Insulinoma

Insulinoma is an insulin-secreting tumour of pancreatic beta cells. Despite being more frequent than other endocrine pancreatic tumours (gastronoma, glucagonoma), insulinoma is nevertheless a rare disease in the dog and very rare in the cat. The first case of insulinoma in a dog was described in 1935; in that same year, Dr. Whipple documented the first series of human insulinoma cases treated successfully with surgery.

AETIOPATHOGENESIS

In the dog, in approximately 70% of cases insulinoma is sustained by a carcinoma or, less frequently, by a pancreatic β-cell adenoma; in both cases, the tumour is hormonally active and potentially able to secrete various hormones (insulin, pancreatic polypeptide, somatostatin, glucagon, serotonin, and gastrin). In most cases, the hormone produced in greater amounts is insulin, and the clinical signs are essentially correlated to the hypoglycaemia triggered bystates ofhyperinsulinism. In fact, insulin is secreted by the tumour in an independent manner and is not inhibited by low blood concentrations of glucose.

In 80% of cases the tumour is solitary and can be located in one of the side lobes or, less frequently, in the body of the pancreas.

Staging of the tumour is performed according to the Tumour-Node-Metastasis (TNM) classification of the World Health Organization (Tab. 1).

At the time of diagnosis, most dogs are already in stages II (T₁N₁M₀) or III  (T₁N_(0-1)M₁). Metastatic lesions mainly involve the liver and the regional lymph nodes; other reported possible metastatic sites are the mesentery, the duodenum, the spleen, the heart and the spinal cord. Pulmonary metastases are infrequent. The high incidence of metastases at the time of diagnosis is likely due to a delay in the identification of the clinical manifestations of the animal.

SIGNALMENT

Insulin-secreting tumours typically affect middle-aged or elderly dogs. The mean age at the time of diagnosis is of about 9 years (range 3 to 15 years). Although no breed or gender predisposition has yet been demonstrated in the canine species, the disease has been shown to be more frequently present in medium or large-sized subjects; however, this does not rule out the possible presence of the disease in small-sized dogs. The 6 cases of feline insulinoma reported in literature were aged between 12 and 17 years.

Table 1. Clinical staging of insulinoma

CLINICAL HISTORY OF PATIENTS

The clinical manifestations of insulinoma are typically caused by the effects of hypoglycaemia on the central nervous system (neuroglycopenia) or by the release, induced by hypoglycaemia, of counter-regulatory insulin-antagonising hormones  (mainly catecholamines). In patients affected by the disease the most frequent symptoms are seizures, generalized weakness, episodes of collapse, ataxia, muscle fasciculation, apparent blindness, disorientation andbehavioral changes, which usually occur intermittently. Although most affected dogs usually manifest more than one clinical sign, some subjects may be completely asymptomatic. The severity of these conditions depends on the duration, the degree and rapidity with which hypoglycaemia is established. The duration of symptoms is often short (seconds or minutes), because the compensatory synergistic response of the counter-regulatory hormones suddenly increases blood glucose to above the critical threshold levels. Affected subjects who are chronically hypoglycaemic or have recurrent episodes of hypoglycaemia may tolerate blood glucose values under the normal range for long periods of time, even without clinical manifestations, but in these cases even minor changes in blood glucose may trigger symptomatic episodes. Fasting, physical exercise and states of agitation generally worsen the symptoms. A meal can cause blood sugar levels to rise, but sometimes it can also trigger an abnormal secretion of insulin by the tumour, and consequently cause the symptoms.

CLINICAL EXAMINATION

The physical examination does not usually reveal anything particular, except at times for the finding of a slightly overweight subject, as a result of the powerful anabolic effect of insulin. Weakness and a tendency to lethargy may also be present, while seizures and episodes of collapse are more difficult to detect during the examination. Subjects taken in for a visit after a seizure may present postictal neurological deficits. A peripheral polyneuropathy – mainly characterized by tetraparesis and a reduction or absence of spinal reflexes - has been a rare finding in some patients.

LABORATORY FINDINGS

The basic diagnostic laboratory protocol for the evaluation of dogs in which the presence of hypoglycaemia has been confirmed and in which an insulin-secreting tumour is suspected should include: complete blood count, blood-biochemical profile and urinalysis.

