, and 3) diminished osteoclastic bone resorption. BothPTH and calcitriol promote calcium retention within the body, while calcitonin reduces calcium mobilization from the skeletonchiefly by inhibiting osteoclastic bone resorption.9,15 While PTH has a positive feedback effect on calcitriol synthesis, the mainnegative feedback mechanisms on calcitriol production are calcitriol itself, as well as hypercalcemia and high phosphorusconcentrations.16 Calcitriol also provides a negative feedback effect on PTH secretion.

SERUM CALCIUM CONCENTRATION

Measured total serum calcium is composed of three organic forms: 1) It is bound to plasma proteins (40%); 2) it is complexedas citrates, acetates, and phosphates (10%); and 3) it is ionized or free (50%). Because only the latter form possessesbiological activity, ionized calcium measurements are the most physiologically relevant values to obtain when hypercalcemia issuspected based on an elevated total serum calcium concentration.15,16 Depending on the reference laboratory, hypercalcemiais usually defined by a total serum calcium concentration of ≥ 12 mg/dl (3 mmol/L) in dogs and ≥ 11 mg/dl (2.75 mmol/L) incats.10 True hypercalcemia is confirmed when the ionized calcium concentration is > 1.45 mmol/L in dogs or > 1.4 mmol/L incats.7

Accurately determining the calcium concentration in critically ill patients is important. So being aware of certain factors'influence on the reliable and precise laboratory assessment of calcium is fundamental. Fasting blood samples are necessary foraccurate quantification, as lipemia may falsely increase the measurement of serum calcium.17,18 Appropriate blood samplingtechnique is equally important to minimize laboratory errors secondary to hemolysis that may interfere with colorimetric analyzerreadings.18

Furthermore, hypoproteinemia, especially from hypoalbuminemia, may lead to a relative or spurious decrease in total serumcalcium. To compensate for albumin, an adjusted total calcium concentration (mg/dl) can be calculated in dogs by subtracting themeasured serum albumin concentration (g/dl) from the measured total serum calcium concentration (mg/dl) and adding 3.5.15,19

However, in some disease conditions, total calcium concentrations corrected for protein may still poorly correlate with ionizedcalcium concentrations, so they should not be considered a substitute for assessing ionized calcium.20 Also, this formula is notvalid in dogs younger than 1 year of age or in cats of any age.

In addition, although ionized calcium is physiologically active, interconversion among all three organic forms can occur andshould be considered when managing a critically ill patient. Blood pH or the plasma hydrogen ion concentration may affect theprotein binding of calcium, as a larger proportion of total serum calcium exists in a protein-bound form under alkalotic conditions,while acidosis favors calcium ionization.15 So samples collected and processed anaerobically ensure more accurate results,since the pH is less likely to increase from loss of carbon dioxide.15

Finally, ionized calcium and pH are more stable in serum than in whole or heparinized blood, and measured ionized calcium inserum is stable for seven days when collected anaerobically and stored at 39.2 F (4 C).15

CLINICAL SIGNS

Hypercalcemia of malignancy generally results in nonspecific signs that may be insidious and vary in severity. Regardless ofthe cause of the hypercalcemia, the urinary, neuromuscular, and gastrointestinal systems are most susceptible to the effects ofa high calcium concentration. The clinical signs' severity correlates not only with the magnitude of the hypercalcemia but alsowith the rate of calcium concentration elevation.15 In addition, in cases of hypercalcemia of malignancy, certain clinical signsmay be related to the underlying neoplastic disease rather than the secondary hypercalcemia. Thus, therapies should be aimedat treating the underlying cause in addition to the associated clinical consequences.

Urinary signs

The urinary system is severely affected by pathologic elevations in serum calcium concentrations, with primary polyuria andcompensatory polydipsia being the most common clinical signs seen in hypercalcemic dogs. Elevated serum calciumconcentrations lead to excessive production of dilute urine by inhibiting antidiuretic hormone receptors at the level of the distalrenal tubules, causing a secondary nephrogenic diabetes insipidus.15,19 In addition to these functional changes, structuraldamage in the renal tubules such as mineralization of the basement membrane and secondary tubular degeneration withresulting interstitial fibrosis can exacerbate kidney dysfunction and predispose affected animals to progressive renal failure.

Clinically, azotemia with decreased urine specific gravity or isosthenuria is often detected, and signs of uremia may be presentwhen renal tubule damage is severe and prolonged. Hypercalcemic nephropathy may be partially reversible with appropriatetherapy, but progressive renal failure with oliguria and anuria can occur if the condition is left untreated. Overt polydipsia is acompensatory response to the hypercalcemic-induced polyuria and is one of the most common clinical signs reported by petowners. Despite excessive water consumption, most patients are unable to replenish total body water stores, resulting inmoderate to severe dehydration. In an attempt to compensate for the loss of intravascular volume associated with dehydration,an increase in sodium and calcium reabsorption occurs at the proximal tubules, further worsening the ongoing hypercalcemia.

Neurologic signs

In addition to renal tubular epithelium, neurons are also sensitive to abnormal serum calcium concentrations. High ionizedcalcium concentrations decrease neuronal membrane permeability to sodium, which increases action potential thresholds and

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Table 1: Differential Diagnoses in Petswith Hypercalcemia and TypicalDiagnostic Test Findings*

Table 2: Diagnostic Tests toIdentify the Cause ofHypercalcemia in Dogs and Cats*

1A & 1B. A ventrodorsal radiograph of the righthumerus (1A) and a right lateral radiograph ofthe lumbar spine (1B) of an 11-year-old femalespayed mixed-breed dog presenting with signsof pain. Hypercalcemia, hypoalbuminemia, andhyperglobulinemia were noted on the serumchemistry profile. Multifocal purely lytic lesionsare seen. Bone marrow cytology and proteinelectrophoresis confirmed a diagnosis ofmultiple myeloma.

