Endocrinological Paraneoplastic Syndromes in Small Animals

Cancer is the most common cause of hypercalcemia in dogs, and the second most common cause in cats. Malignancies most frequently associated with hypercalcemia include lymphoma (notably, 35–55% of T-cell lymphoma patients), leukemia, multiple myeloma, thymoma, carcinomas (primarily anal sac adenocarcinoma in dogs and squamous cell carcinoma in cats), and parathyroid tumors (1).

Paraneoplastic mechanisms of hypercalcemia include tumor production and release of soluble mediators (such as parathyroid hormone–related protein [PTHrP], interleukin-1 and interleukin-6 [IL-1, IL-6], and calcitriol) by tumor cells into circulation; release of osteoclast-activating factors by bony metastatic lesions; excessive production of 1,25-dihydroxyvitamin D; and excessive production of parathyroid hormone (PTH) (1).

Patients with hypercalcemia can demonstrate evidence of renal compromise or failure (polyuria/polydipsia, isosthenuria, or hyposthenuria on urine testing), in addition to a host of other nonspecific clinical signs (anorexia or other GI distress, lethargy, neurological deficits, arrhythmias, etc). Overt evidence of cancer (eg, palpable anal sac mass, marked organomegaly, peripheral lymph node enlargement, skin lesions, oral mass in a cat) can be apparent on physical examination (see hypercalcemia image). 

Hypercalcemia, dog

Image

Courtesy of Dr. Brooke Britton.

In addition to hypercalcemia, bloodwork abnormalities such as marked lymphocytosis, visible/circulating lymphoblasts on a blood smear, hyperglobulinemia, cytopenias, azotemia, and/or liver enzyme elevations can be present.

Imaging might reveal a cranial mediastinal mass or metastatic pulmonary nodules, organomegaly, nodal or bony metastases, or neoplastic effusion.

When evaluating hypercalcemia in dogs and cats, a veterinarian must measure ionized calcium concentration in addition to total calcium concentration, because ionized calcium concentration more precisely characterizes the importance of the hypercalcemia. Ionized calcium concentrations > 1.4–1.5 mmol/L are considered to be in the hypercalcemic range.

Measurement of PTH, vitamin D, and PTHrP concentrations should be considered when physical examination, clinicopathological, and imaging findings are unrewarding in determining the cause of ionized hypercalcemia.

PTH concentrations are typically low in the face of elevated ionized calcium concentration when cancer is present and renal function is normal.

With hypercalcemia secondary to a parathyroid tumor (primary hyperparathyroidism), PTH concentrations are within the normal to high range; these results should prompt the use of cervical ultrasonography, if available, to look for a parathyroid mass.

Elevated PTHrP concentrations are typically indicative of underlying cancer. However, PTHrP is undetectable in most patients, in the author’s experience, even when cancer is present (2).

Treatment of paraneoplastic hypercalcemiatypically centers on correction of hydration deficits, diuresis, antineoplastic chemotherapy where appropriate, and the use of steroids, if warranted. In addition, bisphosphonates (eg, pamidronate, zoledronate) can be used to control calcium concentrations.

Fluid diuresis with saline solution (0.9% NaCl) should be performed, because the relatively high sodium content of this fluid competes with calcium for renal tubular absorption, therefore enhancing calciuresis.

Bisphosphonates inhibit osteoclastic activity and often rapidly and markedly decrease calcium concentrations. Because of poor oral absorption of alendronate, parenterally administered pamidronate or zoledronate are preferred for ameliorating hypercalcemia in cancer patients. This treatment is administered as an IV infusion and is typically reserved for patients with moderate to severe hypercalcemia and good renal function.

Steroids such as dexamethasone, prednisolone (in dogs or cats), or prednisone (in dogs) should be reserved for cases of moderate to severe hypercalcemia in which a definitive diagnosis of cancer has already been made, because the use of these medications can confound the ability to interpret diagnostic tests and confirm a diagnosis. Steroids can also induce resistance to certain chemotherapy agents, if used prematurely or inappropriately.

