Pancreatic insulin-secreting neoplasia in a 9-year-old Afghan hound

Abstract

An Afghan hound was presented with recurring episodes of weakness progressing to seizures after exercise. Insulinoma was diagnosed by demonstrating excessive insulin secretion in the presence of hypoglycemia. A pancreatic mass was identified and removed during an exploratory laparotomy. Surgical and pathological findings, diagnosis, and clinical management are discussed.

A 9-year-old, castrated male, Afghan hound was referred to the Western College of Veterinary Medicine, Veterinary Teaching Hospital Small Animal Clinic (VTH SAC) for a possible magnetic resonance imaging (MRI) to investigate the cause of seizures he was experiencing after exercise. The dog had been examined 1 y previously by the referring veterinarian for a 2-month history of weakness following vigorous exercise. At this time, a blood chemistry panel, urinalysis, and adrenocorticotropic hormone (ACTH) stimulation test were performed, yet the only abnormalities noted were high creatinine and low-normal blood glucose (3.1 mmol/L; reference range, 3.1 to 6.3 mmol/L) levels. A change in diet (removal of rice from the home-made diet) resulted in some improvement until 8 mo later, when the episodes of weakness returned. Each episode had a duration of ~ 2 min and had an aura preceding it. The attending veterinarian suspected a brain tumor. The dog's condition worsened progressively, with episodes occurring more frequently. The owner described the initial episodes as being limited to staggering at the end of walks, after which the dog seemed anxious to eat. Later the episodes consisted of whole-body tremors for approximately 1 min whenever walks exceeded 20 min in length. Lethargy was apparent immediately prior to each episode, yet resolved when the tremors halted.

A physical examination at the VTH SAC revealed that the dog was lethargic and tense on abdominal palpation. A complete neurologic examination was performed; other than a slightly depressed mentation, no other neurologic deficits were found. A complete blood cell (CBC) count (Abbott Cell-Dyn 3500R; Abbott Laboratories, Chicago, Illinois, USA), biochemical profile (Roche Hitachi 912; Roche Hitachi, Montreal, Quebec), and urinalysis were requested. Laboratory findings indicated polycythemia (red blood cells 8.74 × 10¹²/L; reference range 5.20 to 8.20 × 10¹²/L), common in sighthounds; lymphopenia (0.392 × 10⁹/L; reference range 1.2 to 5.0 × 10⁹/L), attributed to stress; a mild increase in alanine aminotransferase (ALT) (66 U/L, reference range 19 to 59 U/L), suggestive of hepatocellular injury; and a low-normal blood glucose (4.2 mmol/L; reference range, 3.1 to 6.3 mmol/L). Blood samples were then taken to measure both fasted and postprandial bile acids in order to to asses liver function; all values were determined to be within normal ranges. Given the history and clinical signs, and the documented low-normal blood glucose, it was decided to conduct further tests. A blood sample was collected after a 14-hour fast; the blood glucose was found to be low (2.8 mmol/L). The dog was then exercised for 5 min and the blood glucose measured again, when it was found to be 2.7 mmol/L. After feeding, a 3rd blood glucose level was 1.7 mmol/L. A blood sample was also obtained at this time in order to determine the serum insulin level, which was found to be greatly elevated (622.3 pmol/L; reference range 62.5 to 171.6 pmol/L) (Roche Hitachi 917; Roche Hitachi). The amended insulin:glucose ratio was 1493. A ratio > 30 with appropriate clinical signs and concurrent elevation in serum insulin is diagnostic for insulinoma.

Abdominal radiographs revealed an enlarged spleen and possible mass in the right cranial quadrant of the abdomen, causing a deviation of the duodenum. Ultrasonography of the abdomen to further evaluate the liver, spleen, and pancreas was performed. This confirmed an unusually large spleen of normal consistency, as well as an enlarged pancreas with a discrete mass present within it. Cytological examination of ultrasound-guided splenic aspirates revealed findings consistent with normal reactive splenic tissue.

