Insulin-secreting beta cell neoplasia in a 10-year-old dog

Abstract

A 10-year-old collie-cross presented with intermittent episodes of pelvic limb weakness and collapse. Hypoglycemia, secondary to an insulin-secreting beta cell tumor, was suspected on the basis of clinical signs and serum biochemistry. Conservative dietary therapy consisted of multiple small meals, limited exercise, and avoidance of foods containing simple sugars.

A 10-year old, spayed, female collie-cross was presented with a history of intermittent disorientation, ataxia, pelvic limb weakness, and collapse during the previous 2 wk. Episodes lasted approximately 5 min. Physical examination immediately after an episode revealed mild posterior weakness, generalized muscle fasciculations, and depression. Differential diagnoses included cardiopulmonary disease, episodic hemorrhage, hypoglycemia, hypoadrenocorticism, polymyositis, myasthenia gravis, orthopedic or articular disease, and toxicosis.

A complete blood cell (CBC) count and serum biochemical profile were performed (Animal Health Laboratory, Guelph, Ontario). The results were unremarkable, except for moderate hypoglycemia (2.8 mmol/L; reference range, 3.6 to 7.0 mmol/L) and mild hypophosphatemia (0.6 mmol/L; reference range, 0.8 to 2.2 mmol/L). The following differential diagnoses for hypoglycemia were considered: beta cell tumor, other extrapancreatic insulin-secreting tumors, hepatic insufficiency, sepsis, hypoadrenocorticism, hypopituitarism, idiopathic neonatal and juvenile hypoglycemia, and hunting dog hypoglycemia. Other causes of hypoglycemia include renal failure, exocrine pancreatic neoplasia, hepatic enzyme deficiencies, polycythemia, starvation, iatrogenic drug reactions, and sample error. Causes of hypophosphatemia include decreased intestinal absorption due to vomiting, diarrhea, and use of antacids. Increased urinary excretion due to hypercalcemia, diabetic ketoacidosis, and diuresis may also decrease serum phosphorous. Other causes of hypophosphatemia include elevated insulin levels, alkalosis, and parenteral glucose administration. Due to a lack of other physical and laboratory abnormalities, a tentative diagnosis of beta cell tumor was made. Confirmation of insulin-secreting neoplasm was achieved through evaluation of insulin levels (Animal Health Laboratory) during a hypoglycemic episode. A blood sample was collected before treatment was initiated. Serum insulin was 401 pmol/L (reference range, 58 to 229 pmol/L). There was also moderate hypoglycemia (2.1 mmol/L; reference range 4.2 to 5.6 mmol/L). The insulin/glucose ratio was 191 (reference range, 14 to 43). On the basis of these results, a diagnosis of insulin-secreting beta cell tumor (insulinoma) was made. The owner refused either abdominal ultrasonography or exploratory celiotomy to identify a pancreatic or extrapancreatic tumor. Accordingly, the dog was treated conservatively and released. The owner was instructed to feed multiple small meals 6 times daily, avoiding foods containing simple sugars, and to limit exercise. Approximately 1 mo after diagnosis, the dog had had only 1 hypoglycemic episode, which had been treated by the owner by rubbing corn syrup on the buccal mucosa.

Insulin-secreting beta cell tumors arise from beta cells in the pancreatic islets, often producing large amounts of insulin, as well as other hormones, including somatostatin, glucagon, serotonin, and gastrin (1). However, hyperinsulinism produces hypoglycemia that is responsible for clinical signs. The tumor is frequently malignant and metastasizes to the lymphatics, associated lymph nodes, liver, mesentery, and omentum. By the time an insulinoma is diagnosed, it is likely to have already metastasized (2). For this reason, hypoglycemia often recurs months after surgical excision of the tumor, or surgery fails to entirely correct the problem.

Insulin-secreting tumors are usually diagnosed in middle-age or older dogs, without sex predisposition. Large breed dogs, such as Irish setters, boxers, and German shepherds, and fox terriers are predisposed to insulinoma, although it may occur in any breed (3). Clinical signs are related to blood glucose levels, the rate at which blood glucose declines, and the duration of the hypoglycemic episode. If there is a rapid decrease in glucose, the sympathetic nervous system is activated, causing tachycardia, tremors, nervousness, irritability, and polyphagia. More commonly, the rate of decline in blood glucose is gradual and the clinical signs are related to neuroglucopenia. These include hypothermia, mental dullness, seizures, weakness, collapse, and muscle fasciculations, as in this dog (4). Due to compensatory counter-regulatory mechanisms, clinical signs tend to be episodic and to last from a few seconds to a few minutes.

