Pancreas: neoplasia: insulinoma (Hyperinsulinism, insulin-secreting tumor, islet cell tumor)

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• Functional (ie insulin-producing) tumors of the endocrine pancreas affecting beta-islet cells. Malignant, with high metastatic potential spreading locally to lymph nodes and liver. Pulmonary metastasis unusual. Most cases have visible or invisible metastasis at time of diagnosis.
• Cause : excessive secretion of insulin.
• Signs : (hypoglycemia), episodic seizures, weakness, collapse, nervousness, tremors.
• Diagnosis : signs, hypoglycemia and hyperinsulinemia.
• Treatment : dextrose injections, anticonvulsant therapy (in acute phase), surgery, feeding change, medical management.
• Prognosis : guarded long-term but controllable in the short term with good quality of life extending to many months if diagnosed early. Death (or euthanasia) eventually results due to metastatic disease and uncontrollable hypoglycemia.

• Episodic seizures, ataxia, weakness and collapse. Seizures may last up to 5 min. May be focal and self-limiting due to counter-regulatory measures such as release of insulin antagonists (eg glucagon, growth hormone, catecholamines) causing blood glucose to rise.
• Bizarre behavior/confusion, disorientation, apparent blindness.
• Above symptoms are all episodic and provoked by fasting (worsens hypoglycemia  ), muscular activity and excitement.

• Muscle fasciculations.
• Depression and lethargy.
• Polyphagia with weight gain. Eating may initially provoke symptoms as food intake provokes further insulin release by normal physiological mechanisms and worsens pre-existing hypoglycemia. Ultimately, food intake reduces symptoms.
• Exercise intolerance.

• Polyuria/polydipsia.

• Seizures, ataxia, collapse.

• Middle-aged to older dogs (mean age 9 years).

• Medium to large breeds of dog:
  • Irish Setter .
  • Boxer .
  • Golden Retriever .
  • Standard Poodle .
  • German Shepherd dog .
  • Labrador Retriever .

• Require surgery and/or long-term medical management and monitoring.

Pathogenesis

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• Neoplastic beta-cells produce insulin (and other hormones) as a result of hypoglycemia  , which normally inhibits insulin release.
• Clinical signs due to low blood glucose ensue   .
• Hypoglycemia affects cerebral cells first as these cells have limited glycogen stores and poor potential for gluconeogenesis.
• Sustained hypoglycemia leads to release of insulin antagonists (eg glucagon, growth hormone, catecholamines) to try and elevate blood glucose levels.
• Insulin antagonists cause muscle tremor, nervousness, panting, hunger.

• The major inhibitory stimulus for insulin secretion is hypoglycemia.
• Insulinomas continue to release insulin despite hypoglycemia  continued tissue utilization of glucose  worsening hypoglycemia.
• Hypoglycemia  reduced glucose available to the central nervous system (CNS) and later to peripheral nervous system and organs  seizures, lethargy, weakness, ataxia, bizarre behavior, coma.
• Prolonged, severe hypoglycemia may  irreversible brain damage  rarely death.
• Hypoglycemia  sympathetic nervous stimulation  behavior changes, shaking, nervousness, excitation.

• 1 day-3 years.
• Low blood glucose tolerated for prolonged periods without symptoms, further lowering of blood glucose produce symptomatic episodes.

Diagnosis

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• Seizures .
• Episodic weakness.
• Tremors.

• Progressive signs related to exercise and fasting. May also be related to eating (1-2 hours later).

• Repeated seizures .
• Episodic weakness, ataxia.

• Muscle fasciculations.
• Bizarre behavior.
• Polyphagia.
• Exercise intolerance.
• Polyuria/polydipsia.
• Weight gain.

• Diarrhea.
• Syncope.

• No visible or palpable abnormalities.

• Weight gain.
• Muscle fasciculations.
• Bizarre behavior.
• Seizures.

• Peripheral neuropathies  : proprioceptive deficits, depressed reflexes, muscle atrophy, gait abnormalities.
• Head tilt.
• Blindness/impaired vision.
• Hypothermia.

