Insulin-secreting beta cell tumors are also called insulinomas, adenomas, or adenocarcinomas. They arise from the pancreatic islet cells. Although rare in their incidence, insulinomas are the most common pancreatic endocrine tumor reported in dogs. They are rare in cats.
Insulinomas are a functional tumor of pancreatic beta cells that causes a decrease in glucose production and an increase in glucose utilization via excessive production of either insulin or proinsulin. Insulin production and release is independent of the normal negative feedback effects of hypoglycemia. This causes:
(1) inhibition of the hepatic enzymes needed for gluconeogenesis and glycogenolysis, resulting in decreased glucose release from the liver
(2) decreased release of amino acids from muscle, resulting in decreased gluconeogenesis
(3) increased insulin-dependent glucose uptake
(4) increased release of the counter-regulatory hormones catecholamine, glucagon, glucocorticoid, and growth hormone, resulting in insulin antagonism that results in hyperglycemia and the resolution of clinical signs.
Whipple’s triad is a collection of three criteria used in the diagnosis of insulinoma. The criteria include (1) the presence of clinical signs associated with fasting or exercise, (2) the presence of hypoglycemia when the patient is symptomatic, and (3) the presence of clinical sign resolution with glucose therapy.24
In veterinary medicine, insulinoma-affected patients are middle to older aged, medium to large breed dogs. The mean age is 9 years, ranging from 3.5 to 15 years. The mean weight of affected dogs is 27 kg, ranging from 6 to 52 kg, with 75% of dogs weighing greater than 25 kg and 48% of dogs weighing greater than 35 kg. Representative canine breeds include mixed breeds (22% of cases), Irish setters (10%), German shepherd dogs (10%), boxers (8%), golden retrievers (6%), poodles (6%), and Labrador retrievers (5%). Affected cats are 12 to 15 years of age with Siamese and Persian cats being most commonly represented. There is no gender predilection for both dogs and cats.
Clinical sign severity is proportional to the rate of hypoglycemia development, and may or may not be due to the severity of hypoglycemia. Clinical signs attributed to (1) neuroglycopenia, (2) hypoglycemia-mediated stimulation of the sympathoadrenal system, or (3) both. Clinical signs attributable to neuroglycopenia include focal or grand mal seizures (68% of cases), fatigue or collapse (34%), weakness (33%), ataxia (19% to 32%), lethargy (19%), disorientation or bizarre behavior (15%), convulsion, coma, peripheral polyneuropathy, and central blindness. Clinical signs due to hypoglycemia-mediated stimulation of the sympathoadrenal system include muscle tremors (18% of cases), excessive hunger (11%), nervousness, and restlessness. These signs are due to a release in counter-regulatory hormones from the hypothalamus-stimulated sympathetic nervous system. This begins with catecholamines and glucagon, followed by cortisol and growth hormone. The polyneuropathy that develops is due to chronic hypoglycemia, where neuronal demyelination and axonal degeneration occur. Clinical signs may be present anywhere from 1 to 6 months with ranges from one day to 3 years. These signs are episodic and progressive. They may be associated with fasting or eating, due to paradoxical post-prandial hypoglycemia from an exaggerated insulin release. This results in hypoglycemia 2 to 6 hours after the fast or food ingestion. Exercise also causes clinical signs due to increased muscle utilization of glucose.
Biochemistry profiles show hypoglycemia in 93% of patients, and is usually less than 60 mg/dL. A mean of 46 mg/dL, a median of 39 mg/dL, and a range of 15 mg/dL to 78 mg/dL have been reported. A random sample taken from affected individual will have a blood glucose less than 60 mg/dL 87% of the time. Uncommon findings on a biochemistry profile may include hypoalbuminemia, hypophosphatemia, hypokalemia, increased alkaline phosphatase (21% of cases) and increased alanine aminotransferase (28%).
Insulin to glucose ratios and glucose to insulin ratios have been used with inconsistent results. An amended insulin to glucose ratio has been formulated. The patient’s serum insulin level (µU/mL) is multiplied by 100. That whole value is then divided by the difference between the patient’s serum glucose level (mg/dL) and 30. If the patient has a blood glucose value less than 30 mg/dL then the divisor used is 1. If the amended insulin to glucose ratio is greater than 30, a diagnosis of an insulinoma is suggestive. However, veterinarians need to be aware that the specificity is low so other causes of hypoglycemia need to be ruled-out (hepatic disease, sepsis, and non-islet cell tumors).
Studies have shown that abdominal ultrasonography may show spherical or lobular hypoechoic pancreatic nodules in 22 to 69% of cases. Hypoechoic hepatic nodules may also be seen on abdominal ultrasonography in 43% of cases. Lymph node disease may appear as focal hypoechogenic lesions in the region of the porta hepatis.
Surgical biopsy and histopathology provides a definitive diagnosis of both primary and metastatic disease. The most common sites for metastatic insulinoma include lymph nodes and liver. Less common sites include duodenum, mesentery, spleen, omentum, kidney and spinal cord. Pulmonary lesions are rarely seen.
The goal of surgery is to diagnose the condition, stage the disease process, and debulk or remove the tumor. Treatment is primarily palliative in all affected patients.
Surgical techniques that can be applied in debulking or excising a pancreatic insulinoma include (1) enucleating the primary tumor and (2) performing a partial pancreatectomy (remove of the primary nodule and the pancreas distal to that nodule). A hepatic biopsy is also collected as 25% of patients will have histological evidence of metastatic disease.24Some reports state re-exploring the patient once a diagnosis has been made in an effort to further debulk the mass or surgically remove metastatic disease. This is to prevent post-operative hypoglycemia.
The long term prognosis is poor with recurrence of disease and recurrent hypoglycemia being seen in 100% of affected patients. Prognostic factors include method of treatment, stage of disease, age of the affected patient, higher insulin pre-operatively, glucose levels post-operatively, and the presence of a peripheral neuropathy. The prognosis may also relate to the mitotic rate present.
Survival with partial pancreatectomy is a median of 381 days, ranging from 20 days to 1758 days. This is significantly longer than the survival of 74 days (ranging from 8 days to 508 days) with medical therapy.When comparing enucleation to partial pancreatectomy, mean survival is 11.5 months and 17.9 months, respectively.
Survival for stage 1 or 2 patients is a median of 8 months to 18 months. Stage 3 patients survive a median of less than 6 months. Stage 1 patients maintain normoglycemia for a median of 14 months. Stage 2 or 3 patients maintain normoglycemia for a median of one month.
The survival for young dogs is worse than for older dogs.
Normoglycemia post-operatively results in a median of 680 day survival and hyperglycemia results in a 90 day median survival. The majority of stage I patients (80%) maintain euglycemia for 14 months, while stage II maintain euglycemia for 8 to 9 months, and stage III for 6 months.
The presence of a peripheral neuropathy is a guarded prognosis that may improve with surgery and steroids.
The long term recurrence rate of hypoglycemia post-operatively will eventually be 100%.
*References are available upon request*