Insulinoma

Introduction

An insulinoma is a functional beta cell tumor causing hyper- insulinism. Insulinomas occur infrequently in dogs and are rare in cats.^3-5 Insulinoma cells produce a wide variety of regula­tory polypeptides, such as insulin, pancreatic polypeptide, so­matostatin, glucagon, serotonin, gastrin, and ACTH.⁶ Despite the variety of polypeptides produced by insulinoma cells, al­most all of the patients diagnosed with an insulinoma show only clinical signs of hyperinsulinism.

Pathogenesis

The etiology of insulinomas remains unknown and risk factors for insulinomas have not been described. Beta cells take up glucose through an insulin-independent process and the intra­cellular glucose concentration of the islet cells mirrors the se-

Table 9.10: Gastrointestinal regulatory peptides

This table shows a list of the most prominent groups of gastrointestinal regulatory peptides. It should be pointed out that there are many more regulatory peptides in the gastrointestinal tract; however, their physiological relevance is less well understood.

Figure 9.16:

Insulinoma.

rum glucose concentration. In normal subjects, insulin secre­tion from beta cells is suppressed when the blood glucose concentration falls below approximately 60 mg/dl. At the same time, secretion of the counterregulatory hormones (immediate response: catecholamines and glucagon; delayed response: cor­tisol and growth hormone) increases. Insulinomas do not re­spond appropriately to a falling blood glucose concentration. This results in hypoglycemia, which in turn can result in cen­tral nervous system (CNS) abnormalities. Glucose uptake into the CNS is by facilitated diffusion and is also non-insulin-de­pendent, so that glucose uptake is low at times of hypogly­cemia. In addition, the CNS utilizes glucose as its primary en­ergy source, and cannot utilize fatty acids and ketone bodies as can other tissues, including the peripheral nervous system. Clinical signs of hyperinsulinism also include signs induced by an increased discharge of the sympathetic nervous system, which is part of its counterregulatory response. However, in­sulinoma patients apparently adjust to repeated or chronic states of hypoglycemia as they can tolerate extremely low blood glucose concentrations without showing any clinical signs.

In addition to the degree of hypoglycemia, the rate of decrease in blood glucose concentration, and the duration of hypogly­cemia all determine the extent of the clinical signs.

Table 9.11: Main functions of important gastrointestinal regulatory peptides

This table shows an alphabetical listing of the most important regulatory peptides of the gastrointestinal tract, their location and cell type of secretion, their most important functions, and the stimulatory and inhibitory factors for their secretion.

Table 9.12: Breed distribution of dogs with insulinoma

This table shows the breed distribution of 222 canine patients with insulinoma and the breed distribution of the canine population seen at the Veterinary Hospital at the University of Pennsylvania (VHUP) for the period 1991-1992.³ Boxers, Irish Setters, German Shorthaired Pointers, and Weimeraners appear to be predisposed.

(Table re-printed with permission from: Steiner JM, Bruyette DS.

Pathology and natural behavior

Insulinomas most commonly appear as tan nodules in the pan­creas (Figure 9.16). They are generally small (i.e., 1 cm in di­ameter or less). Most often they appear to be singular, but in a series of 129 dogs, 14% had multiple masses.³ On histopathol­ogy, the tumor cells appear as normal islet cells, forming ir­regular nests and cords with a variable pattern of dense stromal proliferation.

Malignant tumors are defined as tumors which are locally in­vasive and /or form distant metastasis. In many neoplastic dis­eases, the malignant potential of a tumor can be successfully predicted by histopathological evaluation. However, this is not the case for insulinomas and other endocrine neoplasias, as these neoplasias often lack many of the typical features of ma­lignancy. Thus, estimation of the malignant potential of insuli­nomas based on histopathological findings can be misleading and should not be attempted.

Signalment

Insulinomas mainly occur in older dogs and cats. The mean age of 233 dogs reported in the literature was 8.9 years with a range of 3.5 to 14 years in 128 dogs.³ The sex distribution of 133 dogs with insulinoma showed 45% males and 55% fe­males.³ Table 9.12 shows the breed distribution of 222 dogs with insulinoma.³

Table 9.13: Incidence of clinical signs reported in 113 canine insulinoma patients³

all other clinical signs were reported with a frequency of less than 5%

(Table re-printed with permission from: Steiner JM, Bruyette DS.