2A & 2B. Bone scintigraphy (99-Tc-EDTMP) ina 12-year-old male neutered mixed-breed dog(the dogs head is to the left) with prostatecarcinoma-a tumor type not reported to beassociated with hypercalcemia in this species.Increased uptake represents abnormal boneturnover and can be observed in many ribs(2A-open arrows) , in the sternum (2A-solidarrow), in the thoracic spine (2A-arrowhead),and in the femoral diaphysis and ischium(2B-open arrows). Nonspecific uptake is alsoobserved in the coxofemoral and stifle jointsfrom osteoarthritis (2B-arrowheads). Cytologicexamination confirmed that a target bone lesion(femur) was metastatic.

reduces neuronal depolarization events.16 Lethargy and weakness are clinical signs often reported by pet owners because ofthis electrochemical impairment. The concomitant use of narcotics or sedatives may worsen neurologic signs, and cancerpatients with central nervous system involvement will also be more severely affected by high serum calciumconcentrations.15,19

Gastrointestinal signs

Hypercalcemia also affects the gastrointestinal system, leading to nonspecific signs such asnausea, anorexia, vomiting, constipation, diarrhea, and weight loss. Constipation may developsecondary to depressed contractility of the gastrointestinal smooth muscles, resulting in prolongedintestinal transit times. Furthermore, hypercalcemia may increase gastrin secretion with subsequentincreases in hydrochloric acid secretion by parietal cells, leading to upper gastrointestinal irritationand mucosal ulceration.15,16,21 Gastrointestinal signs are among the most common presenting signsin cats with hypercalcemia.

DIAGNOSTIC APPROACH TO HYPERCALCEMIC PATIENTS

This review focuses on the common causes of paraneoplastichypercalcemia. Other important differential diagnoses associated withhypercalcemia in companion animals are presented in Table 1, using theacronym GOSH DARN IT. Once the list of differential diagnoses isunderstood, it is important to consider a stepwise diagnostic approach inhypercalcemic patients. Table 2 lists diagnostic tests to help you determinethe underlying cause of the hypercalcemia, along with the possible findings.

Obtaining a history and performing a complete and thorough physicalexamination, including rectal palpation in dogs, are always the first steps inevaluating hypercalcemic patients. The CBC and serum chemistry profileresults may help you narrow the potential causes of hypercalcemia. Forexample, if hyperglobulinemia is present (with or without hypoalbuminemia), consider performing serum and urine proteinelectrophoresis, as well as bone survey radiography and a bone marrow aspiration and cytology, to rule out multiple myeloma.

When the history, physical examination, standard imaging (thoracic radiography, abdominalultrasonography), and CBC and serum chemistry profile results fail to identify a potentialcause, further tests can be considered, such as PTH and PTH-related peptide (PTHrP)concentration measurement and an ultrasonographic examination of the ventral cervical area,ideally by an experienced radiologist. Generally, as with other disorders, the most commonconditions are ruled out first by using the least invasive techniques initially.

Routine tests to detect tumors ("tumor hunting") or completestaging procedures are recommended to better determine thehistologic origin and extent of malignancy. Bone survey, viaplain radiographs of the long bones and spine (Figures 1A &1B), or bone scan, via nuclear scintigraphy (Figures 2A & 2B)generally with technetium 99m-ethylenediamine-tetramethylenephosphonic acid (99-Tc-EDTMP), may providediagnostic clues in cases of occult or unexplainedhypercalcemia.

HYPERCALCEMIA OF MALIGNANCY: PATHOGENESIS

Hypercalcemia of malignancy may arise through three mainmechanisms. First, tumor cells may produce and liberatesoluble mediators capable of acting on bone and kidneysthrough endocrine and paracrine pathways, a mechanismreferred to as humoral hypercalcemia ofmalignancy.3-5,7,8,15,19 Second, cancer cells may subvert the enzymatic activity of 1 alpha-hydroxylase, thereby causing theunregulated conversion of calcidiol to active calcitriol, which enhances intestinal absorption of calcium.8,22-26 This mechanism ispoorly described with tumors in companion animals. Finally, certain tumor histologies such as leukemias, lymphomas, myeloma,and certain carcinomas may directly cause osteolysis when they invade or metastasize to bones, resulting in the dissolution ofhydroxyapatite crystals through an agonist effect on osteoclasts during tumor progression.9,27

Humoral hypercalcemia of malignancy

Humoral hypercalcemia of malignancy may involve the malignant secretion of PTHrP, a polypeptide structurally similar to intactPTH, as well as the liberation of cytokines such as interleukin-1, interleukin-6, or tumor necrosis factor.3-5,7,8,15,19 Theproduction and secretion of these humoral mediators lead to pathologic increases in osteoclastic resorption, often withoutvisible radiographic bone lesions. The most common cancers associated with humoral hypercalcemia of malignancy in dogs areT-cell lymphoma (see boxed text titled "Canine T-cell lymphoma: The most common cause of hypercalcemia of malignancy indogs") and apocrine gland anal sac adenocarcinoma (see boxed text titled "Apocrine gland anal sac adenocarcinoma: Thesecond most common cause of hypercalcemia of malignancy in dogs")8 ; while in cats lymphoma, bronchogenic carcinoma,