Treatment options for paraneoplastic hypercalcemia include the following:

For mild hypercalcemia (ionized calcium concentration, 1.5–1.9 mmol/L) with minimal clinical signs:

• Fluid diuresis with saline solution (0.9% NaCl)—ideally IV, but SC is an alternative if hospitalization is not feasible.

For moderate to severe hypercalcemia (ionized calcium concentration > 1.9 mmol/L) with or without clinical signs:

• Aggressive in-patient fluid diuresis with saline solution (0.9% NaCl), IV (1.5–2 times maintenance fluid rates after correction of existing hydration deficits).

• Bisphosphonates:

  • Zoledronate (dogs, cats): 0.1–0.25 mg/kg diluted in 60 mL of saline solution (0.9% NaCl), IV, as a CRI over 15 minutes every 2–4 weeks, depending on clinical response, not to exceed total dose of 4 mg per infusion). Zoledronate is 100–1,000 times more potent than pamidronate and therefore is preferred because of increased efficacy and far shorter infusion time (3).

• Furosemide: for fully hydrated, renally competent patients with refractory hypercalcemia: 2–4 mg/kg, IV, SC, or PO, every 8–12 hours in dogs, or 0.25–2 mg/kg, IV, SC, or PO, every 8–12 hours in cats, depending on clinical response

• Steroid therapy:

  • Prednisone: in dogs, 1–2 mg/kg, PO, every 24 hours, depending on clinical response

  • Prednisolone: in dogs and cats, 1–2 mg/kg, PO, every 24 hours, depending on clinical response

  • Dexamethasone sodium phosphate: 0.1–0.2 mg/kg, IV, every 24 hours, depending on clinical response (inpatient setting)

The most common cause of paraneoplastic hypoglycemia in dogs is insulinoma, which arises from pancreatic beta cells. Functional pancreatic beta-cell tumors release excessive amounts of insulin; they might also release insulin-like growth factors 1 and 2 (IGF-1 and IGF-2). The diagnosis of insulinoma is typically supported by identification of persistent, marked hypoglycemia (blood glucose concentration < 60 mg/dL), as well as an inappropriately normal or elevated serum insulin concentration in the presence of hypoglycemia, as measured via insulin-glucose pairing.

Abdominal imaging (ultrasonography or CT) might reveal a pancreatic mass; however, a definitive primary tumor is not always apparent, and < 50% of canine insulinomas are readily identifiable on ultrasonography (4). Nevertheless, very small or nonvisible tumors are capable of producing profound hypoglycemia. 

Insulinomas are highly metastatic tumors; many patients have at least microscopic spread of disease at the time of diagnosis. Affected patients usually develop hypoglycemic seizures, lethargy/weakness, weight loss, or other nonspecific clinical signs referable to their tumor. However, some patients are remarkably able to compensate for their hypoglycemia, particularly if it is long-standing, and they might show only subtle, if any, clinical signs.

Treatment of insulinoma involves surgical removal of the pancreatic mass if visualized, or exploratory laparotomy with partial pancreatectomy even if a mass is not visualized. If surgery is not feasible (ie, if metastasis is widespread at diagnosis), or if hypoglycemia persists or recurs after surgical management, medical treatment of hypoglycemia with prednisone, diazoxide, octreotide, or pasireotide, or the chemotherapeutic drug streptozotocin, can be pursued:

• Prednisone mitigates hypoglycemia by decreasing insulin sensitivity and increasing endogenous hepatic glucose production (5).

• Diazoxide suppresses insulin release from beta cells, stimulates hepatic gluconeogenesis and glycogenolysis, and inhibits cellular uptake of glucose. Response rates approach 70% in patients with insulinoma (5).

• Octreotide inhibits synthesis and secretion of insulin by pancreatic beta cells, and resolves hypoglycemia in approximately 50% of dogs (5). Pasireotide is a newer somatostatin analogue with a higher affinity for somatostatin receptor subtype 5 (6).

• Streptozotocin requires intensive diuresis during administration because of its nephrotoxicity. In addition, it is a highly emetic drug and can cause liver enzyme elevations and myelosuppression (5). Given the potential for appreciable side effects and questionable long-term benefit of this therapy, streptozotocin is rarely used.