Clinical presentation

Dogs presenting with insulinomas generally present with two types of clinical signs: neuroglycopenic signs, such as weakness, ataxia, depression, or seizures or signs related to an increased discharge of the sympathetic nervous system, such as behavio­ral changes, shaking, trembling, and muscle fasciculations.^3,4 The incidence of clinical signs reported in 113 dogs with in­sulinoma is shown in Table 9.13.³ Most patients with insu­linoma show only intermittent clinical signs, and will have a rather unremarkable physical examination. A few patients will present in status epilepticus or even comatose. Due to the age of the affected population, a number of geriatric abnormalities may be evident that are unrelated to the presence of an insu­linoma. Rather rare are those patients presenting with peri­pheral polyneuropathies. Subclinical polyneuropathy appears to be more common than symptomatic disease.

Diagnosis

A fasting blood glucose concentration should be part of the workup of a patient with clinical signs suggestive of hypogly­cemia, preferably during times when the patient is sympto-

matic. Most dogs diagnosed with an insulinoma will present with a low blood glucose concentration, even in the absence of clinical signs. If hypoglycemia is confirmed, the causative relationship between the observed clinical signs and the hy­poglycemia needs to be established. This is best accomplished by demonstrating Whipple’s triad, which consists of 1) dem­onstrating a subnormal blood glucose concentration, 2) pres­ence of clinical signs of hypoglycemia, and 3) cessation of clinical signs with resolution of hypoglycemia. After Whipple’s triad has been established, the cause of hypoglycemia must be identified. A basic workup should include a complete blood count, a chemistry profile, and a urinalysis. In insulinoma pa­tients these basic parameters will usually be within normal limits.

Figure 9.17:

Insulinoma metastases in the liver. This figure shows a liver with diffuse dissemina­tion of metastatic lesions of an insulinoma in a dog. (Courtesy of Dr. Thomas J. Van Winkle, University of Pennsylvania, Philadelphia, PA.)

Many tests have been employed in human and veterinary pa­tients with a suspected insulinoma. The single most reliable test for an insulinoma is the demonstration of an inappropri­ately high serum insulin concentration in the face of hypogly­cemia, also referred to as insulin-glucose pair. Serum for the determination of insulin concentration needs to be collected at the time of the hypoglycemia. This is accomplished by serial blood glucose measurements while food is withheld from the animal. It is best to start early in the morning with the patient being closely monitored throughout the day. Blood glucose concentration is measured every 30-60 minutes. When the blood glucose falls below 60 mg/dl, a sample for the measure­ment of serum insulin concentration is drawn and the animal is fed. It is important to verify blood glucose concentrations measured by a glucometer through the use of a chemistry analyzer. Interpretation of the insulin-glucose pair is straight forward if the insulin concentration exceeds the reference range (the reference range is dependant on the laboratory used) in the face of hypoglycemia. However, the serum insulin concentration may be within the reference range and still be inappropriately high with respect to the blood glucose con­centration. Several ratios have been evaluated to help docu­ment inappropriate insulin secretion: glucose-insulin ratio, insulin-glucose ratio, and the amended insulin-glucose ratio. Unfortunately, none of these ratios improve the diagnostic ac­curacy in either humans or dogs with a suspected insulinoma and the use of these ratios is not recommended. An insulin- glucose pair is the single most reliable test to diagnose an in­sulinoma as the cause of hypoglycemia.

A variety of provocative tests have been suggested to aid in the diagnosis of an insulinoma. These include the glucagon toler­ance test, the IV glucose tolerance test, the tolbutamide toler­ance test, the L-leucine test, the oral glucose tolerance test, the epinephrine stimulation test, and the calcium infusion test. All of these tests are time consuming, expensive, and, at least in people, have lower sensitivities than a simple insulin-glucose pair. In addition, some of these tests put the patient at risk for severe hypoglycemia. In cases where the cause for the hy­poglycemia can not been determined, and the evaluation of serum insulin and glucose concentrations have been equivocal, the measurement of serum insulin and glucose should be re­peated whilst food is withheld from the patient.

