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Insulinomas are neuroendocrine tumours of the pancreatic beta cells. They are functional tumours that produce insulin in excess of normal physiological requirements4. As a result, patients typically present with symptoms of hypoglycaemia, including weakness, seizures, ataxia and changes in consciousness or behaviour1. Common patient signalment is that of a large to medium breed dog between 8.5 to 10 years of age2. This clinical case report highlights the diagnostic pathway, treatment and outcome in a patient with metastatic insulinoma.
A five-year-old female Japanese spitz dog first presented to her primary care veterinarian with a recent history of pelvic limb weakness. Examination was unremarkable aside from a cystic lesion on her dorsum. Complete blood count (CBC) and biochemistry demonstrated hypoglycaemia and leukocytosis. One month later the patient re-presented due to ongoing episodes of collapse with pelvic limb weakness. She had also been hyporexic for the week prior.
Paired glucose and insulin assay was recommended and planned for the following day. However, later that evening, the patient experienced two brief seizures which prompted presentation through a 24-hour veterinary emergency hospital. In-house CBC, biochemistry and blood gas analysis was performed, demonstrating hypoglycaemia (1.2 mmol/L), mild hypokalaemia (3.5 mmol/L), mild hyperchloraemia (117 mmol/L), as well as mildly elevated ALT (157 U/L), and leukopaenia (3.2×10^9/L) due to neutropaenia (2.36×10^9/L) and lymphopaenia (0.60×10^9/L). Two 0.5 mL/kg dextrose 50% IV boluses were administered, followed by a 5% dextrose constant rate infusion (CRI) for management of the hypoglycaemia.
Pre- and post-contrast enhanced computed tomography (CT) of the abdomen and thorax was performed the following day. This revealed a 1.5cm soft tissue attenuating, strongly homogeneously contrast-enhancing mesenteric nodule which was suspected to be an ectopic insulinoma (Figure 1). The pancreas appeared small, with no discrete nodules visible. Incidentally, the uterus was fluid distended with changes consistent with hydrometra or mucometra. No other significant findings were noted.
The dextrose CRI was discontinued, and blood was collected for a paired blood glucose and insulin assay. Results of this demonstrated a blood glucose of 1.0 mmol/L with an insulin assay of 36 mU/L. The insulin level, while within the normal range, was inappropriately high for the concurrent blood glucose concentration. This supported the tentative diagnosis of an insulinoma. Prednisolone 1mg/kg was started orally once daily to assist with maintaining normoglycaemia. The patient was discharged, and the owner was advised to feed frequent meals. Surgery was planned to remove the mesenteric nodule, explore the abdomen and perform ovariohysterectomy.
The patient was referred to a specialist veterinary surgeon the following week. A continuous glucose monitoring sensor (FreeStyle Libre 2) was applied pre-operatively to facilitate peri-operative glucose monitoring. A ventral midline coeliotomy was performed and the abdomen was explored. The pancreas was grossly smaller than typical, with an approximately 1mm white firm nodule in the left limb, 3cm from the tip. The mesenteric nodule identified on CT was evident adjacent to, but separate from, the left limb of the pancreas.
The splenic artery and vein were closely associated with the mesenteric nodule which was dissected away from the splenic vessels and excised using a bipolar vessel sealing device (Ligasure). The tip of the left limb of the pancreas was dissected from the omentum, preserving the splenic artery and vein. A partial pancreatectomy of the left limb was performed 1cm proximal to the 1mm firm nodule using a guillotine technique with 3-0 polydioxanone (PDS II, Ethicon, Johnson & Johnson), with one encircling ligature and one transfixating ligature.
A biopsy of the liver was also performed from the left lateral liver lobe using the guillotine method with 3-0 PDS. Routine ovariohysterectomy was subsequently performed using a bipolar vessel sealing device (Ligasure). The remainder of the abdomen was explored and appeared grossly normal. The abdomen was lavaged and then closed routinely.
Tissue samples from the pancreas, mesenteric nodule and liver were submitted for histopathology.
Histopathology of the nodule in the pancreatic tissue confirmed a malignant neuroendocrine neoplasm, consistent with an insulinoma. The mesenteric nodule was identified as lymph node with evidence of neuroendocrine neoplasm metastasis. Moderate multifocal sinusoidal and capsular fibrosis and mild to moderate hepatocellular vacuolation was seen in the submitted liver tissue, but there was no evidence of metastasis in the liver sample.