The following day, the dog underwent exploratory laparotomy to investigate the possible mass in the pancreas. The dog was premedicated with hydromorphone (Hydromorphone; Sabex, Boucherville, Quebec), 0.1 mg/kg bodyweight (BW), IM, and midazolam (Midazolam; Sabex), 0.2 mg/kg BW, IM; induced with ketamine (Vetalar; Vetrepharm Canada, Belleville, Ontario), 100 mg/mL, and diazepam (Diazepam; Sabex), 5 mg/mL (total 5.0 mL, 2.5mL of each), IV. Anesthesia was then maintained by using inhaled isoflurane (Isoflurane; Technilab, Mirabel, Quebec) and oxygen. Intravenous fluids containing 2.5% dextrose were administered. Blood glucose was monitored and remained normal throughout surgery. During surgery, cefazolin (Cefazolin Sodium; Novopharm, Toronto, Ontario) was administered at 22 mg/kg BW. Surgical findings included a 1.5-cm, round, red lesion in the tip of the left limb of the pancreas. Approximately 7.5% of the left limb of the pancreas was isolated and resected with wide margins. The liver was examined for evidence of gross metastasis; none could be visualized. The spleen was grossly enlarged but otherwise appeared normal. Biopsies of liver, spleen, and the pancreatic mass were submitted for histopathologic examination.

Upon recovery from surgery, the dog was maintained on IV fluids and monitored closely for signs of pancreatitis. Histopathologic examination of the pancreas suggested that the lesion in question was a large, round, expansile, encapsulated neoplasm. The cells present were polygonal and arranged into acini, separated by fibrovascular septa. Islands of exocrine pancreatic tissue were identified in the peribasilar part of the tumor. Three small foci were noted in a 2nd section of the pancreas. No abnormalities or evidence of metastasis were found in the biopsies of the liver and spleen. The tentative diagnosis of pancreatic insulinoma was confirmed.

For 4 d postsurgery, blood glucose was closely monitored and remained above 4.0 mmol/L. The dogs mental status improved dramatically, and within 24 h, he was no longer depressed or lethargic. Five months after surgery, the dog was doing well, his blood glucose remained within normal limits, and he had had no clinical signs of reoccurrence of hypoglycemia.

An insulinoma is a neoplastic growth of the endocrine cells of the pancreas. Neoplastic pancreatic islet cells secrete insulin and proinsulin, in spite of negative feedback resulting from hypoglycemia (8). Insulinomas have been shown to produce various polypeptides (somatostatin, glucagon, serotonin, and pancreatic polypeptide) (5). Most patients only have clinical signs of hyperinsulinism.

Pancreatic islet cell tumors are rare neoplasms occurring most often in older dogs with a mean age of 8.93 y (3). There are generally 2 types of clinical presentation: First, neuroglycopenic signs of weakness, ataxia, depression, and seizures; second, signs of increased sympathetic nervous system discharge, including shaking, trembling, muscle fasciculations (6). On presentation, most affected animals are relatively unremarkable on physical examination and the clinical signs are usually described as intermittent.

Hyperinsulinism associated with an insulinoma interferes with glucose homeostasis by decreasing hepatic glucose release and, concurrently, increasing the uptake of glucose by tissues sensitive to insulin (3). Insulin also has a direct inhibitory affect on the enzymes required to mobilize amino acids from muscle and glycerol from adipose tissue (7). This decrease in substrates required for gluconeogenesis interferes with hepatic glucose production and release. With increased tissue utilization and decreased gluconeogenesis and glycogenolysis, the net result is a decrease in blood glucose.

The central nervous system is not insulin dependent, because glucose is the primary energy source and its uptake into cells is via diffusion (4). Carbohydrate reserves are limited in neural tissue, so, in order to function, these cells require a constant supply of glucose from an outside source. In animals with insulinoma, there is a deficiency of circulating glucose, resulting in system dysfunction (6).