Staging

As with any other neoplastic disease, patients with an insuli­noma should be staged. Unfortunately, the available modalities to stage canine and feline insulinoma patients are limited. Ab­dominal ultrasound is inconsistent in detecting the primary tumor, but can be helpful in demonstrating evidence of local extension and distant metastasis of the disease. Currently, the most reliable staging tool in veterinary patients appears to be abdominal exploration.

In a compilation of 129 abdominal exploratories of canine insulinoma patients, 66 (51%) of the dogs had metastatic disease detected during the exploratory laparotomy.³ Of those, 29 (22%) had metastatic lesions in the liver (Figure 9.17), 19 (15%) had metastases to regional lymph nodes, 7 (5%) had metastatic lesions in both liver and lymph nodes, and 11 (8%) had metastatic lesions in other locations.³

Treatment

Emergency treatment

Patients presenting for clinical signs of hypoglycemia need to be treated as quickly as possible. If hypoglycemia has been documented, a dextrose bolus (0.5 g/kg as a 25% solution IV over approximately one minute) should be administered and a dextrose constant rate infusion should be initiated. Suitable infusion solutions are 5% dextrose or balanced electrolyte so­lutions with added dextrose. It is important to note that the goal of emergency therapy is to eliminate the clinical signs of hypoglycemia rather than to restore euglycemia. If neurogly- copenic signs persist, cerebral edema should be suspected and treatment using mannitol and corticosteroids should be con­sidered. If seizures still persist, diazepam or other anticonvul­sants may be indicated.

Pancreatic surgery

Surgical exploration is the treatment of choice for the man­agement of canine and feline patients with an insulinoma. It is crucial to stabilize the blood glucose concentration of the pa­tient prior to surgery. Also, the surgeon should be aware that handling of the tumor can lead to increased insulin release. In contrast, removal of the tumor may suddenly lower plasma insulin concentrations. Therefore, blood glucose must be monitored closely throughout the procedure.

In order to stage the disease, a careful abdominal exploratory should be performed, and biopsies of suspicious lymph nodes or areas within the liver should be obtained.

Identification of the insulinoma can be difficult. In a compila­tion of 129 abdominal exploratories of canine patients with a suspected insulinoma, a pancreatic nodule could not be identi­fied in 26 patients (20%).³ Even though some of these cases might have had a rarely described diffuse infiltration of the pancreas, further evaluation of localization techniques seems warranted in canine insulinoma patients. Some investigators have suggested the intravenous infusion of methylene blue.⁷ However, this procedure has only been described in five pa­tients and the drug can cause a Heinz body hemolytic anemia, so further investigation of this technique is necessary. In hu­man medicine, a variety of localization techniques have been described and compared. Currently, endoscopic ultrasonogra­phy and somatostatin receptor scintigraphy (SRS) are consid­ered the most sensitive modalities in human insulinoma pa- tients.⁸ Othermodalitiesinclude intraoperativeultrasonography, CT, MRI, selective arteriography, intraoperative quick frozen sections, and transhepatic venous sampling.

The majority of localization techniques reported in the hu­man literature are either very expensive or of limited availabil­ity in veterinary medicine. Thus, intraoperative inspection and palpation remain the primary mode of localization of an in­sulinoma in veterinary patients. However, other modalities may be employed. Intraoperative ultrasonography is techni­cally feasible and relatively inexpensive, but has never been systematically evaluated for the localization of insulinomas in small animals. However, the author believes that it should be considered in cases where intraoperative visualization and pal­pation are unsuccessful. It also can be utilized to scan the liver for possible metastasis. The use of CT has recently been evalu­ated for the localization of insulinomas in dogs and was able to visualize the primary tumor in 10/14 (71%) patients.⁹ This was superior to transabdominal ultrasound, which was suc­cessfully used to identify the primary tumor in 5/14 (36%).⁹

