Islet Cell Tumors in Dogs and Cats

Clinical signs of insulinomas result from excessive insulin secretion, which leads to an increased rate of glucose transfer from the extracellular fluid to body tissues and thus to severe hypoglycemia. The clinical signs are a reflection of the hypoglycemia and are not specific for hyperinsulinism associated with insulinomas. Dogs are easily agitated, and there are intermittent periods of excitability and restlessness. Periodic seizures may occur, and episodes of collapse resembling syncope have also been reported.

The most common clinical signs include the following:

• seizures

• generalized weakness

• hindlimb weakness

• collapse

• muscle fasciculations

Clinical signs are characteristically episodic and occur initially at widely spaced intervals; however, they become more frequent and prolonged as the disease progresses. Attacks of hypoglycemia may be precipitated by physical exercise (increased use of glucose) or fasting (decreased availability of glucose), as well as by the ingestion of food (stimulation of insulin release). Administration of glucose rapidly alleviates the signs.

The predominance of clinical signs relating to the CNSin cases of hypoglycemia demonstrates the primary dependence of the brain on the metabolism of glucose for energy. When the brain is not supplied with glucose, cerebral oxidation decreases and signs of anoxia appear. Because clinical signs are compatible with primary disease of the CNS, insulinomas may be misdiagnosed as idiopathic epilepsy, brain tumors, or other organic neurological disease.

Repeated episodes of prolonged and severe hypoglycemia may result in irreversible neuronal degeneration throughout the brain. Permanent neurological disability probably accounts for the terminal coma, unresponsiveness to glucose, and eventual death of some dogs.

Lesions

Insulinomas usually appear as single, yellow to dark red, spherical, small (1–3 cm) nodules visible from the serosal surface (see insulinoma image). They occur as single or occasionally multiple nodules in the lobes or body of the pancreas, and they are slightly firmer than the surrounding pancreatic parenchyma. A thin layer of fibrous connective tissue separates the neoplasm from the adjacent parenchyma.

Insulinoma, dog

Image

Courtesy of Dr. Floryne Buishand.

In 40%–50% of cases, insulinomas metastasize to regional lymph nodes or the liver (or both) before diagnosis.

• Demonstration of hypoglycemia with a concurrent normal or elevated serum insulin concentration

Blood glucose concentration should be measured in all older dogs with a history of periodic weakness, collapse, or seizures. When an insulinoma is clinically suspected but the dog is not hypoglycemic, food withholding may be required to reveal hypoglycemia. 

Food withholding in dogs with insulinomas must be carefully managed, with hourly blood glucose concentration evaluations, because concentrations may decrease before signs of hypoglycemia manifest, potentially resulting in rapid and serious clinical signs.

Most dogs with insulinomas, when food is withheld, develop hypoglycemia within 24 hours. Canine insulinomas are characterized by a concurrent blood glucose concentration < 63 mg/dL (3.5 mmol/L) and plasma insulin concentration > 10 mcU/mL.

Differential diagnoses for hypoglycemia include the following:

• hypoadrenocorticism

• hepatic failure

• large extrapancreatic neoplasms

• sepsis

• polycythemia

• insulin overdose

• laboratory error

Upon diagnostic confirmation of insulinoma, efforts should be directed toward determining where it is located within the pancreas and whether it has metastasized. Although ultrasonography is widely available and frequently used in general practice, it has a low sensitivity (36%) in detecting canine insulinomas.

Contrast-enhanced CT (CECT) is the preferred imaging modality because of its high sensitivity and specificity for detecting canine insulinomas. However, ultrasonography is valuable when ultrasonography-guided fine-needle aspiration biopsy (FNAB) is deemed necessary for liver lesions, regional lymph nodes, and any enlarged lymph nodes identified on CECT. CECT and ultrasonography-guided FNAB facilitate precise preoperative staging.

The staging of insulinomas adheres to the World Health Organization's TNM (tumor-node-metastasis) system. Canine insulinomas are categorized into three stages: T1N0M0 (stage I); T1N1M0 (stage II); and T0N0M1, T1N0M1, or T1N1M1 (stage III).

The TNM stage of the insulinoma is a prognostic factor and should be discussed with clients to inform their decision between medical management and surgery. In addition, knowing the specific anatomical location within the pancreas informs the choice between specific surgical techniques (eg, open versus laparoscopic pancreatic surgery, and local enucleation of the tumor versus resection via partial pancreatectomy).

• Surgery

• Palliative care

• Chemotherapy

Surgery is generally the best option to control clinical signs and improve the survival time of patients with insulinomas, especially in cases of a solitary TNM stage I insulinoma. Although insulinomas are usually solitary tumors, the entire pancreas should be examined carefully for multiple tumors.

Complete excision of the tumor ameliorates the hypoglycemia and associated neurological signs, unless there have been irreversible changes in the CNS. Excision of macroscopically enlarged lymph nodes is recommended, and for liver metastases, debulking is necessary to enhance the efficacy of medical adjuvant treatment. If there are nonvisible or inoperable metastases, hypoglycemia may persist after surgery.

Even though insulinomas are malignant, dogs may live > 2 years with an acceptable quality of life if all visible tumors are debulked at surgery and normo- or hyperglycemia is achieved after surgery. Dogs with inoperable tumors may be managed fairly well with frequent feeding of four to six small meals daily of a diet rich in proteins, fats, and complex carbohydrates to decrease postprandial hyperglycemia. Exercise should be limited to short leash walks. 