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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 secretePTHrP in dogs.36-40

Like its physiologic counterpart, PTHrP binds to PTH1 receptors on osteoblasts and renal tubular cells to exert itshypercalcemic 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 exhibitmoderate to marked hypercalcemia, hypophosphatemia, and hypercalciuria with decreased fractional calcium excretion andincreased fractional phosphorus excretion. For a supportive diagnosis of humoral hypercalcemia of malignancy, circulatingPTHrP 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 producedby normal tissues in certain conditions and participates in calcium homeostasis and metabolism. For example, PTHrP is knownto function in an endocrine manner in the fetus and is produced by the fetal parathyroid glands and the placenta, permittingionized calcium uptake by the fetus.15 It is also produced by the mammary gland in lactating dams to facilitate calciummobilization from maternal bones and may play a role in the transport of calcium into the milk.15 Finally, although the circulatingblood 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 boththrough humoral hypercalcemia of malignancy or direct osteolytic mechanisms. These tumors express osteotropism, or theaffinity 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 theparacrine 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 metastaticcarcinomas of urinary bladder, prostate, and mammary gland origins and occasionally with lymphoma and leukemias.19,42-44 Incats, squamous cell carcinoma and osteosarcoma have been associated with hypercalcemia, possibly resulting from localosteolysis.10

THERAPY

Fluid therapy

For any paraneoplastic syndrome, diagnosing and treating the underlying neoplastic disorder is mandatory to best manage thepatient. However, pending definitive diagnosis of the primary disease, initial intervention for hypercalcemia should ideallyconsist of vigorous rehydration with isotonic saline solution (0.9% sodium chloride). Severe dehydration andhemoconcentration associated with hypercalcemia are common because of the anorexia, vomiting, and calcium-associatedpolyuria, despite the compensatory polydipsia. A decreased glomerular filtration rate leads to additional calcium retention as thekidneys attempt to conserve sodium. To reverse the established vicious cycle and increase calciuresis through an improvedglomerular filtration rate, fluids devoid of calcium such as physiologic saline are usually recommended. In addition, the fluid ofchoice will have a high sodium concentration, since the sodium will compete with calcium for tubular reabsorption, resulting inenhanced calciuresis.15 However, the aggressive fluid therapy per se is more important than the actual type of fluid given, andlactated Ringer's solution can be used if saline solution is not available.

After adequate hydration, a patient's kidneys will first excrete sodium and then calcium, with clinical improvement usually seenwithin 24 hours of fluid therapy. Take the patient's hydration, renal, and cardiovascular status into consideration whendetermining the fluid rate. Potassium supplementation may be required in some cases to avoid hypokalemia, especially ifprolonged potassium-free intravenous fluid therapy is administered. Intravenous fluid therapy should aim to correct thedehydration over four to six hours after diagnosis in patients with moderate to severe hypercalcemia.

Loop diuretics

A loop diuretic, most commonly furosemide, may be added to the therapeutic regimen once the patient is adequately rehydrated.Furosemide inhibits the renal membrane sodium-potassium-dichloride cotransporter present in the thick ascending limb ofHenle's loop.45,46 The Handbook of Small Animal Therapeutics, edited by Lloyd E. Davis in 1985, is one of the first referencesrecommending the use of furosemide for hypercalcemia treatment in dogs. The original recommended dosage was an initialbolus of 5 mg/kg followed by a constant-rate infusion (CRI) of 5 mg/kg/hr intravenously. This high dose of furosemide is basedon human antihypercalcemic therapy and strictly requires a high rate of intravenous fluid administration (> three timesmaintenance fluid requirement) to avoid iatrogenic dehydration. We prefer using a lower dose of furosemide initially (2 to 4mg/kg t.i.d. to q.i.d. intravenously, subcutaneously, or orally) to minimize the need for a high fluid rate.

In a recent study of six normocalcemic greyhounds, a 0.66-mg/kg loading dose of furosemide followed by a CRI of 0.66mg/kg/hr (equivalent to 6 mg/kg over eight hours) was evaluated for its calciuretic efficacy compared with the same total doseof furosemide administered via two intravenous boluses of 3 mg/kg given four hours apart.47 Urine sodium and calcium loss as

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well as urine production and water intake were significantly larger in the CRI group compared with the intravenous bolus groups.The study concluded that the same total dose of furosemide over a given time frame resulted in more diuresis, natriuresis, andcalciuresis, as well as less kaliuresis, compared with repeated intravenous boluses.47 Similar to the results obtained in normalgreyhounds, it is our experience that the low-dose bolus followed by a CRI effectively reduces the degree of hypercalcemia.

Thiazide diuretics are absolutely contraindicated because of their hypercalcemic effect, as they cause tubular reabsorption ofcalcium rather than calciuresis.15,22

Glucocorticoids

The use of glucocorticoids is controversial for treating hypercalcemia and is not a component of standard therapy in peoplebecause of glucocorticoids' side effects and limited therapeutic value. The exact mechanisms of action of glucocorticoids inhypercalcemia are unknown, though it has been suggested that they increase renal calcium excretion, reduce bone resorption,and potentially decrease intestinal absorption.15,16,19 Glucocorticoids are most effective for hypercalcemia secondary tolymphoma, as they then also are part of the cytotoxic therapy aimed at the underlying cause. Prednisone at a dosage of 1 to2.2 mg/kg given twice a day intravenously, subcutaneously, or orally or dexamethasone at a dosage of 0.1 to 0.22 mg/kg giventwice a day intravenously, subcutaneously, or orally has been recommended.19,22 These high dosages should not bemaintained indefinitely, and appropriate tapering is advised.