• Use of Whipple's triad:
  • Neurological symptoms consistent with hypoglycemia.
  • Hypoglycemia (>3 mmol/l) during clinical symptoms.
  • Resolution of symptoms after feeding or glucose administration .

Biochemistry

• Blood glucose  <3 mmol/l.
• Insulin assay .
• Blood glucose <3.3 mmol/l and insulin concentrations >20 mmol/l.
• Low fructosamine  <250-350 nmol/l.
• Insulin/glucose ratio  greater than 4.2.
• Blood glucose 3.3 mmol/l and insulin concentration normal (5-20 mmol/l) is still abnormal.
• IV glucose tolerance test   may be helpful in borderline cases.
  Insulin level should be low with low blood glucose.

• Mass in region of pancreas .
• +/- within hepatic parenchyma .
• +/1 associated lymph nodes.
• Ultrasound may identify 50% of pancreatic masses. U/S is key for evaluating liver and lymph node metastases.

• Thoracic radiographs  for demonstration of metastasis, although very rarely metastasize to lungs.
• Abdominal radiography  may demonstrate metastatic diseases (ultrasound is the preferred test by far).
  Primary tumor invariably too small to visualize.

• History.
• Signs.
• Ultrasonography.
• Radiography.

• Insulin assay  :
  • Blood glucose 3.3 mmol/l and insulin concentrations >20 mmol/l or normal insulin level with low blood glucose. Insulin level should be low.
• Identification of pancreatic mass.

• Pancreatic neoplasm   .

• Neoplasm of beta cells of pancreas (islet cells).

• Trauma.
• Brain neoplasia.
• Lead poisoning .
• Idiopathic epilepsy .

Infections :

• Canine distemper .
• Cryptococcosis .
• Toxoplasmosis .

Congenital :

• Hydrocephalus .

Acquired :

• Myasthenia gravis .
• Tetanus .
• Diskospondylitis .
• Idiopathic polyradiculoneuritis .
• Polymyositis.
• Polyarthritis.

Others :

• Idiopathic polyneuropathy.

Cardiovascular disorders

• Arrhythmias .
• CHF .
• Heartworm .
• Hemangiosarcoma .
• Warfarin-induced coagulopathy .
• Bacterial endocarditis .

Metabolic disorders

• Other causes of hypoglycemia .
• Hepatic encephalopathy .
• Hypocalcemia .
• Anemia .
• Hypoadrenocorticism .
• Hypokalemia .
• Uremia, eg renal failure .
• Polycythemia.
• Hyperviscosity syndrome .
• Phaeochromocytoma .
• Excessive insulin administration.

Other

• Liver disease   .
• Sample artifact.

Treatment

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• 50% dextrose (1-5 ml) slowly over 5-10 min IV until clinical signs are controlled.

  Administer small amounts slowly to prevent overstimulation of the tumor and excessive insulin release/aim to control clinical signs not correct hypoglycemia.

• If animal at home rub sugar-containing solution on the buccal mucosa.

• Discontinue bolus injections of dextrose.
• Continuous IV infusion of 2.5-5.0% dextrose at 90-120 ml/kg/over 24 h plus dexamethasone  0.5-1.0 mg/kg over 6h.
• Glucagon continuous infusion - 5-15 ng/kg/min is very successful at controlling hypoglycemia due to insulinomas.
• Somatostatin analog SMS 201-995, octreotide  : 10-40 ug, SC, BID-TID.
• Anticonvulsant therapy  if required.
• Mannitol  1 g/kg IV over 20 min.

• Surgical excision, even if metastatic disease present; debulking all gross disease leads to greatly increased survival times over medical management alone.
• Remaining metastatic deposits will remain and eventually cause symptoms to recur.

• Surgery refused by owner.
• Inoperable tumor - debulking is worth trying.
• Metastasis results in recurrence of clinical signs. Still recommend debulking metastases first if possible.
• Diet:  - small , frequent meals high in fat, protein and complex carbohydrates, low in simple sugars, 5-6x daily.
• Glucocorticoid therapy if dietary management no longer effective, prednisolone  0.5 - 1.0 mg/kg/day in divided doses, increase as needed to maximum of 6 mg/kg/day (inhibits insulin; stimulates gluconeogenesis).
• When signs of iatrogenic hyperadrenocorticism develop reduce prednisolone and initiate diazoxide  therapy. 5 - 30 mg/kg 2x daily BID (inhibits insulin secretion).
• Regular limited exercise.
• Streptozotocin - chemotherapy selective for beta cells. Nephrotoxic - must be given with heavy diuresis. Studies ongoing.