The blood count and urinalysis are usually normal, as well as the biochemical profile, in which hypoglycaemia is the only truly significant feature.

Approximately 90% of dogs with insulinoma have blood glucose values below 60 mg/dl, with a range from 15 to 80 mg/dl (mean 38 mg/dl). Occasionally, blood glucose values between 70 and 80 mg/dl are found, and therefore the presence of such values do not allow to rule out the disease in case of strong clinical suspicion (Table 2). In these cases a fasting period of 4-12 hours will be sufficient to demonstrate the presence of hypoglycaemia.

To support the suspicion of insulinoma, especially when the presence of hypoglycaemia cannot be proven, the measurement of fructosamine may be helpful. Often, dogs with insulinoma have serum fructosamine values lower than the reference range, indicating a state of persistent hypoglycaemia.

Table 2. Differential diagnosis of hypoglycaemia (A fictitious hypoglycaemia caused by a delay in the separation of serum from the red blood cells should first be ruled out) (From:Ettinger S. J., Feldman E. C. Textbook of Veterinary Internal Medicine, VII edition Elsevier Saunders, 2010).

Determination of basal insulinaemia and of blood glucose concentration
A presumptive diagnosis of insulinoma in dogs with clinical symptoms can be made by documenting the presence of hypoglycaemia (blood glucose <60 mg/dl) and a concomitant hyperinsulinaemia ( >20 μU/ml).

Protocol
Most dogs with insulin-secreting tumours are persistently hypoglycaemic, a finding easily verifiable with a blood sample taken from the subject. In the presence of a blood glucose value below 60 mg/dl (preferably less than 50 mg/dl), the serum should be sent to a laboratory specialised in veterinary endocrine evaluations, in order to determine the concentrations of insulin and glucose.

Should the blood glucose value be higher than 60 mg/dl, to show an eventual hypoglycaemia it may be necessary to fast the animal for 4-12 hours. During this time period blood glucose should be monitored every hour until the levels are below 60 mg/dl. Once hypoglycaemia is ascertained, a blood sample should be taken and the serum sent to the laboratory for its examination.

Interpretation of results
In the fasting healthy subject, blood concentrations of glucose and insulin are between 70 and 100 mg/dl and between 5 and 20 μU/ml respectively. In the dog with symptoms referable to insulinoma, insulin concentrations >20 μU/ml together with blood glucose values <60 mg/dl strongly support the suspected diagnosis. Occasionally, in the dog with insulinoma, the values of insulin, always in combination with hypoglycaemia, may be within either the upper or the lower range of normality, i.e. from 10 to 20 μU/ml or from 5 to 10 μU/ml. In these cases, in the presence of a marked suspicion based on the clinical history and the clinical findings, a second measurement of insulinaemia is recommended.

DIAGNOSTIC IMAGING

Once a strong suspicion of insulinoma has been established, based on anamnestic data, clinical findings and, most important, on laboratory findings, imaging studies become necessary both to support the suspected diagnosis and to provide prognostic information on the risks correlated to surgery and on the possibilities of therapeutic success.

Abdominal ultrasound
Abdominal ultrasound examination is an easily accessible, non-invasive and inexpensive examination that, both in human and in veterinary medicine, represents the first imaging technique used for the visualisation of the pancreas.Nonetheless, the sensitivity of ultrasonography in finding pancreatic tumours is still limited (false negatives), especially in the presence of small tumours. In any case, an abdominal ultrasound examination can be advantageous: besides allowing an attempt to visualise the primary pancreatic lesion or possible other abdominal diseases, it also allows to identify the potential presence of metastatic lesions, which are mainly localised in the peripancreatic, hepatic and lymph node regions.

Computed tomography (CT)
CT angiography has recently been investigated also in veterinary medicine for the visualisation of pancreatic tumours. Compared to normal pancreatic tissue, in the arterial phase insulinomas show a marked enhancement, making them more hyperdense and more observable. Although the sensitivity of this examination has not yet been determined, recent studies have shown that CT angiography is superior to ultrasound in the identification of the tumour.

Radiographic examination of the chest
Numerous studies have confirmed that in patients with insulinoma the presence of lung metastases is extremely uncommon. Nevertheless, the acquisition of chest radiographs may be helpful in revealing the presence of other metastases, and therefore in diagnosing potential additional causes of the hypoglycaemia

TREATMENT

The treatment of insulinoma may be divided into treatment of the acute hypoglycaemic crisis and the long-term management of the patient.