Glucocorticoids are included in most conventional lymphoma chemotherapy protocols, but their initial use should be avoided fortwo reasons. First, they may delay the definitive diagnosis and appropriate therapy of a malignant lymphoproliferative diseasesuch as lymphoma. Additionally, their prolonged use may result in an increased risk of multidrug resistance (MDR phenotype),thereby negatively affecting the prognosis and chance of a long-lasting remission once appropriate multiagent cytotoxic therapyis instituted.48

Aminobisphosphonates

Together with rehydration, potent injectable aminobisphosphonates, chiefly zoledronate and pamidronate, are currently thecornerstone of therapy for malignancy-associated hypercalcemia in people.9,49,50 They are considered the safest and mosteffective drugs for that purpose. Human malignant hypercalcemia most commonly results from multiple myeloma and solidcarcinomas (e.g. breast, lung, prostate, renal) with bone metastases.9,15 Bisphosphonates are organic pyrophosphateanalogues that possess high affinity for bone hydroxyapatite crystals and, thus, highly concentrate in sites of active boneturnover.

Bisphosphonates exert their main biologic effect by inducing osteoclast apoptosis.49 The inhibition of global osteoclastic activitydecreases overall bone resorption and calcium release from the bone compartment.51-53 In people, bisphosphonates are usuallyinitiated as soon as hypercalcemia is discovered since the response is not immediate. Blood calcium concentrations normalizewithin four to 10 days, and the effect lasts for about one to four weeks.52,53 Either pamidronate or zoledronate is acceptable;however, zoledronate is the most potent of the two formulations and is the current best choice in human medicine.9Bisphosphonates that do not contain a nitrogen atom in their side chain, such as etidronate and clodronate, are not as potentas aminobisphosphonates in their antiresorptive activity and are generally not recommended for hypercalcemia ofmalignancy.51

While zoledronate administration also appears effective in dogs and cats, it remains cost-prohibitive in veterinary medicine. Onthe other hand, pamidronate is less expensive and is a good choice in hypercalcemic companion animals. Its use has beendemonstrated in dogs at the recommended dosage of 1.3 to 2 mg/kg given once intravenously over 20 minutes or two hours incases of experimental vitamin D toxicosis.54-56 An alternative safe dosage we are familiar with is 1 to 2 mg/kg givenintravenously over two hours every 21 to 28 days in dogs.57 A dosage we are familiar with in cats is 1 to 1.5 mg/kg givenintravenously over two hours every 21 to 28 days.

Because aminobisphosphonates act strictly at the bone level, a more pronounced effect on the hypercalcemia is obtained, bothin human and veterinary patients, when their use is combined with therapies acting at the kidney level (saline diuresis, a loopdiuretic) or in cases of hypercalcemia resulting from pure osteolytic processes rather than hypercalcemia secondary toincreased quantities of calcitriol, PTH, or PTHrP.8

Other therapies

Other therapeutic agents have been recommended but have minor use in small-animal medicine because of their cost, sideeffects, or scheduling of administration. These agents include mithramycin, calcitonin, and gallium nitrate.

Mithramycin, also known as plicamycin, is an antitumor antibiotic with potent inhibitory effects on osteoclasts, leading to rapidinhibition of bone resorption. In a study of dogs with cancer-associated hypercalcemia, mithramycin was used as a singleinfusion of 0.1 mg/kg.58 Unfortunately, patients developed clinical signs of fever, vomiting, and diarrhea shortly afteradministration and suffered hepatocellular injury with subsequent hepatic necrosis. Other clinical consequences such asthrombocytopenia and renal necrosis have also been reported.59 Although unacceptable toxicosis is observed at 0.1 mg/kg, theuse of mithramycin at a lower dosage (25 µg/kg infused over four hours) successfully controlled hypercalcemia for 24 to 72hours.19

Similarly to the mechanism of mithramycin, calcitonin reduces osteoclastic activity and reduces hypercalcemia in small animals

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with vitamin D toxicosis.60,61 Reported dosages range from 4.5 to 8 IU/kg given subcutaneously every eight hours to 5 IU/kggiven subcutaneously every 12 hours.61,62 For cats with rodenticide toxicosis, a dosage of 4 IU/kg given intramuscularly every12 hours was effective and well-tolerated.63 Unlike calcitonin's documented modest efficacy for the treatment of hypercalcemiasecondary to vitamin D toxicosis, calcitonin's utility in successfully managing hypercalcemia of malignancy in companionanimals remains to be investigated. Calcitonin is used in people with Paget's disease and hypercalcemia of malignancy, but theeffects of treatment can be quite variable.64-66 The main side effects of calcitonin are anorexia and vomiting. Its use is limitedby cost and the fact that its effects are short-lived and because resistance frequently develops in a matter of days.15

Gallium nitrate is an antineoplastic that binds to the hydroxyapatite crystals in bone, thereby reducing their solubility.67,68 Insome studies, gallium nitrate was demonstrated to be more effective than bisphosphonates at reducing calcium concentrationsin people with hypercalcemia.69 However, despite this apparent efficacy, it is not considered a first-line treatment option formanaging hypercalcemia given its potential for nephrotoxicity.

