VCAWLAspecialty.com David Bruyette, DVM, DACVIM Medical Director The pancreas is made up of endocrine and exocrine tissue. The endocrine pancreas is composed of islets of Langerhans, which make up approximately 1-2% of the mass of the pancreas. Within the islets there are four cell types including alpha, beta, delta and polypeptide cells. Beta cells secrete various hormones with insulin being the primary product. Approximately 60-75% of the islets are of beta cell origin. The CNS has limited glycogen storage and is unable to use energy sources other than glucose. Thus, it is dependent on blood glucose to maintain its energy requirements. With hypoglycemia, cells within the cerebral cortex are affected first due to their higher metabolic rate. Counter-regulatory hormones such as catecholamines, glucagon, growth hormone and cortisol are secreted in response to hypoglycemia and aid in recovery from the hypoglycemic episode. Insulinomas (also known as beta cell insulin secreting tumor, beta cell adenocarcinoma/ adenoma) are insulin-secreting tumors of the pancreatic beta cells. They are the most common endocrine pancreatic tumor in companion animals and are usually malignant. Insulinomas can be found in both the right and left lobes of the pancreas with equal frequency. Occult insulinomas are most frequently found in the pancreatic body. Insulinomas are uncommon in dogs and rare in cats though these tumors are the most common cause of hypoglycemia in older dogs. Insulinomas have been associated with multiple endocrine neoplasia (MEN) type I in people. This is an inherited disease that also results in parathyroid and pituitary tumors. Although we do not have a clear understanding of the epidemiology of canine insulinomas, there have been rare cases of canine MEN that involve an insulinoma. In dogs, middle aged to older, medium to large breeds are predisposed. Large breed dogs are over represented. Breed dispositions have not been noted in cats. 1
Clinical signs are predominately related to hypoglycemia. The degree and onset of clinical signs is related to the severity and rate of development of hypoglycemia. Gradual or chronic hypoglycemia may go unnoticed. When chronically affected by hypoglycemia, some animals adjust to blood glucose levels of 20-30 mg/dl. Clinical symptoms consistent with hypoglycemia include: seizures, lethargy, weakness, coma, and ataxia. Catecholamine release can cause tachycardia, muscle fasciculations, hunger and restlessness. Exercise causes rapid consumption of glucose and may precipitate an episode of collapse or seizure. Differential diagnosis for hypoglycemia include: hypoadrenocorticism, juvenile hypoglycemia, sepsis, growth hormone deficiency, non-pancreatic tumors, insulin overdose, hepatic disease, glycogen storage diseases, artifacts related to sample handling, and toxins. Other types of neoplasms that can lead to paraneoplastic hypoglycemia include hepatocellular carcinoma, hepatoma, leiomyosarcoma, leiomyoma, lymphoma, myeloma and hemangiosarcoma. Whipple s triad is the demonstration of hypoglycemia, clinical signs consistent with hypoglycemia, and an appropriate response to treatment with dextrose. Demonstration of Whipple s triad supports a presumptive diagnosis of an insulinoma but similar responses can be seen with other causes of hypoglycemia. A minimum database (complete blood count, serum chemistry, and urinalysis) should be collected to rule out other causes of hypoglycemia. Nonspecific findings that may be associated with insulinomas include elevated liver enzymes, hypokalemia and hypophosphatemia. Radiographs may help rule out other causes of hypoglycemia. However, radiographic changes directly related to insulinomas should not be expected. Sensitivity of identifying insulinomas with abdominal ultrasound is low. It may be more beneficial to identify metastasis in the liver and local lymph nodes. Failure to identify a pancreatic mass does not rule out an insulinoma. Serum insulin concentrations that are normal to high in the presence of hypoglycemia support a diagnosis of insulinoma. Insulin:glucose and glucose:insulin ratios have high false positive rates and are not recommended. Rather, insulin concentration should be measured on a serum sample taken when the blood glucose is below 60 mg/dl. Insulin concentrations should be low or undetectable at this blood glucose concentration. Normal or elevated insulin concentrations in the face of hypoglycemia support a diagnosis of insulinoma. 2
Additional preoperative and intraoperative methods of tumor identification may be utilized. Nuclear scintigraphy with indium 111-labeled penteteotide has been used to image somatostatin receptors in dogs with insulinomas. Insulinomas express high-affinity somatostatin receptors of subtype 2 (SST2) thus allowing abnormal foci of activity to be detected. Direct intraoperative ultrasonography and intravenous injection of methylene blue injection may also be beneficial in identifying insulinomas. Methylene blue concentrates in neoplastic tissue, however, side effects including Heinz-body anemia and renal failure have been reported to occur. Dual phase CT with angiography can also be used to identify pancreatic masses and metastases in dogs with insulinoma. (See Figures 1 and 2). Figure 1: Axial pre and post contrast images showing a mass in the pancreas from a patient with an insulinoma. 3