• Somatostatin analog SMS 201-995, Octreotide  : 10-20 ug/animal, SC, BID/TID.
  Use has not been fully investigated.

• For development of hyperglycemia.
• Signs of iatrogenic hypercortisolism: polydipsia, polyuria, polyphagia, obesity, weakness, symmetrical alopecia.
• Side-effects of diazoxide therapy: vomiting and anorexia.
• Monitor for signs of metastasis.
  Metastasis to liver or regional lymph node present in appoximately 45% of cases at time of surgery.

• Treat post-surgical hyperglycemia with insulin .
• Reduce dose of prednisolone and institute diazoxide therapy if iatrogenic hypercortisolism occurs.
• Give diazoxide with a meal or temporarily reduce dose if side-effects occur.

Sequelae

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• Long-term prognosis guarded due to metastatic disease.

• Surgery gives a period of remission from signs in most cases.
• No metastasis at time of surgery: 50% cases free of hypoglycemia 14 months later but 80% dead by 24 months.
• Metastasis present at time of surgery: less than 20% free of hypoglycemia 14 months later and all those with liver metastasis dead by 18 months.

• Medical management alone has median survival time = 74 days.

Surgical and medical management

• Good quality life for 10 - 33 months.

• Rapid resolution of clinical signs.

• Side-effects of therapy.
• Metastasis/recurrence.

Sources

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• Recent references from PubMed.
• Bell R, Mooney C T, Mansfield C S & Jones B R (2005) Treatment of insulinoma in a springer spaniel with streptozotocin. JSAP 46 , 247-250.
• Fischer J R et al(2000) Glucagon constant-rate infusion - a novel strategy for the management of hyperinsulinemic-hypoglycemic crisis in the dog. JAAHA 36 , 27-32.
• Shimada A et al(2000) Hypoglycemic brain lesions in a dog with insulinoma. J Comp Pathol 122 , (1) 67-71.
• Tobin R L et al(1999) Outcome of surgical versus medical treatment of dogs with beta cell neoplasia - 39 cases (1990-1997). JAVMA 215 , 226-230.
• Trifonidou M A et al(1998) A retrospective evaluation of 51 dogs with insulinoma. Vet Q 20 , S114-S115.
• Steiner J M & Bruyette D S (1996) Canine insulinoma. Comp Cont Ed Prac Vet 18 , 13-16.
• Dunn J K, Heath M F, Herrtage M E, Jackson K F & Walker M J (1993) Insulin secreting tumors of the canine pancreas; clinical and pathological features of 11 cases. JSAP 34 , 325-331.
• Dunn J K, Heath M F, Herrtage M E, Jackson K F & Walker M J (1992) Clinical diagnosis of insulinoma in the dog; a study of 11 cases. JSAP 33 , 514-520.
• Caywood D D et al(1987) Pancreatic insulin-secreting neoplasms - clinical, diagnostic, and prognostic features in 73 dogs. JAAHA 24 , 577-584.
• Leifer C E et al(1986) Insulin-secreting tumor - diagnosis and medical and surgical management in 55 dogs. JAVMA 188 , 60-64.

• Torrance A G (ed) et al(1998) Manual of SA Endocrinology. BSAVA publication.

• Dr David Bruyette DVM DipACVIM, VCA West Los Angeles, 1818 South Sepulveda Boulevard, Los Angeles, CA 90025, USA.
• Dr Laura Garrett DVM DipACVIM, School of Veterinary Medicine, Kansas State University, Manhattan, KS 66506-5606, USA.
• Andrew Gardiner DVM&S, CertSAS, MRCVS, 8/6 Hermits's Croft, St Leonards, Edinburgh EH8 9RF, UK.

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