Novel therapies targeting the intercellular communication of osteoblasts and osteoclasts are under investigation. RANKL isexpressed by osteoblasts and T lymphocytes and binds to its cognate receptor, receptor activator of nuclear factor kappa-B(RANK), present on the surface of osteoclast precursors and osteoclasts, leading to their proliferation, maturation, andactivation. Promising antiresorptive molecules such as osteoprotegerin analogues, a soluble decoy RANKL receptor, or RANKnonfunctional constructs are being evaluated to decrease osteoclast activity and pathologic bone resorption.9,70

CONCLUSION

Paraneoplastic hypercalcemia is a common and serious complication observed in small-animal cancer patients. Various tumortypes are capable of inducing hypercalcemia in cancer patients through multiple mechanisms that subvert or dysregulatecalcium homeostasis. Canine T-cell lymphoma is the most common neoplasia associated with hypercalcemia, but other lessfrequent cancers and non-neoplastic diseases should be considered as important differential diagnoses in any patient withpathologic serum calcium elevations. Familiarity with clinical signs associated with hypercalcemia may allow for the earlydetection of underlying disease processes. The timely institution of definitive treatments and supportive management strategieswill minimize the morbidity, and potential mortality, in companion animals suffering from hypercalcemia of malignancy.

Pamela Lucas, DVMHugues Lacoste, DVM, DACVIM (oncology)Louis-Philippe de Lorimier, DVM, DACVIM (oncology)Timothy M. Fan, DVM, PhD, DACVIM (oncology, internal medicine)Department of Veterinary Clinical MedicineCollege of Veterinary MedicineUniversity of IllinoisUrbana, IL 61802

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27. Rosol TJ. Pathogenesis of bone metastasis: role of tumor-related proteins. J Bone Miner Res 2000;15:844-850.

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29. Tannehill-Gregg S, Kergosien E, Rosol TJ. Feline head and neck squamous cell carcinoma cell line: characterization,production of parathyroid hormone-related protein, and regulation by transforming growth factor-beta. In Vitro Cell Dev BiolAnim 2001;37:676-683.

30. Kleiter M, Hirt R, Kirtz G, et al. Hypercalcaemia associated with chronic lymphocytic leukaemia in a Giant Schnauzer. AustVet J 2001;79:335-338.

31. Henry CJ, Lanevschi A, Marks SL, et al. Acute lymphoblastic leukemia, hypercalcemia, and pseudohyperkalemia in a dog. JAm Vet Med Assoc 1996;208:237-239.

32. Foley P, Shaw D, Runyon C, et al. Serum parathyroid hormone-related protein concentration in a dog with a thymoma andpersistent hypercalcemia. Can Vet J 2000;41:867-870.

33. Mellanby RJ, Mellor PJ, Herrtage ME. What is your diagnosis? Thymoma. J Small Anim Pract 2004;45:589, 626-628.

34. Pressler BM, Rotstein DS, Law JM, et al. Hypercalcemia and high parathyroid hormone-related protein concentrationassociated with malignant melanoma in a dog. J Am Vet Med Assoc 2002;221:263-265.

35. Dhaliwal RS, Tang KN. Parathyroid hormone-related peptide and hypercalcaemia in a dog with functional keratinizingameloblastoma. Vet Comp Oncol 2005;3:98-100.

36. Bennett PF, DeNicola DB, Bonney P, et al. Canine anal sac adenocarcinomas: clinical presentation and response totherapy. J Vet Intern Med 2002;16:100-104.

37. Bertazzolo W, Comazzi S, Roccabianca P, et al. Hypercalcaemia associated with a retroperitoneal apocrine glandadenocarcinoma in a dog. J Small Anim Pract 2003;44:221-224.

38. Konno A, Sukegawa A, Kusano M, et al. Immunohistochemistry for parathyroid hormone-related protein (PTHrP) in benignand malignant mammary mixed tumors of dogs with and without hypercalcemia. Jpn J Vet Res 2000;47:155-162.

39. Anderson GM, Lane I, Fischer J, et al. Hypercalcemia and parathyroid hormone-related protein in a dog with undifferentiated

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nasal carcinoma. Can Vet J 1999;40:341-342.

40. Hori Y, Uechi M, Kanakubo K, et al. Canine ovarian serous papillary adenocarcinoma with neoplastic hypercalcemia. J VetMed Sci 2006;68:979-982.

41. Motellon JL, Jimenez FJ, de Miguel F, et al. Relationship of plasma bone cytokines with hypercalcemia in cancer patients.Clin Chim Acta 2000;302:59-68.

42. Barthez PY, Davis CR, Pool RR, et al. Multiple metaphyseal involvement of a thymic lymphoma associated withhypercalcemia in a puppy. J Am Anim Hosp Assoc 1995;31:82-85.

43. Villiers E, Dobson J. Multiple myeloma with associated polyneuropathy in a German shepherd dog. J Small Anim Pract1998;39:249-251.

44. Matus RE, Leifer CE, MacEwen EG, et al. Prognostic factors for multiple myeloma in the dog. J Am Vet Med Assoc1986;188:1288-1292.

45. Brater DC. Clinical pharmacology of loop diuretics. Drugs 1991;41(Suppl 3):14-22.

46. Puschett JB. Pharmacological classification and renal actions of diuretics. Cardiology 1994;84(Suppl 2):4-13.

47. Adin DB, Taylor AW, Hill RC, et al. Intermittent bolus injection versus continuous infusion of furosemide in normal adultgreyhound dogs. J Vet Intern Med 2003;17:632-636.

