Insulinoma

Description

Islet cell tumour (Image sourced from Bristol Biomed Image Archive with permission)

Insulinomas are slow growing, well-encapsulated, functional tumours of the beta cells of the pancreatic islet cells. They secrete inappropriately high amount of insulin, irrespective of the serum glucose level. They are predominantly malignant (90% of canine insulinomas), with a high metastatic rate to regional lymph nodes, liver and omentum. 60% of isulinomas are carcinomas, which are more likely to be endocrinologically active whereas the others are adenomas.

Blood glucose concentration is maintained within a narrow homeostatic range because several tissues are able to use only glucose as an energetic substrate. These tissues are particularly affected by the hypoglycaemia which occurs with hyperinsulinaemia and they include neurones, blood cells, renal medullary cells and fibroblasts in healing wounds. The release of hormones antagonistic hormones (such as glucagon, growth hormone, glucocorticoids and catecholamines) also contributes to the pathogenesis and clinical signs observed in animals with insulinoma.

Signalment

Insulinomas occur most commonly in middle-aged or older dogs of the larger breeds. There is no sex predilection and the condition occurs less commonly in cats. Older cattle may rarely develop insulin-secreting tumours.

Diagnosis

Clinical Signs

The following signs are related primarily to hypoglycaemia but the release of catecholamines during episodes of hypogylcaemia may be contributory:

• Collapse
• Seizures
• Muscle tremors and weakness
• Ataxia
• Lethargy and depression
• Exercise intolerance

These signs may be intermittent early in the course of the disease, but they become more frequent and sustained with time. In between hypoglycaemic episodes, the animals often appear to be normal. Hypoglycaemic episodes may occur shortly after feeding (as insulin secretion is stimulated) or a long time after feeding (as the animal cannot maintain its blood glucose in the acceptable range) and they may also be associated with exercise or excitement.

A presumptive diagnosis can be made on the basis of Wipple's triad, which refers to the presence of:

• Clinical signs associated with hypoglycaemia
• Fasting hypoglycaemia
• Amelioration of clinical signs with the administration of glucose

Laboratory Tests

Biochemistry

• Hypoglycaemia which should be a persistent finding during fasting.
• Serum ALT and ALK are often elevated but the significance of these findings is not known.

Other Tests

• Serum insulin concentration is usually elevated in the face of profound hypoglycaemia, with an insulin: glucose ratio of >4.2 considered to be diagnostic for insulinoma.
• Serum fructosamine levels can also be assessed to gauge whether the animal has been persistently hypoglycaemic over the previous 2-3 weeks. A level <250-350 umol/l is suggestive of insulinoma

Pathology

This is needed for definitive confirmation of the diagnosis. The following features may be identified:

• Usually single, or less often multiple, small (1-3cm) spherical nodules, yellow to dark red, in one or more lobes
• Small islets of acinar tissue are sometimes present within the neoplasm
• Pancreatic beta cells can readily be identified using immunocytochemistry

Diagnostic Imaging

Radiography

Thoracic radiographs may be used to identify any pulmonary metastases, but it is uncommon for insulinomas to metastasise to the lungs.

Ultrasonography

Occasionally, it may be possible to visualise the location of the neoplasm on the pancreas as a hypoechoic nodule. However, this may not always be possible, especially if the tumour is very small. Metastases to lymph nodes and liver can sometimes be identified but suspected hepatic metastases should always be biopsied.

Treatment

Emergency Stabilisation

In the event of a hypoglycaemic episode, a bolus of 50% dextrose solution should be given immediately. Glucose syrup can also be rubbed onto the gums of an affected animal or a meal could be provided and this approach may reduce the risk of rebound hypoglycaemia encountered with administration of 50% dextrose solution. Intra-venous fluid therapy can then be maintained using 2.5% dextrose solution.

Medical Management

This is suitable for patients in which surgery has been declined or when clinical signs recur after surgical treatment due to the presence of metastases. A suitable regime would include:

• Small and frequent meals (3-6 times/day) of with high fat and protein content and some complex carbohydrate.
• Exercise restriction.
• Glucocorticoids such as prednisolone prescribed to increase hepatic gluconeogenesis and to decrease cellular glucose uptake.
• Diazoxide, an oral hyperglycaemic drug, used to inhibit pancreatic insulin secretion and tissue glucose uptake.
• Octreotide, a somatostatin analogue which reduces the synthesis of insulin, is rarely used for management of insulinomas.

Surgical Management

A partial pancreatectomy is suitable for patients with a solitary tumour and any suspected metastases may be removed or biopsied during the procedure. An intra-operative ultrasound scan can be performed if the mass is not evident when the pancreas has been exposed. Possible post-operative complications include:

• Persistent hypoglycaemia, probably due to the presence of unidentified metastases.
• Pancreatitis or Diabetes mellitus due to disruption to the pancreatic parenchyma during the procedure.
• Epilepsy and diffuse polyneuropathy due to chronic hypoglycaemia.
• Duodenal necrosis and perforation as the cranial pancreatico-duodenal artery may be disrupted when the right limb of the pancreas is dissected away the duodenum.

Prognosis

This is related to the WHO stage of the tumour at diagnosis. An animal with a stage I and II neoplastic process could expect a median survival time of 18 months but this falls to only 6 months for an animal with stage III disease. Patients which undergo surgery to remove an insulinoma have a better prognosis than those treated medically but the condition will recur invariably after surgical removal. Those animals which show a recurrence of clinical signs after surgery may then be treated medically, an approach that produces a significant increase in median survival time (from approximately 2 years to 4 years).

References

• Polton GA, White RN, Brearley MJ, Eastwood JM (2007) Improved survival in a retrospective cohort of 28 dogs with insulinoma. J Small Anim Pract. 2007 Mar;48(3):151-6.
• Ettinger, S.J. and Feldman, E. C. (2000) Textbook of Veterinary Internal Medicine Diseases of the Dog and Cat Volume 2 (Fifth Edition) W.B. Saunders Company.
• Fossum, T. W. et. al. (2007) Small Animal Surgery (Third Edition) Mosby Elsevier
• Nelson, R.W. and Couto, C.G. (2009) Small Animal Internal Medicine (Fourth Edition) Mosby Elsevier.
• Polton, G. A., White, R. N., Brearley, M. J. and Eastwood, J. M. (2007) Improved survival in a retrospective cohort of 28 dogs with insulinoma Journal of Small Animal Practice 48:151-156 [1]