In a state of prolonged hypoglycemia, irreversible brain damage may result, but animals with insulinoma rarely die from hypoglycemia (6). In a normal animal, when blood glucose falls below 3.33 mmol/L, insulin release from pancreatic β cells is suppressed, and counterregulatory hormones are released. Initially, catecholamines and glucagon are released; in the later stages, cortisol and growth hormone are released (7). These counterregulatory hormones antagonize the effects of insulin, stimulating an increase in the blood glucose concentration (4). If these counterregulatory mechanisms are inadequate, a patient with insulinoma will present with severe hypoglycemia, syncope, and seizures or coma. Most patients with insulinoma commonly adapt to tolerate chronic or recurring low blood glucose concentrations and may have prolonged periods with severely low blood glucose concentration and no apparent clinical signs (8). Relatively minor further decreases in glucose concentrations will produce clinical hypoglycemia.

Exercise normally increases the uptake and utilization of glucose by tissues while stimulating the sympathetic nervous system, which inhibits insulin secretion and enhances glucose release from the liver (4). When a dog with hyperinsulinism due to an insulinoma exercises, there is increased peripheral demand for glucose in spite of impaired gluconeogenesis and glycogenolysis. Insulin secretion continues even as blood glucose concentrations fall, resulting in more severe hypoglycemia. Insulinomas are not totally autonomous and will often secrete insulin in response to increased blood glucose concentrations, thus postprandial hypoglycemia can be very severe (7).

Attempting to diagnose insulinoma can be difficult, as clinical signs of hypoglycemia are often intermittent and findings on physical examination are usually unremarkable (7). In most cases, thoracic and abdominal radiographs are normal (8). The presence of an insulinoma may be suggested by finding a mass lesion in the pancreas during ultrasonographic evaluation of the cranial abdomen. It is important to rule out other causes of hypoglycemia, such as sepsis, nonpancreatic neoplasia, and hypoadrenocorticism (4). The “gold standard” diagnostic test for insulinoma is the measurement of excessive insulin secretion in the presence of hypoglycemia (6).

In managing a case of insulinoma, the first mode of treatment should be surgical resection of the tumor and any gross metastatic lesions (2). With removal of the turmor, diagnosis can be confirmed with histopathologic examination, and the abdomen can be evaluated for the extent of metastasis. Surgery is generally considered to be palliative, as microscopic metastases are usually present even when there are no visible metastatic lesions. Medical management may be useful in cases of inoperable or diffuse metastatic disease, as well as to augment postsurgical treatment (2). Medical management includes a change in diet to a high protein, high fat, and complex carbohydrate diet, and feeding small meals 3 to 6 times a day (5). This diet change should coincide with a decrease in exercise. The signs of hypoglycemia are rarely controlled by this management and some form of drug therapy is usually required. Prednisolone stimulates hepatic glycogenolysis while inhibiting insulin effects on peripheral tissues (5). Diazoxide is a nondiuretic, benzothiadiazene antihypertensive drug that is effective in controlling hypoglycemia in approximately 70% of dogs with insulinoma (6). Diazoxide has multiple effects including inhibition of the cellular uptake of glucose, catalyzing the breakdown of glycogen to glucose, and blocking calcium entry into β cells, thus decreasing secretion of insulin (4). Diazoxide occasionally has significant adverse effects including hyperglycemia, bone marrow suppression, and gastrointestinal disturbances (4).

Long-term prognosis for dogs with insulinoma is poor (8). In previous studies, no correlation has been found between the clinical stage of disease, survival, and duration of clinical signs (5). Longer survival times have been found to correlate more with surgical excision than with medical management alone (6). Virtually all insulinomas should be considered malignant, even when metastases are not grossly visible at surgery. The most common sites for metastasis are lymphatics and lymph nodes, liver, mesentery, and omentum (4). When there is no gross or microscopic evidence of metastasis, the only way to differentiate a benign from a malignant insulinoma is by documenting recurrence of hyperinsulinism. Clinical signs and blood glucose concentrations should be monitored periodically, so that more aggressive medical management can be initiated, if warranted.