48. Price GS, Page RL, Fischer BM, et al. Efficacy and toxicity of doxorubicin/cyclophosphamide maintenance therapy in dogswith multicentric lymphosarcoma. J Vet Intern Med 1991;5:259-262.

49. Body JJ, Coleman RE, Piccart M. Use of bisphosphonates in cancer patients. Cancer Treat Rev 1996;22:265-287.

50. Tenta R, Sourla A, Lembessis P, et al. Bone-related growth factors and zoledronic acid regulate the PTHrP/PTH.1 receptorbioregulation systems in MG-63 human osteosarcoma cells. Anticancer Res 2006;26(1A):283-291.

51. Milner RJ, Farese J, Henry CJ, et al. Bisphosphonates and cancer. J Vet Intern Med 2004;18:597-604.

52. Rogers MJ, Watts DJ, Russell RG. Overview of bisphosphonates. Cancer 1997;80(8 Suppl):1652-1660.

53. Sonnemann J, Eckervogt V, Truckenbrod B, et al. The bisphosphonate pamidronate is a potent inhibitor of humanosteosarcoma cell growth in vitro. Anticancer Drugs 2001;12:459-465.

54. Rumbeiha WK, Fitzgerald SD, Kruger JM, et al. Use of pamidronate disodium to reduce cholecalciferol-induced toxicosis indogs. Am J Vet Res 2000;61:9-13.

55. Rumbeiha WK, Kruger JM, Fitzgerald SF, et al. Use of pamidronate to reverse vitamin D3-induced toxicosis in dogs. Am JVet Res 1999;60:1092-1097.

56. Hostutler RA, Chew DJ, Jaeger JQ, et al. Uses and effectiveness of pamidronate disodium for treatment of dogs and catswith hypercalcemia. J Vet Intern Med 2005;19:29-33.

57. Fan TM, de Lorimier LP, Charney SC, et al. Evaluation of intravenous pamidronate administration in 33 cancer-bearingdogs with primary or secondary bone involvement. J Vet Intern Med 2005;19:74-80.

58. Rosol T, Chew D, Hammer A. Effect of mithramycin on hypercalcemia in dogs. J Am Anim Hosp Assoc 1994;30:244-250.

59. Rosol TJ, Chew DJ, Couto CG, et al. Effects of mithramycin on calcium metabolism and bone in dogs. Vet Pathol1992;29:223-229.

60. Scheftel J, Setzer S, Walser M, et al. Elevated 25-hydroxy and normal 1,25-dihydroxy cholecalciferol serum concentrationsin a successfully-treated case of vitamin D3 toxicosis in a dog. Vet Hum Toxicol 1991;33:345-348.

61. Dougherty SA, Center SA, Dzanis DA. Salmon calcitonin as adjunct treatment for vitamin D toxicosis in a dog. J Am VetMed Assoc 1990;196:1269-1272.

62. Fooshee SK, Forrester SD. Hypercalcemia secondary to cholecalciferol rodenticide toxicosis in two dogs. J Am Vet MedAssoc 1990;196:1265-1268.

63. Peterson EN, Kirby R, Sommer M, et al. Cholecalciferol rodenticide intoxication in a cat. J Am Vet Med Assoc1991;199:904-906.

64. Inzerillo AM, Zaidi M, Huang CL. Calcitonin: physiological actions and clinical applications. J Pediatr Endocrinol Metab2004;17:931-940.

65. Chen P, Lai JM, Deng JF, et al. Relative bioavailability of salmon calcitonin given intramuscularly. Zhonghua Yi Xue Za Zhi(Taipei) 2000;63:619-627.

66. Grauer A, Ziegler R, Raue F. Clinical significance of antibodies against calcitonin. Exp Clin Endocrinol Diabetes

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1995;103:345-351.

67. Warrell RP Jr. Gallium nitrate for the treatment of bone metastases. Cancer 1997;80(8 Suppl):1680-1685.

68. Hughes TE, Hansen LA. Gallium nitrate. Ann Pharmacother 1992;26:354-362.

69. Cvitkovic F, Armand JP, Tubiana-Hulin M, et al. Randomized, double-blind, phase II trial of gallium nitrate compared withpamidronate for acute control of cancer-related hypercalcemia. Cancer J 2006;12:47-53.

70. Morony S, Warmington K, Adamu S, et al. The inhibition of RANKL causes greater suppression of bone resorption andhypercalcemia compared with bisphosphonates in two models of humoral hypercalcemia of malignancy. Endocrinology2005;146:3235-3243.

Canine T-cell lymphoma

The most common cause of hypercalcemia ofmalignancy in dogs

Dogs with hypercalcemia-associated lymphoma are considered to have clinical substage B disease and more likely have aT-cell immunophenotype, both known negative prognostic variables for remission duration and survival time.1-7 These malignantcells have the potential to secrete PTHrP.8-14

Lymphoma (T-cell) is the most common underlying cause of severe hypercalcemia in dogs and should be considered a topdifferential diagnosis for any dog presenting with this finding on a serum chemistry profile. Palpable lymph nodes (Figure A) orskin masses should be aspirated or biopsied for cytologic or histologic evaluation, respectively. A cranial mediastinal mass canbe identified on plain thoracic radiographs, which should be part of a hypercalcemia workup (Figures B-E).

