Canine Insulinoma

A 7-year-old female spayed Australian Shepherd presented to the Emergency Service for weakness and collapse following a long walk.  Several episodes of weakness and tremors had been noted over the previous few weeks, always associated with exercise.

A complete blood count and serum chemistry were normal at the time of admission to the hospital other than and blood glucose of 35 mg/dl.

Abdominal ultrasound was performed.   The right lobe of the pancreas was mildly thickened and heteroechoic, however, a discrete mass or nodule within the pancreas was not noted.

Blood was submitted for insulin level and the patient was referred for abdominal computed tomography (CT).  Insulin level was subsequently confirmed high at 66 uU/ml.  Thoracic radiographs were normal with no evidence of pulmonary metastasis.

A pre-contrast abdominal CT, dual phase CT angiography, and delayed post-contrast CT of the abdomen was performed.  The dual phase CT angiography is timed to acquire a series of images with the IV contrast within the arterial vascular compartment followed by a series of images with contrast present in the venous and portal vascular compartments.  A non-ionic iodinated contrast agent such as iohexol is used at a dose of 600-800 mg I/kg.  Use of a power injector is valuable to obtain a relative tight intravascular bolus of the contrast.

The pre-contrast CT showed mild thickening of the right lobe of the pancreas, alongside the duodenum.  In the arterial phase of the CT angiography study a strongly contrast enhancing nodule was present within the right pancreatic lobe (Figure 1).  In the venous phase, the pancreatic nodule was less conspicuous.  Two mesenteric nodules adjacent to the right lobe of the pancreas and suspected to represent metastatic lymph nodes were also noted to have similar contrast enhancing characteristics as the pancreatic nodule.

Exploratory laparotomy confirmed the presence of the pancreatic nodule in the right lobe and several mildly enlarged pancreaticoduodenal lymph nodes.  Partial pancreatectomy and lymph node extirpation were performed.  Final diagnosis on histopathology was pancreatic islet cell carcinoma (Insulinoma) with local lymph node metastasis.

Pancreatic islet cell neoplasias are rare cancers of dogs and cats with insulin-secreting beta cell neoplasia (insulinoma) the most common.  The majority are carcinomas with a small percentage of adenomas.   Metastasis is common with vascular, lymphatic and hepatic metastasis noted.  Pulmonary metastases are less common but do occur.  No breed or sex predilection exists for canine insulinomas however they are reported to occur mainly in medium to large breed dogs and mean age at the time of diagnosis is around 9 years with a range of 3-15 years.

Most clinical signs associated with canine insulinoma are related to the hypoglycemia, which is induced by excessive secretion of insulin from the neoplastic islet beta cells.  Clinical signs can also occur with excessive catecholamine release which is induced by the hypoglycemia.  Seizure, collapse, and generalized weakness are the most commonly noted signs.  Other signs may include, shaking/trembling/twitching, ataxia, exercise intolerance, disorientation, PU/PD, stupor, coma, and death.  Duration of clinical signs can vary from 1 day to 3 years.

Diagnosis of insulinoma is based on a combination of suspicious clinical signs, concurrent hypoglycemia, absolute or relative hyperinsulinemia and supportive imaging findings.    Ideally, blood insulin levels are measured when blood glucose is less than 60 mg/dl.

Abdominal ultrasound has been the initial imaging modality of choice however in one study a pancreatic mass was identified in only 56% of cases and abdominal metastasis noted in 19% of cases.

More recently dual phase CT angiography is becoming the preferred imaging modality for cases of possible insulinoma.  Both the primary pancreatic tumors and the local, lymphatic and hepatic metastasis demonstrate marked contrast enhancement in the arterial phase of the CT angiography study.  This enhancement becomes less conspicuous in the venous phase and in delayed phase post-contrast images.  Ideally, a power injector is used for rapid infusion of the contrast media to maintain a tight intravascular bolus, which allows for imaging of a pure arterial phase rather more of a mixed arterial-venous angiographic study.  However in the author’s experience, rapid injection by hand through as large bore catheter as possible followed by immediate scanning is often sufficient to obtain a diagnostic study as power injector equipment can be cost prohibitive.

Short-term treatment of canine insulinoma consists of managing the hypoglycemia.   This may require administration of IV dextrose in an acute hypoglycemia crisis.  The addition of dexamethasone or a somatostatin analogue can also be considered in the rare case which fails to respond to dextrose alone.  If seizures are occurring at the time of presentation sedation with diazepam or phenobarbital may be necessary until seizures resolve.

Long-term treatment of choice for canine insulinoma is surgical resection of the primary pancreatic nodule/mass and any metastatic lesions if possible.

