Introduction

Canine insulinoma is a malignant pancreatic beta cell neoplasm that secretes excessive amounts of insulin independent of the blood glucose concentration and despite the presence of hypoglycemia. It is an uncommon and highly metastatic tumor in dogs, with metastasis being suspected in nearly all cases and being confirmed in approximately 50% of cases at the time of diagnosis.^1,2 Presenting clinical signs are most often the result of hypoglycemia, and although variable, most often include weakness, collapse, disorientation, and seizure activity.³ The treatment of choice for insulinoma is surgical resection of the primary tumor and any gross metastatic lesions followed by long-term medical management; however, many dogs are euthanized as a result of recurrence of hypoglycemia despite aggressive treatment.²

The dog reported here had uncontrolled hypoglycemia despite both partial pancreatectomy and medical management consisting of oral prednisone^a and frequent feedings. The addition of toceranib phosphate^b resulted in long-term survival and glycemic control.

Case Report

A 12 yr old, 6 kg, spayed female dachshund was presented to the Louisiana State University Veterinary Teaching Hospital for evaluation of prolonged seizure activity lasting greater than 10 min; the dog was found by the owners and continued to have residual seizure activity upon presentation to the teaching hospital. The dog had a 5 yr history of minor seizure-like episodes that occurred once per year and was not receiving anticonvulsant therapy.

The dog had an altered mental status and was unaware of her surroundings at the time of presentation. Vital parameters were within normal limits and thoracic auscultation and abdominal palpation were unremarkable. Anisocoria was present and direct and indirect pupillary light reflexes were intact bilaterally. When placed on the ground, the dog had a right-sided head turn, ataxia, and walked in tight circles to the right. Continuous paddling, which was consistent with ongoing seizure activity, was present in all limbs when the dog was recumbent or being held. Multiple intravenous boluses of diazepam^c (0.25–0.5 mg/kg IV) were administered with minimal reduction in seizure activity and paddling. Blood glucose (BG) measurement with a hand-held glucometer validated for use in dogs^d revealed marked hypoglycemia (29 mg/dL), which was confirmed with repeat measurement (33 mg/dL). Although administration of an intravenous bolus of dextrose solution resulted in normalization of the BG concentration (108 mg/dL), the dog continued to paddle. Because of ongoing seizure activity and potential for cerebral edema due to prolonged seizures, intravenous boluses of levetiracetam^e and phenobarbital^f were administered as well as an infusion of mannitol^g. An intravenous infusion of a 5% dextrose solution was initiated after a recheck BG concentration revealed recurrent hypoglycemia (51 mg/dL). After multiple failed attempts to stabilize the BG concentration and resolve the seizure activity with dextrose, glucagon^h was administered. The dog received a 50 ng/kg intravenous bolus of glucagon followed by a constant rate infusion at 15 ng/kg/min. The neurological abnormalities resolved following stabilization of the BG concentration with glucagon.

The complete blood count and biochemistry profile performed following stabilization were unremarkable except for mild hypoglycemia (68 mg/dL; reference interval 80–115 mg/dL). No significant findings were identified on four-view thoracic radiographs. Abdominal ultrasound revealed a well-defined, hypoechoic 0.95 cm nodule with distal enhancement and central echogenic foci present in the left liver. The right limb of the pancreas was hypoechoic, enlarged, slightly rounded, and contained an ill-defined, ovoid, hypoechoic 0.3 cm nodule (Figure 1). Ultrasound-guided needle aspiration of the liver nodule was performed and cytology was consistent with neuroendocrine neoplasia, which, when combined with the presence of a pancreatic nodule and severe hypoglycemia, was most consistent with metastatic insulinoma. The owner elected to pursue an exploratory laparotomy with the goal of removing the primary tumor and any identified gross metastases. The dog remained on a glucagon constant rate infusion and was receiving oral prednisone (1 mg/kg per os daily) at the time of surgery.

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During surgery, an ∼1 cm nodule was identified in the right limb of the pancreas as well as two ∼0.5 cm nodules in the right lateral and left medial liver lobes. Intraoperative cytology of the liver nodules was consistent with neuroendocrine neoplasia. The right limb of the pancreas containing the nodule was resected. The decision was made not to resect the metastatic lesions in the liver because it would have required the removal of multiple liver lobes in a dog with confirmed metastatic lesions. The presence of an insulinoma in the right limb of the pancreas was confirmed by histopathology and immunohistochemistry, which showed moderate to strong cytoplasmic immunoreactivity for insulin in the majority of the neoplastic cells (Figure 2). Neoplastic cell emboli were present in several vessels near the neoplasm.

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The surgery was completed without intraoperative complications and recovery from anesthesia was uneventful. Postoperatively, the dog’s BG concentration was maintained within an acceptable range (70–193 mg/dL) with glucagon, prednisone, and frequent feeding of a standard maintenance diet. Glucagon was discontinued and medical treatment at the time of discharge included prednisone (0.5 mg/kg q 24 hr) and frequent feeding. The prednisone dosing frequency was increased to twice daily following a hypoglycemic episode (BG 29 mg/dL) that occurred 6 days after discharge.

The inability to stabilize the dog’s condition with standard medical therapy and the presence of gross metastases prompted the initiation of treatment 7 days after discharge with toceranib phosphate at a dose of 2.5 mg/kg orally q 48 hr. Prednisone (0.63 mg/kg q 12 hr) and frequent feedings were continued. The dog began receiving benazeprilⁱ (0.4 mg/kg q 24 hr) 2 wk after beginning toceranib because of an increase in the urine protein to creatinine ratio from 0.6 prior to treatment to 1.1 with an inactive urine sediment. Approximately 6 mo after the initial presentation, the prednisone dosing frequency was decreased to once daily. The BG remained normal to mildly increased at every recheck for 20 mo. At rechecks 20 and 21 mo postsurgery, mild hypoglycemia was detected at 73 and 52 mg/dL, respectively. The reading at 21 mo was taken fasted and without the dog receiving prednisone, whereas her previous readings were after feeding and steroids.