Other diagnostic tests may be needed to confirm a diagnosis of mediastinal lymphoma, such as thoracic ultrasonography withfine-needle aspiration or Tru-Cut biopsies of the suspect mass. Cytologic or histologic confirmation may differentiate lymphomafrom thymoma, another tumor occasionally associated with paraneoplastic hypercalcemia in dogs and cats (Figures F & G).Abdominal radiography, abdominal ultrasonography, and bone marrow aspiration and cytology are recommended in cases ofhypercalcemia of unknown origin and suspected lymphoid tumors. Humoral hypercalcemia of malignancy with normal PTHrPconcentrations may be identified in some lymphoma cases and may occur because PTHrP can be sporadically released by thetumor or because some lymphoma cells possess 1 alpha-hydroxylase activities that lead to a syndrome of dysregulated1,25-dihydroxycholecalciferol (calcitriol) formation, although this mechanism of paraneoplastic hypercalcemia has been rarelyreported in companion animals.9,15-19

REFERENCES

1. Barthez PY, Davis CR, Pool RR, et al. Multiple metaphyseal involvement of a thymic lymphoma associated withhypercalcemia in a puppy. J Am Anim Hosp Assoc 1995;31:82-85.

2. Wilkerson MJ, Dolce K, Koopman T, et al. Lineage differentiation of canine lymphoma/leukemias and aberrant expression ofCD molecules. Vet Immunol Immunopathol 2005;106:179-196.

3. Garrett LD, Thamm DH, Chun R, et al. Evaluation of a 6-month chemotherapy protocol with no maintenance therapy for dogswith lymphoma. J Vet Intern Med 2002;16:704-709.

4. Chun R, Garrett LD, Vail DM. Evaluation of a high-dose chemotherapy protocol with no maintenance therapy for dogs withlymphoma. J Vet Intern Med 2000;14:120-124.

5. Greenlee PG, Filippa DA, Quimby FW, et al. Lymphomas in dogs. A morphologic, immunologic, and clinical study. Cancer1990;66:480-490.

6. Sarmiento UM, Valli VE. Lymphocyte 5'-nucleotidase activities in normal dogs and in dogs with malignant lymphoma. VetImmunol Immunopathol 1986;13:281-288.

7. Ruslander DA, Gebhard DH, Tompkins MB, et al. Immunophenotypic characterization of canine lymphoproliferative disorders.In Vivo 1997;11:169-172.

8. Weir EC, Norrdin RW, Matus RE, et al. Humoral hypercalcemia of malignancy in canine lymphosarcoma. Endocrinology1988;122;602-608.

9. Rosol TJ, Nagode LA, Couto CG, et al. Parathyroid hormone (PTH)-related protein, PTH, and 1,25-dihydroxyvitamin D indogs with cancer-associated hypercalcemia. Endocrinology 1992;131:1157-1164.

10. Clines GA, Guise TA. Hypercalcaemia of malignancy and basic research on mechanisms responsible for osteolytic andosteoblastic metastasis to bone. Endocr Relat Cancer 2005;12:549-583.

11. Schenck PA, Chew DJ, Nagode LA, et al. Disorders of calcium: hypercalcemia and hypocalcemia. In: DiBartola S, ed. Fluid,electrolyte, and acid-base disorders in small animal practice. 3rd Ed. St. Louis, Mo: Elsevier, 2006;122-194.

12. Feldman EC, Nelson RW. Canine and feline endocrinology and reproduction. 3rd ed. St. Louis, Mo: Saunders,2004;660-715.

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13. Fournel-Fleury C, Ponce F, Felman P, et al. Canine T-cell lymphomas: a morphological, immunological, and clinical study of46 new cases. Vet Pathol 2002;39:92-109.

14. Grone A, Werkmeister JR, Steinmeyer CL, et al. Parathyroid hormone-related protein in normal and neoplastic caninetissues: immunohistochemical localization and biochemical extraction. Vet Pathol 1994;31:308-315.

15. Morrison WB. Paraneoplastic syndromes and the tumors that cause them. In: Morrison WB. Cancer in dogs and cats:medical and surgical management. 2nd ed. Jackson, Wyo: Teton NewMedia, 2002;731-735.

16. Schenck PA, Chew DJ. Prediction of serum ionized calcium concentration by use of serum total calcium concentration indogs. Am J Vet Res 2005;66:1330-1336.

17. Kowalewski K, Kolodej A. Effects of calcium infusion on secretion and motor activity of totally isolated canine stomachperfused with homologous blood. Pharmacology 1976;14:537-549.

18. Sakals S, Peta HG, Fernandez NJ, et al. Determining the cause of hypercalcemia in a dog. Can Vet J 2006;47:819-821.

19. Uehlinger P, Glaus T, Hauser B, et al. Differential diagnosis of hypercalcemia—a retrospective study of 46 dogs [German].Schweiz Arch Tierheilkd 1998;140:188-197.

A. A 10-year-old intact female American bulldog presenting with pronounced peripheral lymphadenopathy,eventually diagnosed as diffuse large T-cell lymphoma on histologic examination. Markedly enlarged superficialcervical (prescapular) and mandibular lymph nodes are easily visible.

B & C. Lateral and ventrodorsal thoracic radiographs of a 6-year-old spayed female boxer presentingwith dyspnea, polyuria, and polydipsia. Severe hypercalcemia (20.4 mg/dl) and azotemia were noted onthe serum chemistry profile. Note the pleural effusion and a large soft tissue opacity in the cranialmediastinum displacing the lungs caudodorsally.