Figure 2: Post contrast coronal images showing a mass in the right limb of the pancreas from the patient in Fig. 1. 4
Surgery is the mainstay of treatment. However, even when resectable, a cure is still unlikely. Gross or occult metastasis should be expected. Debulking of gross disease may significantly assist in controlling clinical signs. The goal of surgery is to remove as much neoplastic tissue as possible. Special attention should be given to regional lymph nodes and the liver. Complications include hyperglycemia (diabetes mellitus), hypoglycemia, exocrine pancreatic insufficiency and pancreatitis. First-line medical management is glucocorticoid therapy. In particular prednisone administered at 0.25-3 mg/kg orally twice daily can be utilized. The dose should be increased as needed to control hypoglycemia. Prednisone is used with small frequent feedings (4 times daily) and limited exercise. Exercise leads to an increased peripheral demand for glucose in spite of impaired gluconeogenesis and glycogenolysis. As a result, insulin secretion continues even as blood glucose falls. Diazoxide decreases insulin release from beta cells and stimulates epinephrine releases from adrenergic cells. The result is decreased insulin release and increased hepatic glycogenolysis and gluconeogenesis. It is effective in 64-85% of dogs. The recommended dose is 5mg/kg every 12 hours but may be increased up to 30 mg/kg every 12 hours if necessary. Thiazide diuretics potentiate the effects of diazoxide. The most common side effects of diazoxide are gastrointestinal in nature. Octreotide is a somatostatin analogue that activates somatostatin receptors resulting in the inhibition of synthesis and secretion of insulin. Octreotide is only effective if the malignant beta cells are expressing somatostatin receptors (~60% in people). It is given at a dose of 10-40/kg micrograms subcutaneously two to three times daily. Side effects are limited but the drug is costly. Streptozotocin is a chemotherapeutic agent that has direct toxic effects on pancreatic beta cells. It is nephrotoxic and therefore intravenous fluid diuresis is required. It is administered once every 2-3 weeks at a dosage of 500mg/m 2 for five treatments. If diabetes mellitus occurs, treatment is dis. The World Health Organization (WHO) classification for tumor staging is prognostic for insulinomas. Factors that effect prognosis include presence or absence of tumor (T0 or 5
T1), regional nodal involvement (N0 or N1), and distant metastasis (M0 or M1). Therefore, full staging (thoracic radiographs, abdominal ultrasound, serum chemistry, complete blood count, and urinalysis) is recommended. Overall, the prognosis is guarded because of the high rate of metastasis and reoccurrence of clinical signs. Approximately 36-51% of dogs have detectable metastatic disease at the time of surgery. With surgery alone stage I (T1N0M0), II (T1N1M0) and III (T1N0M1 or T1N1M1), dogs have an expected median survival of 19 months, 9 months and 6 months respectively. Survival time for dogs treated medically is less than when surgery combined with medical management is used. In one study, medical management with prednisone and dietary change alone resulted in a median survival time of 74 days. In a separate study the median survival time for dogs that had a partial pancreatectomy was reported at 496 days. In a subset of 9 dogs that received post-surgical medical treatment at the time of relapse, the median survival time was extended to 1316 days. Streptozocin therapy, especially as an adjunctive to surgery, should be considered. Although data is limited, normoglycemia has been shown to be prolonged with use of streptozocin when compared to dogs that were medically managed with diet and prednisone (163 versus 90 days respectively). In addition, reduction in metastatic lesions and resolution of hypoglycemic polyneuropathy in dogs has been reported. Persistent postoperative hypoglycemia has also been reported to be prognostic. In one study, dogs that became normoglycemic postoperatively had a median survival of 680 days compared to those that remained hypoglycemic which had a MST of 90 days. 6
David Bruyette, DVM, DACVIM Medical Director and Veterinary Specialist Dr. Bruyette received his Doctor of Veterinary Medicine degree from the University of Missouri in 1984. He completed an internship at Purdue University and a residency program in internal medicine at the University of California Davis. He was a staff internist at the West Los Angeles Veterinary Medical Group, as well as a member of the Department of Comparative Medicine at Stanford University, an Assistant Professor and Head of Internal Medicine at Kansas State University, and Director of the Analytical Chemistry Laboratory at Kansas State. In addition to his duties as Medical Director, Dr. Bruyette practices internal medicine and specializes in the hormonal system and its diseases. His interests also include adrenal disease, diabetes and thyroid disorders. Dr. Bruyette joined in 1996. 7