Treatment of acute hypoglycaemic crisis    
An acute hypoglycaemic crisis, which typically occurs with seizures, should be treated as quickly as possible in order to prevent the onset of permanent damage to the cerebral nerve tissue.The goal of the treatment must be that of stopping the crisis, primarily by treating the hypoglycaemia, which triggered it. If the crisis occurs when the animal is at home, the owner should try to put a honey (preferably) or a sugar solution on the gums of the animal. After recovering, a small meal should be given to the pet. In the event of a hospitalised patient, a bolus of glucose solution must be administered;  the solution should be administered with caution, as it may itself stimulate the secretion of insulin by the tumour.

Example of glucose supplementation:

• 0.5 g/kg i.v. diluted with NaCl 0.9% in a 1:3 ratio, then continue with a CRI of a 2.5% or 5% glucose solution until the crisis is resolved (without necessarily reaching values of euglycaemia).
• A small meal should be given once the patient has recovered.

In cases in which the hypoglycaemia is refractory to the administration of a glucose solution alone, a possible alternative consists in the administration of glucagon by continuous infusion at a dose of 5-10 ng/kg/minute. The dose can be modified in order to maintain blood glucose between 50 and 100 mg/dl. Treatment with glucagon should be gradually suspended in 1 or 2 days, while continuing to monitor blood glucose.

In the most severe and refractory cases, in order to prevent seizures the patient should be sedated with diazepam or pentobarbital for several hours until the symptoms have resolved.

Long-term management of the patient: surgical therapy

The treatment of choice for insulinoma is surgical removal of the tumour and of all visible metastases (Fig. 1).  A careful surgical exploration of the entire abdominal cavity can usually confirm the diagnosis and allows to estimate the survival time of the patient (if this is mentioned, an indication of survival time must be given).According to some authors, surgery is a possible treatment option even for subjects in whom metastases are already visible, since the removal of the primary tumour and of the visible metastatic lesions may improve symptoms and prolong survival times to a greater extent than with drug-therapy alone. In these cases, the risk/benefit ratio of surgery will have to be assessed carefully, especially in relation to the localisation of the tumour.

Generally speaking, most insulinomas are localised in one of the two pancreatic lobes; lobar pancreatectomy is accompanied by a lower risk of complications, usually caused by the onset of post-operative pancreatitis. Insulinomas localised in the body of the pancreas are removed by surgical excision; compared to partial pancreatectomy, such surgery entails higher risks and is associated with a less favorable prognosis due to the possible occurrence of pancreatitis. The macroscopic localisation of the lesion is not always possible, even during surgery. In such cases, if the diagnosis is confirmed by blood glucose and insulin values, some authors recommend performing a pancreatectomy of one of the two lobes, in the hope of removing the portion containing the tumour (Feldman and Nelson). If a lobectomy is not performed, the subject will have to be treated with medical therapy. The histological examination of the tumour and of the other eventually excised or biopsied lesions, will then allow to issue a definitive diagnosis (Figs. 2a and 2b).

Before surgery, blood glucose values of the patient must be stabilised by medical therapy, and during surgery blood glucose must constantly be monitored and adjusted with the possible supplementation of a 5% glucose solution in order to prevent it from dropping below 40 mg/dl.Adequate fluid therapy should be maintained right before, during and for 48 hours after surgery, in order to reduce the risk of pancreatitis.

In the post-operative phase, the most frequent complications are:

• Pancreatitis: the administration of intravenous fluids supplemented with glucose andfasting 24 hours before and 48 hours after surgery, followed by an appropriate diet during the subsequent week, will help reduce the risk of pancreatitis. During fluid therapy blood glucose and electrolytes should be monitored at least twice a day, in order to allow for possible corrections, if needed.
• Hyperglycaemia: occasionally, after the removal of the tumour some dogs may develop a mostly transitory form of diabetes mellitus. This is mainly due to inadequate insulin production by the non-neoplastic beta cells that may be atrophied by the persistent hypoglycaemia. If the hyperglycaemia and glycosuria persist for more than 2-3 days after cessation of supplementation with glucose solution, the administration of insulin may be necessary (usually a rare occurrence). The initial therapy should consist in 0.25 U/kg of slow insulin once a day. Insulin therapy is rarely necessary for the entire life of the animal. The presence of hyperglycaemia in the immediate post-operative phase does not allow to rule out the presence of other possible non-neoplastic lesions that might later manifest themselves through a relapse of hypoglycaemia.
• Persistent hypoglycaemia: after surgical excision, dogs that remain persistently hypoglycaemic are likely to still have some functional metastases. In these cases, a continuous glucose solution supplementation will be required during the 48-72 hours after surgery and, in the long term, to prevent hypoglycaemia, the veterinarian must resort to maintenance medical therapy, which, in any event, prolongs survival times of the animal.