D & E. Lateral and ventrodorsal thoracic radiographs of the same dog five weeks after a standard combinationchemotherapy protocol was initiated. Dyspnea and hypercalcemia rapidly resolved after supportive therapy andcytotoxic chemotherapy were initiated.

F & G. Cytologic preparations of fine-needle aspirates from cranial mediastinal masses in twodifferent dogs. Figure F shows a monomorphic population of intermediate to large lymphocytes, withlarge nuclei, prominent nucleoli (arrowheads), and an open chromatin pattern, consistent withlymphoma (Wright's-Giemsa, 1,000x). Figure G shows a mixed population of small and intermediatelymphocytes, with occasional mast cells (arrowheads), suggestive of thymoma despite the absenceof epithelial cells on this sample (Wright's-Giemsa, 400x). (Photomicrographs courtesy of Dr. LauraD. Garrett.)

Apocrine gland anal sacadenocarcinoma

The second most common cause of hypercalcemia of malignancy in dogs

In dogs, apocrine gland anal sac adenocarcinomas are the second most common neoplastic cause of hypercalcemia ofmalignancy.1 The secretion of pthrp by carcinoma cells is generally the cause of calcium elevations.1-3 It is reported that 25%to 51% of dogs with apocrine gland anal sac adenocarcinomas are hypercalcemic,4-6 and the identification of elevated calciumconcentrations at diagnosis has been inconsistently associated with shorter survival times.4,5

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Given the relatively high incidence of serum calcium elevations in patients with apocrine gland anal sac adenocarcinoma, acareful rectal examination should be an integral part of the physical examination in dogs with hypercalcemia (see figure).Primary anal sac tumors may be small, so thorough and careful palpation of the anal sacs may be necessary for tumordetection. In addition, because it is not uncommon for apocrine gland anal sac adenocarcinomas to have regional metastaticdisease in the iliac lymph nodes that may be much larger than the primary tumor, abdominal ultrasonography with specialattention to the sublumbar area is recommended when an anal sac mass is palpated or in cases of hypercalcemia of unknownorigin.

A transverse computed tomography image of a 9-year-old male neutered Siberian huskydemonstrating a contrast-enhancing mass (arrowheads) originating from the right anal sacarea and extending in the pelvic canal, pushing the rectum (arrow) laterally toward the left. Thisdog was treated with multimodality therapy consisting of surgical excision of the primary tumorand regional lymph nodes, followed by megavoltage radiation therapy and systemicchemotherapy. The dog was lost to follow-up more than two years later. Hypercalcemia rapidlyresolved after supportive therapy and surgical excision of the primary and regional metastaticlesions.

REFERENCES

1. Rosol TJ, Nagode LA, Couto CG, et al. Parathyroid hormone (PTH)-related protein, PTH,and 1,25-dihydroxyvitamin D in dogs with cancer-associated hypercalcemia. Endocrinology 1992;131:1157-1164.

2. Morrison WB. Paraneoplastic syndromes and the tumors that cause them. In: Morrison WB. Cancer in dogs and cats:medical and surgical management. 2nd ed. Jackson, Wyo: Teton NewMedia, 2002;731-735.

3. Grone A, Weckmann MT, Blomme EA, et al. Dependence of humoral hypercalcemia of malignancy on parathyroid hormone-related protein expression in the canine anal sac apocrine gland adenocarcinoma (CAC-8) nude mouse model. Vet Pathol1998;35:344-351.

4. Williams LE, Gliatto JM, Dodge RK, et al. Carcinoma of the apocrine glands of the anal sac in dogs: 113 cases (1985-1995).J Am Vet Med Assoc 2003;223:825-831.

5. Bennett PF, DeNicola DB, Bonney P, et al. Canine anal sac adenocarcinomas: clinical presentation and response to therapy.J Vet Intern Med 2002;16:100-104.

6. Rosol TJ, Capen CC, Danks JA, et al. Identification of parathyroid hormone-related protein in canine apocrineadenocarcinoma of the anal sac. Vet Pathol 1990;27:89-95.

Maria Rendon1A & 1B. A ventrodorsal radiograph of the right humerus (1A) and a right lateral radiograph of the lumbar spine (1B) of an 11-year-old female spayed mixed-breeddog presenting with signs of pain. Hypercalcemia, hypoalbuminemia, and hyperglobulinemia were noted on the serum chemistry profile. Multifocal purely lyticlesions are seen. Bone marrow cytology and protein electrophoresis confirmed a diagnosis of multiple myeloma.

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Table 1: Differential Diagnoses in Pets with Hypercalcemia and Typical Diagnostic Test Findings*Table 2: Diagnostic Tests to Identify the Cause of Hypercalcemia in Dogs and Cats*2A & 2B. Bone scintigraphy (99-Tc-EDTMP) in a 12-year-old male neutered mixed-breed dog (the dogs head is to the left) with prostate carcinoma-a tumor typenot reported to be associated with hypercalcemia in this species. Increased uptake represents abnormal bone turnover and can be observed in many ribs (2A-openarrows) , in the sternum (2A-solid arrow), in the thoracic spine (2A-arrowhead), and in the femoral diaphysis and ischium (2B-open arrows). Nonspecific uptake isalso observed in the coxofemoral and stifle joints from osteoarthritis (2B-arrowheads). Cytologic examination confirmed that a target bone lesion (femur) wasmetastatic.

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