Somatostatin receptor scintigraphy, that is the intravenous ad­ministration of ¹¹¹In-DTPA-D-Phe¹-octreotide (OctreoScan, Mallinckrodt Medical) followed by planar scintigraphy or sin­gle-photon emission CT, has also been evaluated in canine insulinoma patients.^9-11 In one study, the primary lesion was identified in all five dogs evaluated.¹⁰ However, in two other studies the insulinoma was only identified in 6/14 (43%) and 4/17 (24%) dogs.^9,11 This discrepancy can be explained by the fact that the tumor was positive for somatostatin receptor sub­type 2 (sst2), one of the somatostatin receptor subtypes to which octreotide preferentially binds to, in all five dogs in the first study, but only in 7/17 (41%) dogs in one of the other two studies.^10,11 Thus, while SRS may be useful to identify and /or localize an insulinoma in some cases, if the tumor does not express sst2, the tumor may not be able to be visualized with this modality.

Extreme care should be exercised at all times when handling the pancreas. After localization of the insulinoma, it can be removed by enucleation, partial pancreatectomy, and total pancreatectomy +/- duodenectomy. While the surgical tech­nique for total pancreatectomy has been described for the dog, this procedure is associated with a high postsurgical morbidity and mortality, and should thus only be considered if there are no other options. Local enucleation has been shown to result in shorter survival times than partial pancreatectomy, and should therefore only be considered if the tumor is in the body of the pancreas, or very proximally in the right lobe.¹² Thus, the surgical procedure of choice is partial pancreatec­tomy (Figure 9.18). If the tumor cannot be localized on ab­dominal exploratory, a small pancreatic biopsy should be taken to evaluate the pancreas for diffuse infiltration histopathologi- cally. Since the right and left lobes are involved with equal frequencies and occult insulinomas are probably most com­mon in the pancreatic body, random removal of pancreatic tissue should not be performed.

The most common postoperative complication of pancreatic surgery is acute pancreatitis. However, the risk of postopera­tive pancreatitis can be minimized by aggressive fluid therapy during anesthesia and gentle handling of the pancreas during surgery. Other common postoperative complications are hy­poglycemia and hyperglycemia. Persistent hypoglycemia indi­cates that the insulinoma has not been completely removed. The patient either has to be re-explored, or medical therapy has to be instituted. Hyperglycemia, if present, is most often transient, but some patients may require insulin therapy to control the hyperglycemia.

Chemotherapy

If surgical exploration is not an option or if it does not lead to removal of the entire insulinoma, chemotherapy can be con­sidered. Streptozotocin is a nitrosurea compound isolated from Streptomyces achromogenes. The drug has been used in approxi­mately 20 dogs with insulinoma.^13,14 Streptozotocin is highly nephrotoxic and can also be hepatotoxic. Therefore, pre- and post-treatment diuresis is crucial. In addition, the mean dura­tion of normoglycemia in treated dogs was not significantly longer than in untreated controls in one study of 17 dogs. Thus, further studies are needed to evaluate the clinical useful­ness of streptozotocin for the treatment of canine insulinoma.

Alloxan is an unstable uric acid derivative that has two effects, selective cytotoxicity of islet cells and stimulation of hepatic gluconeogenesis. The use of alloxan has been described in five canine insulinoma patients.¹⁵ Two of the five patients devel­oped hyperglycemia for several months without any additional medical therapy. Alloxan, like streptozotocin, is also nephro­toxic and concurrent fluid therapy should be instituted for several days in order to minimize renal toxicity. The use of several other chemotherapeutic drugs has been reported in the human literature, but no data are available for veterinary species.

Radiation therapy

Successful treatment of insulinomas with radiation therapy has been described in isolated human patients. However, to date, data for canine or feline patients are not available.