“Palliative" medical therapy
Medical therapy is indicated before surgery, postoperatively for patients with recurrent hypoglycaemia and in cases where surgery is not performed. Goal of the therapy is to keep the blood glucose of the patient above the critical threshold (not necessarily euglycaemia), so as to prevent the onset of hypoglycaemic crises and reduce their frequency and severity.

Treatment essentially consists in diet control, physical exercise, and the use of prednisone, which can be associated with diazoxide in the more refractory cases. Additional drugs have been used for the long-term control of the disease, including: octreotide (somatostatin analogue), streptozotocin  and alloxan (chemotherapeutic drugs). Nonetheless, further studies are needed to determine their actual efficacy and safety.

Diet :in order to avoid rapid increases in blood glucose, that would stimulate the secretion of insulin by the tumour, meals should be divided into small portions to be given every 4-6 hours. The diet should consist of foods with a higher content of proteins, fibres and lipids, with the addition of complex carbohydrates. Foods containing simple sugars must be avoided because they excessively stimulate insulin secretion.

Physical activity: physical exercise should be limited in order to reduce the consumption of glucose.

Prednisone: in the long term, glucocorticoids are used for their hyperglycaemia-inducing action. The starting dose is 0.5 mg/kg orally every 24 hours; the dose may be increased to 3 mg/kg every 24 hours.

Diazoxide: diazoxide is abenzthiazide diuretic, which inhibits the secretion of insulin, increases gluconeogenesis and hepatic glycogenolysis, and reduces tissue use of glucose. The use of diazoxide is indicated in patients unresponsive to diet therapy and prednisone alone. The dose is administered orally at a dosage of 10-40 mg/kg every 24 hours divided into three doses, starting from the lowest dose and, if necessary, increasing gradually.

PROGNOSIS

In most cases insulinoma is a pathology supported by a malignant tumour. Though surgery improves survival times compared to the use of medical therapy alone, the prognosis remains guarded in all cases. The survival times of patients undergoing partial pancreatectomy vary from 12 to 14 months, with a range from 0 days to 5 years. For dogs treated with medical therapy alone, the prognosis, according to recent studies, is of approximately 200 days (range 0-549). Among the identified prognostic factors, the clinical stage at presentation is probably the most indicative one. Dogs in stage I have a more favourable prognosis than dogs in stages II or III.

Suggested readings

1. Feldman E.C., Nelson R.W.: Beta-cell neoplasma: insulinoma. In:Canine and Feline Endocrinology and Reproduction,  III edizione Saunders, pg 616-644, 2004.
2. Hess R.B.: Insulin-Secreting Islet Cell Neoplasia. In: Ettinger S.J., Feldman E.C.: Textbook of Veterinary Internal Medicine,VII edizione Elsevier Saunders, pg 1779-1782, 2010.
3. Polton G.A. et al.: Improved survival in a retrospective color of 28 dogs with insulinoma. J Small Anim Pract, 48, 2007.
4. Reush C.E et al: Endocrine Pancreas. In: Rijnberk A., Kooistra H.S.: Clinical Endocrinolgy of Dogs and Cats, II edizione Schlutesche, pg 155-185, 2010.
5. Robben J.K. et al.: Comparison of ultrasonography, computed tomography, and single-photon emission computed tomography for detection and localization of canine insulinoma. J Vet Intern Med, 19, 2005.
6. Stockham L.S., Scott M.A.: Glucose, ketoamines, and related regulatory hormones. In: Stockham L.S., Scott M.A.: Foundamentals of Veterinary Clinical Pathology, II edizione, Blackell Publishing, pg 707-737, 2008.