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Hypercalcemia of Malignancy (HM)

Jessica Lee Talbott, DVM, DACVIM (Medical Oncology)

www.angell.org/oncology
617-541-5136
oncology@angell.org

Hypercalcemia of malignancy (HM) is one of the most commonly encountered paraneoplastic syndromes in veterinary medicine. HM is the inappropriate elevation of ionized calcium as a result of underlying neoplasia. The elevation in calcium is typically related to an overproduction of a substance (i.e. peptides, hormones, etc.) that is not normally released within the body. Often the paraneoplastic syndrome parallels the underlying cancer diagnosis and may be the first clinical sign observed in patients, as is the case with HM. Additionally the clinical morbidity associated with HM is often greater than that associated with the primary tumor. Therefore it is imperative that every clinician have an understanding and appreciation of HM for early cancer detection and therapy.

 

The most common cause of hypercalcemia in veterinary patients is neoplasia, accounting for hypercalcemia in approximately two-thirds of dogs1,2 and one-third of cats.3 There are several types of tumors associated with hypercalcemia with the most common cause of HM being lymphoma (10-35% occurrence). Other tumor types include anal sac apocrine gland adenocarcinoma (≥25%), multiple myeloma (20%), parathyroid tumors, mammary gland carcinoma, thyroid carcinoma, bone tumors, thymoma, squamous cell carcinoma, melanoma, primary lung tumors, and chronic lymphocytic leukemia.4 Other non-neoplastic differential diagnoses for hypercalcemia include chronic renal disease/failure, hypoadrenocorticism, hypervitaminosis D, and granulomatous disease.5

 

There is a variety of proposed mechanisms that cause HM, most notably ectopic production of parathormone (PTH) or PTH-related peptide (PTH-rp) by the tumor. The HM present in patients diagnosed with lymphoma and anal sac apocrine gland adenocarcinoma is most commonly associated with increased production of PTH-rp by the tumor. PTH-rp is a 16-kDa protein with significant sequence homology to PTH, therefore it acts and functions in a similar fashion to PTH in order to increase serum calcium. Other mechanisms that cause HM include extensive and multifocal osteolytic metastases, tumor-associated prostaglandins, interleukin-1-β (IL-1β, previously known as osteoclast-activating factor [OAF], transforming growth factor-β (TGF-β), and receptor activator of nuclear factor kappa-B ligand (RANKL).5,6

 

Clinical Signs

Dogs with HM often present with signs due to renal function impairment that begins as a decreased ability to concentrate urine then progresses to polyuria (PU), polydipsia (PD), and progressive dehydration. This inability to concentrate urine is the direct effect of elevated serum calcium at the level of the distal tubule, decreasing its responsiveness to antidiuretic hormone (ADH). Other renal effects include decreased renal blood flow and glomerular filtration rate (GFR) as a result of severe vasoconstriction and sometimes changes to the urothelium that may cause exposure of the basement membrane of the renal tubule. In addition to changes observed within the renal system, systemic clinical signs in more severely hypercalcemic patients may include twitching, shaking, weakness, depression, vomiting, anorexia, constipation, hypertension, arrhythmias, bradycardia, stupor, coma and/or death.5 It is less common for cats to exhibit PU, PD, and weight loss as a result of hypercalcemia.

 

Diagnosis

The diagnosis of hypercalcemia is made by documenting the presence of elevated ionized calcium (iCa), the biologically active fraction of calcium. The author’s current recommendation is to perform an ionized calcium in those cases with elevated total serum calcium (tCa), as well as those cases where neoplasia is strongly suspected and the tCa is normal. This is because there are newer reports of discordance between tCa and iCa measurements. The author advises against using formulas to correct the total serum calcium to the total protein or albumin as these formulas do not accurately predict ionized calcium. Instead we recommend referral to a hospital where an ionized calcium can be performed. It is important to remember that severe lipemia or a hemolyzed sample (i.e “lab error”) may account for an elevated tCa in patients.7