Abdominal ultrasound examinations have been performed every 3 mo since the time of diagnosis. The size of the solitary metastatic liver nodule remained unchanged when compared with the initial ultrasound for ∼1 yr after diagnosis. Approximately 1 yr after the initial presentation, the patient developed progressive liver nodules (increase in size and number). These nodules have remained stable to mildly progressive in size and number on subsequent ultrasound examinations. Although these nodules are suspected to be metastatic, needle aspiration and cytology has not been performed because the dog’s clinical condition has remained stable, and it is unlikely that the results would result in an alteration to the current treatment protocol. Repeat abdominal ultrasound at 21 mo showed no progressive disease compared with the ultrasound 3 mo prior.

The dog is currently 24 mo from initial presentation, remained euglycemic for just under 20 mo, and has shown no clinical signs of hypoglycemia since the addition of toceranib, despite a potential increase in tumor volume, reduction in prednisone dose, and lack of consistent frequent feedings.

Discussion

Medical management following surgery is often recommended for dogs with insulinoma even in the absence of confirmed metastasis.⁴ This includes prednisone, frequent feeding, avoidance of foods containing simple sugars, and a reduction in activity and exercise. The initial dose of prednisone required to maintain an acceptable BG concentration is often low (0.5 mg/kg/day) and well tolerated. As the tumor volume increases, dogs become refractory to treatment, and the effective prednisone doses often lead to excessive and intolerable signs of glucocorticoid excess (i.e., iatrogenic hyperadrenocorticism).¹ Streptozotocin is a chemotherapeutic agent that is cytotoxic to pancreatic beta cells and has been used to treat pancreatic insulinoma in humans.⁵ Although its use in dogs historically was limited by the high potential risk of nephrotoxicity, it can be safely administered when combined with aggressive saline diuresis.⁶ The median duration of normoglycemia when used in an adjuvant setting (n = 14 dogs) is 160 days.⁶ However, serial blood glucose monitoring is warranted as severe diabetes mellitus is a potential complication.^6,7 Other potential medical therapies include octreotide and diazoxide. Octreotide induces hyperglycemia by inhibiting the production of insulin and growth hormone, but its suppressive effect appears to be short-lived.⁸ Also, in a small case series, no long-term benefit compared with placebo was noted.⁹ Diazoxide has multiple targets through which it increases glucose and has been reported to control hypoglycemia in up to 70% of cases. However, its availability and cost may prevent many veterinarians from using it.³

Prognosis, when considering overall survival time, for dogs treated with partial pancreatectomy is ∼12–14 mo.¹⁰ A retrospective cohort study of 28 dogs reported superior survival times with surgery alone (785 days) and surgery in combination with medical therapy (1316 days).¹¹ This is in contrast to other studies that have failed to find a difference in overall survival in dogs treated with surgery versus surgery and medical therapy.^12,13 Medical management as the sole treatment is associated with a shorter overall survival ranging from 74 to 196 days.^11,12

Prognosis for canine insulinoma is also dependent on clinical stage of the disease. Stage I (tumor localized to the pancreas) has the best prognosis after surgery, with >50% of dogs being disease-free 14 mo after surgery, whereas <20% of dogs with stages II and III are disease-free at 14 mo.¹⁴ Stage III dogs (distant metastasis with or without lymph node involvement) have significantly shorter survival times, with a median survival of ∼6 mo.^2,14

Additional treatment options are desperately needed for dogs with advanced stages of insulinoma. Toceranib phosphate is a multireceptor tyrosine kinase inhibitor that acts on important growth factor receptors, including vascular endothelial growth factor (VEGF) receptor and platelet-derived growth factor receptor.¹⁵ Although toceranib phosphate is only approved for the treatment of mast cell tumors in dogs, efficacy has been reported against other tumors, particularly neuroendocrine tumors.^16,17 Neuroendocrine tumors have been shown to express known targets of toceranib phosphate (VEGF receptor and platelet-derived growth factor receptor).¹⁸ Clinical benefits of tyrosine kinase inhibition in neuroendocrine tumors have been shown in a phase 3 randomized, double-blind, and placebo-controlled trial of toceranib’s sister drug, sunitinib, in human patients with advanced pancreatic neuroendocrine tumors.¹⁹ A significant increase in progression-free survival, tumor response rate, and lower hazard ratio for death were all reported for patients in the sunitinib group.¹⁹ Based on this data, and the neuroendocrine origin of insulinoma, it was theorized that toceranib phosphate would be an effective treatment for canine insulinoma. Defects in murine islet vasculature structure, modified via VEGF-A signaling, have been shown to be associated with abnormal insulin secretion.²⁰ Transient increases in VEGF-A production by β cells results in increased intra-islet endothelial cells and reduced β cell numbers.²¹ In these islets, removal of the VEGF-A stimulus results in normalization of β cell mass, function, and structure.²¹ It is possible that toceranib also results in β cell function normalization in insulinoma; however, an exact mechanism is unknown.

Conclusion

This case report describes the use of toceranib phosphate and prednisone to achieve long-term glycemic control and survival in a dog with stage III metastatic insulinoma. The use of toceranib phosphate to improve glycemic control and slow disease progression should be evaluated in a larger group of dogs with insulinoma.