Treatment options for paraneoplastic hypoglycemia due to insulinoma include the following:

• Prednisone or prednisolone: 0.25 mg/kg, PO, every 12 hours, increasing to 1 mg/kg every 24 hours, depending on clinical response. These steroids can be used long-term if necessary.

• Diazoxide: starting dose of 5 mg/kg, PO, every 12 hours, increased gradually to maximum 30 mg/kg every 24 hours, depending on clinical response. Diazoxide can be used long-term if necessary.

• Octreotide: 10–40 mcg, SC, every 8–12 hours, depending on clinical response.

For emergency treatment of a hypoglycemic crisis, 50% dextrose solution can be administered (0.5–1 mL/kg [or, practically, 1–5 mL] diluted 1:3 with saline solution [0.9% NaCl], IV slowly over 10 minutes as needed to reverse clinical signs but not necessarily to normalize blood glucose concentration). Large boluses of dextrose (approaching 1 g/kg) should be avoided because they can stimulate insulin release and cause rebound hypoglycemia. Patients are then continued on dextrose-containing IV fluids (2.5–5%); 5% dextrose solution should be avoided as the sole IV fluid for glucose supplementation because it can cause hyponatremia.

Finally, dietary modification can be used to attempt mitigation of hypoglycemia. Balanced diets that include complex carbohydrates should be fed in small amounts frequently throughout the day. Simple sugars should be avoided.

Liver tumors (hepatocellular adenocarcinoma/adenoma) and smooth muscle tumors (leiomyosarcoma/leiomyoma) arising from the stomach, spleen, liver, or intestinal tract cause hypoglycemia primarily via tumor cell production of IGF-2 (7). Most non–islet-cell tumors that cause hypoglycemia are larger and readily identifiable on abdominal palpation or imaging (see splenic tumor image). Surgery to remove the tumor (with or without postoperative chemotherapy, if warranted, as in the case of high-grade tumors), typically resolves the hypoglycemia.

Hypoglycemia, splenic tumor, dog

Image

Courtesy of Dr. Brooke Britton.

Hyperestrogenism is most commonly associated with Sertoli cell tumors, occurring in 25–50% of dogs with this disease, Approximately half of canine Sertoli cell tumors develop in cryptorchid testes (8). This paraneoplastic syndrome has not been reported in cats.

Other testicular tumors (seminoma, interstitial cell tumor) and ovarian granulosa cell tumor, can also cause hyperestrogenism. Hyperestrogenism occurs via direct estrogen production by neoplastic cells (8). 

Clinical signs of hyperestrogenism include symmetrical alopecia, epidermal thinning, gynecomastia, hyperpigmentation, penile atrophy, pendulous prepuce, galactorrhea, and prostatic atrophy or prostatomegaly (see hyperestrogenism image). Increased estrogen concentrations can also cause bone marrow toxicosis, characterized by progressive bone marrow hypoplasia or aplasia/pancytopenia, because increased estrogen concentrations markedly affect bone marrow cell differentiation and function.

Hyperestrogenism, dog

Image

Courtesy of Dr. Brooke Britton.

Clinical signs of hyperestrogenism typically resolve with tumor removal; however, resolution can be gradual. For dogs with severe myelotoxicosis at diagnosis that leads to aplastic anemia, signs of GI bleeding, weakness, tachycardia, epistaxis, and infection or sepsis can occur, and mortality rates are high.

In dogs with signs of hyperestrogenism, Sertoli cell tumor must be a differential diagnosis, regardless of whether a testicular mass is present, and imaging is essential to investigate for a cryptorchid testis. Hormone profiles in dogs might reveal appreciable elevations in plasma estradiol concentration​; a low testosterone:estradiol ratio; low expression of 5-alpha-reductase type 1​; and/or a low plasma testosterone concentration (9).

Treatment of hyperestrogenism consists of surgical removal of the primary tumor​, with or without additional antineoplastic therapy, if residual disease or metastases are present. Clinical signs typically improve or resolve with removal of the primary tumor; however, improvement or resolution can take several months​.

Morbidity and mortality rates are high in dogs that develop myelotoxicosis.

In cats,acromegaly is the syndrome caused by excessive growth hormone (GH) secretion (hypersomatotropism) by a functional pituitary adenoma of the pars distalis (10). 