Medical treatment can also be considered prior to surgery, following incomplete surgical resection of insulinoma or if surgery is not elected.  The most common medical treatment options include feeding of small frequent meals with a diet high in protein, fat and complex carbohydrates recommended.  Glucocorticoids such as prednisone (0.5-4 mg/kg/day) also help to increase blood glucose by increasing gluconeogenesis, elevating glucose-6-phosphatase activity and decreasing blood glucose uptake in tissue.

Other medications that can be considered include Streptozocin, diazoxide, and Octreotide.  Streptozocin is a cytotoxic drug that selectively destroys beta cells both within the pancreas and metastatic lesions.  Diazoxide acts on ATP-dependent K+ channels leading to decreased exocytosis of insulin-containing secretory vesicles in beta cells as well as increasing glycogenolysis and gluconeogenesis.  While effective in 70% of dogs with insulinoma, diazoxide is very costly compared to prednisone.  Octreotide is a long-acting synthetic somatostatin analogue that also inhibits insulin secretion, however, is also very costly.

Combining several larger retrospective studies, the median survival time in dogs which underwent surgical resection of a pancreatic mass or nodule was 12-14 months (range 0 days to 5 years).  Surgical intervention does improve survival over medical treatment alone, however, most dogs will die of metastatic disease regardless of treatment.  Positive prognostic indicators include dogs with stage one disease at the time of surgery (ie. No local metastasis or distant metastasis detected) with 50% remaining normoglycemia at 14 months postoperatively compared to 20% of dogs with stage II or III disease.  Dogs which are hyperglycemic or normoglycemic postoperatively have a better prognosis than dogs that remain hypoglycemic post-operatively.  While one study reported a median survival time of 2.1 years in dogs with insulinoma that underwent partial pancreatectomy, median survival time increased to 3.6 years in dogs treated surgically followed by the addition of prednisone.

Figure 1.Pre-contrast (A) and Arterial phase CT angiography (B) images at the level of the pancreas demonstrating strong arterial contrast enhancement of a pancreatic nodule (yellow arrow) which is not apparent in the pre-contrast images.Insulinoma

 

 

 

 

 

 

 

Figure 2.  Sonographic image of a hypoechoic nodule within the pancreas, between the duodenum to the left in the image and the antrum of the stomach to the right in the image.  This nodule was later confirmed to be insulinoma based on histopathology.

Sonogram Insulinoma

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Submitted by: Dr. Christopher Ryan, VMD, DABVP, DACVR

References:

  1. Caywood DD, Klausner JS, O’Leary TP, et al. Pancreatic insulin secreting neoplasms:  Clinical, diagnostic and prognostic features in 73 dogs.  J Am Anima Hosp Assoc 1988;24:577-584.  http://agris.fao.org/agris-search/search.do?recordID=US8868180
  2. Iseri T, Yamada k, Chijiwa K, eta al. Dynamic computed tomography of the pancreas in normal dogs and in a dog with pancreatic insulinoma. Vet Rad and Ultrasound 2007;48:328-331.  http://onlinelibrary.wiley.com/doi/10.1111/j.1740-8261.2007.00251.x/abstract;jsessionid=30A5F80B1BD240605E9CAAF1B429879B.f04t02?userIsAuthenticated=false&deniedAccessCustomisedMessage=
  3. Kruth SA, Feldman EC, Kennedy PC. Insulin-secreting islet cell tumors: Establishing a diagnosis and the clinical course for 25 dogs.  JAVMA 1982;181:54-58.  http://europepmc.org/abstract/med/6286582
  4. Lamb CR, Simpson KW, Boswood A, et al. Ultrasonography of pancreatic neoplasia in the dog: a retrospective review of 16 cases.  Vet Rec 1995;137: 65-68.  http://europepmc.org/abstract/med/8533234
  5. Leifer CE, Peterson ME, Matus RE. Insulin-secreting tumor: diagnosis and medical and surgical management in 55 dogs.  JAVMA 1986;188:60-65. http://europepmc.org/abstract/med/3003016
  6. Mai W, Caceres AV. Dual-phase computed tomographic angiography in three dogs with pancreatic insulinoma.  Vet Radiol and Ultrasound 2008;49:141-148.  http://onlinelibrary.wiley.com/doi/10.1111/j.1740-8261.2008.00340.x/abstract?userIsAuthenticated=false&deniedAccessCustomisedMessage=
  7. Polton GA, White RN, Brearley MJ, et al. Improved survival in a retrospective cohort of 28 dogs with insulinoma. J Small Anim Pract 2007;48:151-156.  http://onlinelibrary.wiley.com/doi/10.1111/j.1748-5827.2006.00187.x/abstract?userIsAuthenticated=false&deniedAccessCustomisedMessage=
  8. Tobin RL, Nelson RW, Lucory MD, et al. Outcome of surgical versus medical treatment of dogs with beta cell neoplasia: 39 cases (1990-1997). JAVMA 1999;215:226-230.   http://europepmc.org/abstract/med/10416477

 

 

 

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