 

Following a diagnosis of hypercalcemia, appropriate steps should be taken for identification of the underlying neoplasm. A thorough physical exam including a rectal exam is imperative to evaluate the anal sac glands. Additional diagnostics including a minimum database (CBC, chemistry (if not already performed), urinalysis), thoracic radiographs, abdominal ultrasound, +/- fine needle aspirates and cytology of abnormalities noted is important to consider. Additional blood tests, such as a PTH and PTH-rp assays (typically part of a panel commonly performed at Michigan State University, called the hypercalcemia of malignancy panel) may be necessary during the diagnostic evaluation.

 

Treatment

Hypercalcemia of malignancy represents a potential medical emergency, therefore identifying the underlying cause is vital to treatment of the specific tumor and resolution of the hypercalcemia. The most effective management of HM involves incorporation of aggressive supportive care to treat the hypercalcemia as well as treatment for the primary tumor.

 

The goal of symptomatic therapy is to use treatments that will promote renal excretion of calcium, increase external loss of calcium, and inhibit bone reabsorption. The duration of symptomatic therapy depends on the duration of ionized hypercalcemia in each patient, as well as the ability to identify and treat the primary neoplasm. It is the author’s experience that with rapidly initiated aggressive therapy, the majority of patients show a dramatic reduction in the ionized calcium within 12-24 hours, with some patients having a normal iCa within 3-5 days. Resolution can take up to 3-4 weeks (for some) after treatment of the primary neoplasm, however nearly all patients receiving symptomatic treatment feel better and have greatly improved clinical signs.

 

If the iCa is 1.6 mmol/L or greater, patients often exhibit clinical signs and treatment is recommended. Hospitalization is strongly recommended for any patient that has an iCa of ≥ 1.8mmol/L. When the iCa is 2-2.2mmol/L the patient is often critically ill showing systemic clinical signs (i.e. twitching, bradyarrhythmias, vomiting, anorexia) and hospitalization is required.7 It is the author’s practice to recommend treatment for any patient showing clinical signs associated with hypercalcemia regardless of how mild the elevated iCa may be.

 

The severity of clinical signs and associated hypercalcemia dictate the recommended therapy. While approximate lab values are provided below, each patient is considered based on their iCa and the type and severity of clinical signs present.

 

Mild HM with mild clinical signs (~ 1.6-1.8mmol/L)

  1. Intravenous (IV) fluids using 0.9% NaCl, administered for rehydration.

 

Moderate HM with clinical signs (~1.8mmol/L or greater)

  1. Intravenous (IV) fluids using 0.9% NaCl, administered for rehydration and diuresis.
  2. Furosemide (Lasix®): 1-4 mg/kg every 8-24 hours IV or PO.
    1. After patient has been adequately hydrated.
  3. Prednisone: 1 mg/kg PO SID to BID
    1. After diagnosis has been obtained ideally.

 

Severe HM with severe clinical signs; an oncologic emergency (~1.9 mmol/L or greater)

  1. Intravenous (IV) fluids using 0.9% NaCl, administered for rehydration and diuresis.
  2. Furosemide (Lasix®): 1-4 mg/kg every 8-24 hours IV or PO.
    1. After patient has been adequately hydrated.
  3. Prednisone: 1 mg/kg PO SID to BID
  4. Bisphosphonates
    1. Pamidronate (Aredia®): 1-2 mg/kg IV (diluted in 0.9% NaCl) administered over 2 hours, as often as once per month.
    2. Zoledronate (Zometa®): 0.1 – 0.25 mg/kg IV administered over 15 minutes, as often as once per month.
  5. Salmon calcitonin
    1. This can be reserved for severe refractory cases however is rarely necessary with treatment using the above therapies and treatment of the underlying neoplasm.