Acromegaly is more common in male cats than in female cats, and there is no breed predisposition.

In dogs, acromegaly is commonly caused by progestin-induced GH secretion by mammary ductal epithelium (10). Mammary tumors and pituitary tumors are rare additional causes in dogs. Acromegaly is rare in dogs. GH decreases insulin receptors and interferes with postreceptor signaling and processing; chronic exposure to GH results in overgrowth of connective tissues, bone, and viscera (10).

In most cats with acromegaly, diabetes mellitus and insulin resistance are initially diagnosed. Over time, affected cats develop overgrowth of connective tissue, bone, and viscera (see acromegaly image), as well as organ dysfunction. 

Acromegaly, cat

Image

Courtesy of Dr. Brooke Britton.

Many effects of GH are mediated by IGF-1. Measurement of IGF-1 remains the most practical way to confirm feline hypersomatotropism in conjunction with physical examination and clinical findings. 

The long-term prognosis for cats with acromegaly is poor; however, treatment options include surgery in select cases, in-home glucose monitoring and insulin therapy, radiation therapy, somatostatin analogs (eg, octreotide, pasireotide), and feeding a low-carbohydrate diet.

• Bailey DB. Paraneoplastic syndromes. In: Vail DM, Thamm DH, Lipták JM, eds. Withrow & MacEwen's Small Animal Clinical Oncology. 6th ed. Elsevier; 2020:98-100.

• Kohart NA, Elshafae SM, Breitbach JT, Rosol TJ. Animal models of cancer-associated hypercalcemia. Vet Sci. 2017;4(2):21. doi:10.3390/vetsci4020021

• Greco DS. Endocrine causes of calcium disorders. Top Companion Anim Med. 2012;27(4):150-155. doi:10.1053/j.tcam.2012.11.001

• Also see pet owner content regarding peripheral nerve disorders in dogs and cats.

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2. Vasilopulos RJ, Mackin A. Humoral hypercalcemia of malignancy: diagnosis and treatment. Compend Cont Ed Small Anim Pract North Am Ed. 2003;25(2):129-137.

3. Milner RJ, Farese J, Henry CJ, Selting K, Fan TM, de Lorimier L-P. Bisphosphonates and cancer. J Vet Intern Med. 2004;18(5):597-604. doi:10.1111/j.1939-1676.2004.tb02593.x

4. Tobin RL, Nelson RW, Lucroy MD, et al. Outcome of surgical versus medical treatment of dogs with beta cell neoplasia: 39 cases (1990–1997). J Am Vet Med Assoc. 1999;215(2):226-230.

5. Nelson RW. Beta-cell neoplasia: insulinoma. In: Feldman EC, Nelson RW, Reusch CE, Scott-Moncrieff JCR, Behrend N. Canine and Feline Endocrinology. 4th ed. Elsevier; 2015:348-375.

6. Husni H, Khan SA, Alghaieb B, Abusamaan MS, Donner TW, Hamrahian AH. Pasireotide use for the treatment of endogenous hyperinsulinemic hypoglycemia refractory to conventional medical therapy: a case report and review of the literature. Clin Case Rep. 2022;10(3):e05650. doi:10.1002/ccr3.5650

7. Leifer CE, Peterson ME, Matus RE, et al. Hypoglycemia associated with nonislet cell tumor in 13 dogs. J Am Vet Med Assoc. 1985;186(1):53-55. doi:10.2460/javma.1985.186.01.53

8. Weaver AD. Survey with follow-up of 67 dogs with testicular Sertoli cell tumours. Vet Rec. 1983;113(5):105-107. doi:10.1136/vr.113.5.105

9. Mischke R, Meurer D, Hoppen H-O, Ueberschär S, Hewicker-Trautwein M. Blood plasma concentrations of oestradiol-17B, testosterone, and testosterone/estradiol ratio in dogs with neoplastic and degenerative testicular diseases. Res Vet Sci. 2002;73(3):267-272. doi:10.1016/S0034-5288(02)00100-5

10. Hurty Ca, Flatland B. Feline acromegaly: a review of the syndrome. J Am Anim Hosp Assoc. 2005;41(5):292-297. doi:10.5326/0410292