Symptomatic therapy

Antihypoglycemic therapy

Symptomatic therapy should be instituted in insulinoma pa­tients when surgical exploration is not an option or is not successful. The dog should be fed a high protein, high fat, high complex carbohydrate diet divided into multiple small feed-

Figure 9.18:

Insulinoma. An insulinoma after surgical removal by partial pancreatectomy. Size and appearance of this tumor are typical. (Re-printed with permission from Steiner JM, Bruyette DS. Canine insulinoma. Compend Contin Educ Pract Vet 1996; 18: 13-24.)

ings (4-6 per day). If the patient shows signs of weakness, a small amount of food should be offered immediately. Own­ers should also be familiarized with the clinical signs of hy­poglycemia and instructed that if signs occur, dextrose solu­tion (e.g., Karo-Syrup or honey) should be applied onto the gums of the patient. Excitement should be avoided and exer­cise should be limited to short leash walks.

Glucocorticoids should be administered if frequent feedings alone will not control the clinical signs. Cortisol is an endog­enous counterregulatory hormone to insulin. It increases pe­ripheral lipolysis and protein catabolism, increases hepatic glu­coneogenesis and glycogenolysis, and decreases peripheral glucose utilization. It also decreases the sensitivity of insulin receptors in the periphery. Prednisone or prednisolone can be started at an oral dose of 0.25 mg/kg twice a day. If clinical signs of hypoglycemia cannot be controlled, the dose can be increased up to 2-3 mg/kg twice per day. The development of iatrogenic Cushing’s and GI side effects (e. g., gastritis, gastric ulceration, or colitis), may warrant the discontinuation of ster­oid therapy, and additional medical therapy may be required.

Antihormonal therapy

Another therapeutic option for insulinoma patients is the treatment with agents that depress insulin secretion. Several such agents are available. Diazoxide is a non-diuretic benzo­thiadiazine that has anti-hypertensive as well as hyperglycemic properties. Its hyperglycemic action is due to a depression in

insulin release from beta-cells. Diazoxide does not impair in­sulin synthesis and it is not cytotoxic to beta cells. Survival times in insulinoma patients treated with diazoxide are rather short. However, this might be due to the fact that in most re­ports, diazoxide was only administered after previous medical and surgical therapy had failed. A few long-term responders have been reported, the longest being 18 months.¹⁶ The rec­ommended starting dose is 5 mg/kg orally twice per day, but the dose can be gradually increased to 30 mg/kg twice a day. Since the drug is metabolized in the liver and excreted by the biliary system and the kidneys, dosing should be carefully evaluated for patients with hepatic or renal disease. Also, care should be taken to avoid hyperglycemia. Thiazide diuretics enhance the effects of diazoxide and hydrochlorothiazide can be added to the therapeutic protocol (2-4 mg/kg PO q 24 h). In order to decrease the frequency of GI side effects, the drug should be administered together with a meal.

Somatostatin (i.e., octreotide acetate) decreases several poly­peptides of the gastroenteropancreatic system, including in­sulin. Octreotide consistently suppresses plasma insulin con­centrations in canine insulinoma patients, while it has no effect on counterregulatory hormones, suggesting that it maybe use­ful in the treatment of canine insulinoma.¹⁷ However, of ap­proximately 20 dogs described in the literature that have been treated with octreotide only 50% showed a clinical response.^11,18 As with SRS, the limited response of canine insulinoma pa­tients to octreotide may be due to a lack of sst2 expression of the insulinoma cells. Doses of 20-100 μg octreotide SC q 8-12 h have been described in the literature.^11,18

Prognosis

The long-term prognosis for dogs with insulinoma is grave, although the short-term prognosis is good. In a compilation of 114 dogs with an insulinoma, which had been treated with surgery and with symptomatic therapy after recurrence of clinical signs, the mean survival was 11.5 months.³ Results may be more favorable as 31 dogs were alive and asympto­matic at their last follow-up visit, and time to relapse or death could not be determined. It should also be noted that the mean age of dogs presenting with an insulinoma is 9 years, and therefore many patients may die for other reasons. In one study, the mean survival of canine insulinoma patients without metastatic disease at the time of diagnosis was 17 months, while it was only 8.4 months for dogs that did have metastatic disease.¹⁹ Thus, detection of distant metastases at the time of the abdominal exploratory may serve as a prognostic indicator. Age and serum insulin concentrations at the time of diagnosis have also been proposed as prognostic indicators, but suppor­tive data are not available.¹⁹

9.4.3