The patient recovered well following surgery. Post-operative blood glucose monitoring showed persistent hyperglycaemia, resulting in a subsequent diagnosis of diabetes mellitus. Prednisolone was ceased and lente insulin (Caninsulin 40 IU/mL, MSD Animal Health) was prescribed at an initial dose of 0.22 IU/kg administered subcutaneously. The patient was discharged two days following surgery.
At-home monitoring of the dog’s blood glucose was performed using the FreeStyle Libre 2 scanner. At the two-week post-operative recheck, the surgical wound had healed well. By three weeks after surgery, the clinical symptoms of diabetes mellitus were well controlled with 0.22 IU/kg twice daily dosing of Caninsulin. Adjunctive treatment with a tyrosine kinase inhibitor (Palladia) was discussed at this time but ultimately declined by the owner. It was elected to forgo treatment of the hepatic changes as the patient was otherwise clinically well.
In the treatment of canine insulinoma, surgical removal of any gross tumour is desirable in suitable patients for confirming diagnosis, enhancing medical management efficacy, and improving survival2. Dogs treated surgically have been shown to have longer survival times than those treated medically, with one study suggesting a median survival time of 20 months for those treated with surgery compared to eight months for medically managed dogs1. While beneficial for improving survival, surgery may not be curative in most patients due to high metastatic rates. Approximately 50% of dogs have been shown to have evidence of metastatic disease at the time of surgery, however the proportion of dogs with microscopic metastatic disease is likely higher2.
Post-operative hyperglycaemia, as seen in this case, is a common complication which occurs in approximately 33% of patients following surgery3. This is largely due to suppression of normal beta cell function secondary to insulin release from tumour cells. In some cases, this occurs only in the short term, lasting days to months. Other dogs may require long-term insulin therapy and management of diabetes mellitus. This makes it an important consideration and point of discussion with clients when weighing up the long-term implications of surgery.
Other possible complications associated with surgery include pancreatitis occurring secondary to tissue handling, and persistent hypoglycaemia due to continued insulin release from remnants of tumour cells4.
This case describes the possible challenges in managing canine insulinoma patients. Surgery was effectively utilised for confirming diagnosis and for therapeutic purposes; however post-operative hyperglycaemia and diabetes mellitus developed, necessitating ongoing treatment.
References:
1. Ryan, D., Pérez-Accino, J., Gonçalves, R., Czopowicz, M., Bertolani, C., Tabar, M. D., Puig, J., Ros, C., & Suñol, A. (2021) . Clinical findings, neurological manifestations and survival of dogs with insulinoma: 116 cases (2009-2020). The Journal of Small Animal Practice, 62(7), 531–539. https://doi.org/10.1111/jsap.13318
2. Goutal, C. M., Brugmann, B. L., & Ryan, K. A. (2012). Insulinoma in Dogs: A Review. Journal of the American Animal Hospital Association, 48(3), 151–163. https://doi.org/10.5326/jaaha-ms-5745
3. Del Busto, I., German, A. J., Treggiari, E., Romanelli, G., O’Connell, E. M., Batchelor, D. J., Silvestrini, P., & Murtagh, K. (2020). Incidence of postoperative complications and outcome of 48 dogs undergoing surgical management of insulinoma. Journal of Veterinary Internal Medicine, 34(3), 1135–1143. https://doi.org/10.1111/jvim.15751
4. Cornell, K., Tobias, K. M. 2018. Chapter 97: Pancreas. Tobias, K. M., Johnston, S. A., Veterinary Surgery: Small Animal. (pp. 1886-1901). Elsevier.
Dr Nial Bell BVSc (Dist)
Surgery Intern, Animal Referral Hospital Essendon Fields
Dr Nial Bell graduated from Massey University, Palmerston North in 2020 with a Bachelor of Veterinary Science with distinction. He initially worked in first opinion mixed and companion animal practice in New Zealand before embarking on a surgical internship to pursue his interest in surgery.
He is currently a surgical intern at the Animal Referral Hospital in Melbourne, Victoria.
Dr Tania Shaw BVSc (Hons), Grad Dip Ed, DACVS-SA
Specialist in Small Animal Surgery, Animal Referral Hospital Essendon Fields
Dr Tania Shaw graduated from the University of Sydney in 2007 with first class honours, and then spent three years in general practice in Melbourne.
Following a small animal rotating internship in Brisbane, followed by two surgical internships in Melbourne and in Perth,. Dr Shaw then returned to Melbourne and eventually joined Animal Referral Hospital as a surgery registrar while preparing to sit her ACVS Board examinations in small animal surgery.
She passed her exams in March 2020 and is now a ACVS boarded specialist surgeon.