 

The use of normal saline is recommended for treatment of existing dehydration, expansion of the extracellular fluid volume, increasing GFR, increasing calciuresis, and decreasing calcium reabsorption by the kidneys. Furosemide is used in conjunction with normal saline diuresis to potently inhibit calcium reabsorption in the ascending loop of Henle. Corticosteroids are best used following a diagnosis of HM as they are extremely effective to reduce hypercalcemia by inhibition of prostaglandins, OAF, vitamin D, and intestinal calcium absorption.5

 

Bisphosphonates are often used in treatment of severe hypercalcemia or those cases refractory to supportive care and/or treatment of the underlying neoplasm. Bisphosphonates are synthetic analogs of inorganic pyrophosphate that were originally used for diagnostic purposes in bone scanning, however they possess bone protective effects exerted through induction of osteoclast apoptosis. This results in diminished bone resorption with subsequent reductions in serum calcium levels.8,9 Although the use of bisphosphonates is the standard of care for human oncology patients with HM, further research is necessary to determine if single-agent bisphosphonates are as effective in veterinary patients. Until then, the best use of bisphosphonates for patients with HM is alongside adjuvant therapies (i.e glucocorticoids, loop diuretics) that minimize renal tubular calcium reabsorption.9

 

Figure one shows serial iCa measurements from a canine patient that was diagnosed with HM on 7/9/16. The definitive diagnosis of multiple myeloma was made on 7/11/16 at which point definitive treatment was initiated using chemotherapy. Within 14 days (7/26/16), the iCa was within normal limits and the patient was significantly clinically improved. This patient received initial treatment with saline diuresis, prednisone, furosemide, and a single Zoledronate infusion as well as treatment with chemotherapy (Melphalan), starting 7/11/16.

Figure 1: Serial iCa measurements from a patient with HM secondary to multiple myeloma. Dates are chronological from right to left. The iCa reference range is the far left column.

Prognosis

Ultimately the prognosis associated with HM is directly related to early identification of the underlying cause and rapid initiation of supportive therapy as well as treatment of the primary tumor. The great majority of patients with HM, when treated rapidly and appropriately, can become normocalcemic, experience resolution of clinical signs, and ultimately an improved quality of life.

 

For more information, please contact Dr. Lee Talbott at the Angell Oncology Service (617-541-5136 or oncology@angell.org).

 

References:

  1. Uehlinger P, Glaus T, Hauser B, et al: [Differential diagnosis of hypercalcemia-a retrospective study of 46 dogs], Schweiz Arch Tierheilkd 140(5):188-197, 1998.
  2. Elliot J: Hypercalcemia in the dog: A study of 40 cases, J Small Anim Pract 32:564-567, 1991.
  3. Savary KC, Price GS, Vaden SL: Hypercalcemia in cats: a retrospective study of 71 cases (1991-1997), J Vet Intern Med 14(2): 184-189, 2000.
  4. Messinger JS, Windham WR, Ward CR: Ionized hypercalcemia in dogs: a trestrspective study of 109 cases (1998-2003), J Vet Intern Med 23(3):514-519, 2009.
  5. Bergman Phillip J. Paraneoplastic Syndromes. In: Small Animal Clinical Oncology. 5th ed. Elsevier; 2013. p. 83–86.
  6. Weir EC, Burtis WJ, Morris CA, et al: Isolation of 16000-dalton parathyroid hormone-like proteins from two animal tumors causing humoral hypercalcemia of malignancy. Endocrinology 123(6):2744-2751, 1988.
  7. de Brito Galvao, JF, Schenck PA, Chew DJ: A quick reference on hypercalcemia. Vet Clin Small Anim: 1-8, 2016.
  8. Fan, Timothy M. Pain Management in Veterinary Patients with Cancer. Vet Clin Small Anim 44: 989-1001, 2014.
  9. Fan, Timonthy M. The Role of Bisphosphonates in the Management of Patients That Have Cancer. Vet Clin Small Anim 37:1091-1110, 2007.

 

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