If clinical signs persist, the initiation of medical management is recommended. Diazoxide (5 mg/kg, PO, every 12 hours initially, increased progressively, if needed, up to 30 mg/kg, PO, every 12 hours, longterm) is the preferred drug for treating insulinomas. Diazoxide blocks pancreatic insulin secretion, stimulates hepatic gluconeogenesis and glycogenolysis, and inhibits glucose uptake by the tissues. Contraindications for diazoxide use in dogs include liver, kidney, or heart failure.

Glucocorticoids, such as prednisolone (0.25 mg/kg, PO, every 12 hours longterm), are an alternative to diazoxide. Prednisolone increases hepatic gluconeogenesis and glycogenolysis, antagonizing insulin effects at the cellular level. In refractory cases, prednisolone dosages of up to 2.0–3.0 mg/kg, PO, every 12 hours may be administered longterm, with doses > 1.1 mg/kg every 12 hours considered to suppress the immune system.

There are some reports on use of the chemotherapeutic agent streptozocin for the treatment of canine insulinomas; however, this drug has a high risk of severe adverse effects. The tyrosine kinase inhibitor toceranib phosphate (2–2.75 mg/kg, PO, every 48 hours longterm) has been reported as a treatment for canine insulinomas (1). 

Although some dogs reportedly have longterm glycemic control with toceranib phosphate treatment, the retrospective nature of the studies makes it unclear whether this effect can be attributed solely to toceranib phosphate (1, 2).

Gastrinomas occur less frequently than insulinomas. The prominent functional disturbances appear to result from multiple ulcerations of the GI mucosa that develop from gastrin hypersecretion.

Clinical signs include the following:

• anorexia

• hematemesis

• intermittent diarrhea

• weight loss

• melena

• Blood testing

• Exploratory surgery in some cases

Serum gastrin concentrations have been evaluated in a limited number of dogs with gastrinomas. Gastrin concentration in one dog with a Zollinger-Ellison–like syndrome was 1,266 ng/L ng/L (the reference interval for serum gastrin in healthy dogs after 12 hours of food withholding is 15.1–78.9 ng/L) (4, 5).

Endoscopy of the stomach and duodenum often reveal ulceration. Recurrent gastric or duodenal ulcers in dogs with no identified cause warrant exploratory surgery and careful inspection of the pancreas.

• Surgery

• Supportive care, if inoperable

Excision of the gastrin-secreting mass in the pancreas can be attempted. However, 72% of canine gastrinomas have already metastasized to regional lymph nodes and the liver at the time of surgery (6). The dogs had either single or multiple ulcerations in the gastric or duodenal mucosa associated with free blood in the lumen (3). Surgery also offers a chance to excise GI ulcers that otherwise could perforate and lead to peritonitis.

Medical management with H₂-receptor antagonists such as famotidine (1 mg/kg, PO, SC, or IV, every 12 hours) or the proton pump inhibitor omeprazole (1 mg/kg, PO, every 12–24 hours longterm) may temporarily alleviate clinical signs in animals with inoperable disease.

Limited data are available on the longterm prognosis of gastrinomas. Overall, the prognosis in dogs is grave, with a survival time ranging from 1 week to 18 months (mean 4.8 months); however, one case report documented a survival time of 26 months (3). The prognosis in cats is guarded as well; however, a survival time of 35 months was achieved in a cat that was treated with a combined surgical and medical approach using omeprazole and toceranib phosphate (7).

The exact pathogenesis of glucagonomas is uncertain; however, elevation of serum glucagon leads to a decrease in plasma amino acids and albumin. These changes result in relative deficiencies of plasma concentrations of zinc and essential fatty acids, which are suggested to directly cause the cutaneous manifestation of this tumor: severe skin erosions and ulceration.

Clinical signs include the following:

• skin erosions and ulceration

• hyperkeratosis of the footpads

• crusting and alopecia around the mucocutaneous junctions

• lethargy

• polyuria and polydipsia

• anorexia

• Blood testing

Plasma glucagon concentrations have been reported as elevated in dogs with glucagonomas. However, plasma glucagon concentrations can also be increased in dogs with hepatocutaneous syndrome, without the presence of a glucagonoma. It is therefore important to rule out other dermatological differential diagnoses and liver disease before the diagnosis of glucagonoma can be confirmed. Ultrasonography and CT imaging have been reported to detect primary glucagonomas and metastatic lesions.

• Surgery

• Supportive care, if inoperable

The preferred treatment of glucagonomas is partial pancreatectomy and surgical debulking of metastatic lesions. In addition, dogs should be fed a high-protein diet, which may be supplemented with zinc and fatty acids.

Two cases of nonresectable glucagonomas were treated palliatively with the somatostatin analog octreotide (2–3 mcg/kg, SC, every 12 hours) (8). In one glucagonoma case, skin lesions showed improvement within 10 days after octreotide treatment was started. After 6 weeks, however, the dog had to be euthanized because of progressive metastatic disease (8).

The survival time of three dogs that were treated surgically for their glucagonomas ranged from 3 days to 9 months (9, 10).