As in this case, results of physical examination are often unremarkable. Weight gain may be evident due to the anabolic effects of insulin. Peripheral neuropathies may be observed, including proprioceptive deficits, depressed reflexes, and muscle atrophy. The mechanism of pathogenesis may be increased susceptibility to the effects of hypoglycemia because of a metabolic defect in the peripheral nerves, or similarities between tumor antigens and nervous tissue antigens causing an immune response to the peripheral nerves (5).

The diagnosis of an insulin-secreting tumor requires confirmation of hypoglycemia, evidence of inappropriate insulin secretion, and identification of a pancreatic mass by ultrasonography or exploratory celiotomy. Evidence of inappropriate insulin secretion is indicated by an elevated insulin level during a period of hypoglycemia. An animal that is not hypoglycemic at the time of examination may be fasted under supervision overnight and have the insulin and glucose levels determined in the morning. If that is not possible, the animal may be fed in the morning and fasted during the day with glucose levels being measured every 2 h until hypoglycemia is detected. Serum samples are then collected immediately for simultaneous evaluation of both glucose and insulin levels. When absolute increases in serum insulin concentrations do not develop, glucose and insulin ratios may be used to detect inappropriate insulin secretion, including the glucose/insulin, insulin/glucose, and amended insulin/glucose ratios. These criteria are more sensitive than fasting alone, but they are also less specific and may produce false negative results (3). A definitive diagnosis of beta cell tumor is made only after exploratory celiotomy and histopathologic evaluation of suspected neoplastic tissue. In this case, blood glucose and fasting insulin levels were measured immediately after a hypoglycemic episode. Although histopathologic evaluation of neoplastic tissue could not be performed in this case, a diagnosis of insulinoma was made on the basis of clinical signs, hypoglycemia, and concomitant hyperinsulinism.

The owners in this case elected to treat the dog conservatively, but the usual treatment for insulin-secreting tumors is aimed at reducing the level of hypoglycemia through medical and surgical means. Medical therapy for an acute hypoglycemic episode includes administration of 50% dextrose, 1 mL/kg BW, IV, over 10 min. If clinical signs do not improve, a constant infusion of 5% dextrose containing dexamethasone may be administered at 1.5 to 2 times the maintenance fluid rate (4). Owners managing a hypoglycemic episode at home may rub or pour a sugar solution on the dog's buccal mucosa, as was done in this case.

To date, no specific chemotherapy has been described that is both effective against neoplastic beta cells and devoid of serious adverse effects. Accordingly, long-term medical therapy is aimed at reducing the frequency and severity of clinical signs. This may be achieved by altering the patient's diet to increase the frequency of feeding to 6 times per day and limiting exercise, as was done in this case. Simple sugars in the diet may stimulate insulin secretion and should be avoided. If dietary therapy is unsuccessful, corticosteroids should be used. Corticosteroids ameliorate hypoglycemia by increasing peripheral lipolysis, protein catabolism, and hepatic gluconeogenesis and glycogenolysis, and by decreasing peripheral glucose utilization. They also antagonize the effects of insulin by decreasing the sensitivity of the insulin receptors (1). In this case, corticosteroid therapy will likely begin when the hypoglycemic episodes become more frequent.

The antihormonal drug diazoxide may be used if the patient is unresponsive or intolerant to corticosteroids. Diazoxide, a nondiuretic benzothiadiazene antihypertensive drug, acts to directly inhibit insulin secretion, stimulate gluconeogenesis and glycogenolysis, and inhibit tissue use of glucose (4). The use of a somatostatin analog has also been described as therapy for insulinoma. Such drugs act to inhibit the synthesis and secretion of insulin by beta cells. However, their effect on neoplastic cells is variable and may not produce clinical improvement in many dogs (6).

Surgical exploration and removal of neoplastic tissue permits definitive diagnosis of the tumor, as well as a possible cure in dogs with a resectable mass. In animals where it is impossible to remove all neoplastic tissue, surgically debulking the tumor frequently results in an improvement of clinical signs by decreasing insulin secretion. Dogs that have surgery have significantly longer survival times than do dogs treated with medical therapy alone (2). Although surgery may offer the best prognosis, there is a high frequency of postoperative complications, including pancreatitis, hyperglycemia, and hypoglycemia. For this reason, many older, more debilitated patients are treated medically in a similar manner to the dog reported here.

The long-term prognosis for dogs with insulinoma is guarded at best, due to the high frequency of metastasis. Dogs treated medically do not usually survive longer than 12 mo from the onset of clinical signs (4). Dogs treated surgically may live up to 16 mo from the time of surgery. The prognosis at the time of surgery appears dependent on the presence or absence of metastatic lesions (2). Due to the improved survival time, celiotomy and tumor removal should be recommended for all animals with a suspected insulin-secreting pancreatic neoplasm.