Surgical Treatment of Insulinomas

Surgery is the initial treatment of choice for the long-term management of animals with insulinoma. Exploratory celiotomy is useful in confirming the diagnosis, staging the patient, and removing all identifiable pancreatic nodules (1-4). When possible, these pancreatic masses should be removed by partial pancreatectomy to ensure a more complete resection.

Preoperative Management
The serum glucose concentration should be stabilized before induction of anesthesia and surgery. While it is not necessary for the serum glucose to be in the normal range, the measured levels should be stable and the patient should be seizure-free for a few days prior to surgery.

Frequent feedings, continuous intravenous infusion of dextrose solution (5% dextrose or higher), or both, are the best ways to control symptomatic hypoglycemia (1-4). In some cases, use of prednisone or prednisolone may be helpful to help increase the low blood glucose concentrations. If these methods are unsuccessful, more aggressive medical management should be considered. In dogs, a constant rate infusion of glucagon can be considered to stabilize refractory patients (5). For more information, see my last post on Emergency management of hypoglycemia.

Identifying the Pancreatic Nodule(s)
Careful palpation of the entire pancreas and visualization of the liver and mesenteric lymph nodes is critical (4,6). Insulinomas are typically firmer than the normal parenchyma and may be small and obscured by the normal pancreatic tissue. Therefore, it can be difficult to localize a pancreatic nodule at time of surgery, especially in dogs (4,6-9).

When a nodule cannot be identified intraoperatively, biopsy specimens should be taken from the pancreas, liver, and mesenteric lymph nodes. In dogs, insulinoma develops within the right and left pancreatic lobes with equal frequency, and occult nodules are most common in the body of the pancreas. In addition, multiple nodules are seen in approximately 15% of dogs.  Thus, random removal of an entire pancreatic lobe offers no advantage and is not recommended (1-4,6).

In contrast to dogs, occult insulinoma appears to be rare in the ferret, making the pancreatic nodules less challenging to find. However, as compared to dogs and cats, multiple pancreatic nodules are more common than solitary nodules in ferrets. Full abdominal exploratory celiotomy is strongly recommended in ferrets, since concurrent nonpancreatic neoplasia (e.g., adrenal tumors) are not uncommon in this species (3,10,11).

Surgical Techniques for Partial Pancreatectomy
Surgical technique is similar in both the dog and cat (4,6,9). During surgery, the pancreas should be handled gently, and the surgeon should pay special attention to preserving the blood supply to the pancreas when performing a partial pancreatectomy. Any identifiable pancreatic nodules should be removed by partial pancreatectomy if possible, as this has been reported to result in longer survival times than simple excision of the tumor (12).

Partial pancreatectomy can be performed by the suture-fracture technique, the dissection-ligation technique, or through the use of an electrothermal bipolar vessel-sealing device (4,6,9,13). The bipolar vessel-sealing device (BVSD) denatures collagen and elastin within vessel walls and thus safely seals tissue and vessels while causing less tissue damage than is seen with the higher temperatures used in traditional cautery (13).

Using the BVSD to perform partial pancreatectomy in dogs decreases the incidence of post-operative pancreatitis when compared to dogs undergoing the suture fractionation technique. The BVSD is likely more effective in sealing pancreatic ducts during partial pancreatectomy and minimizes the leakage of pancreatic juices in to the remaining tissue that could cause local or generalized pancreatitis (13).

Whether or not metastatic lesions are visible, biopsy of the liver and mesenteric lymph nodes is recommended for staging (1-4).

Glucose Monitoring During and After Surgery
It is important to monitor the serum glucose concentration throughout and after surgery. Surgical manipulation of insulinoma can enhance the release of insulin from the tumor(s). Anesthesia will mask the signs of neuroglycopenia; thus, the only way of preventing serious hypoglycemia is to monitor the patient carefully and administer dextrose as needed.

While the surgeon is manipulating the pancreas and any metastatic lesions, the serum glucose concentration should be evaluated every 10-20 minutes. After surgery, the glucose concentration should be monitored every 30-60 minutes for the first 4-6 hours, and then every 2-4 hours until the glucose concentration has stabilized and the appropriate concentration of dextrose solution has been selected (1-4). The patient may have hyperglycemia after surgery, and intravenous fluids without dextrose may be appropriate.

Complications of Pancreatectomy
Potential complications include hyperglycemia, persistent hypoglycemia and pancreatitis (1-4,6,9).

• Hyperglycemia and diabetes mellitus— In some animals, the high concentration of circulating insulin secreted by the tumor suppresses the function of normal beta cells, leading to hyperglycemia once the insulin producing tumor is removed. As function of the beta cells returns, postsurgical hyperglycemia is resolved. If treatment with insulin is required after resection of an insulinoma, the clinician and the owner should be aware that endogenous insulin eventually may be produced either by the normal beta cells or by recurrent tumor cells. The owner should monitor glucose in the urine several times per week, and serum glucose should be checked at least monthly to avoid an iatrogenic hypoglycemic crisis.
• Persistent hypoglycemia—Persistent or recurrent hypoglycemia detected any time postoperatively should prompt consideration of symptomatic medical management or the use of chemotherapy. In patients who have had a significant hypoglycemia-free period after surgery, a second operation may result in several months of normoglycemia unless gross metastatic disease is present. In these cases medical management is indicated. This will be discussed in my next post.
• Pancreatitis— In dogs, the most common postoperative complication is pancreatitis. Documented or suspected pancreatitis has been reported in cats and ferrets as well postoperatively.

Relapse of Insulinoma
Although surgery is the most successful treatment we have for controlling hypoglycemia and prolonging survival, surgery will not be able to cure most animals with insulinoma. Almost all will show relapse of hypoglylcemia as the remaining tumor tissue grows and secretes high levels of insulin (1-4).

When a patient that has previously undergone surgery for insulinoma begins to show signs of hypoglycemia, a second surgery may be attempted or medical management instituted (see last post). If all visible tumor can be resected again, animals may remain symptom free for a number of additional months. Alternatively, many of these animals showing relapse can be controlled medically; I'll be discussing long-term medical management in my next post.

References:

1. Feldman EC, Nelson RW. Beta-cell neoplasia: Insulinoma In: Feldman EC, Nelson RW, eds. Canine and Feline Endocrinology and Reproduction. Philadelphia: Saunders Elsevier, 2004;616-644.
2. Kintzer PP. Insulinoma and other gastrointestinal tract tumours In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;148-155.
3. Meleo KA, Peterson ME. Treatment of insulinoma in the dog, cat, and ferret In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2013.
4. Nelson RW, Salisbury SK. Pancreatic beta cell neoplasia In: Birchard SJ, Sherding RJ, eds. Saunders’ Manual of Small Animal Practice. 2nd ed. Philadelphia: WB Saunders, 2000;288–294.
5. Fischer JR, Smith SA, Harkin KR. Glucagon constant-rate infusion: A novel strategy for the management of hyperinsulinemic-hypoglycemic crisis in the dog. J Am Anim Hosp Assoc 2000;36:27-32. 
6. Birchard SJ. The pancreas In: Williams M, Niles JD, eds. BSAVA Manual of Canine and Feline Abdominal Surgery. Gloucester: BSAVA Publications, 2005;210–219.
7. Mehlhaff CJ, Peterson ME, Patnaik AK, et al. Insulin producing islet cell neoplasms: Surgical considerations and general management in 35 dogs. J Am Anim Hosp Assoc 1985;21:607-612.
8. Leifer CE, Peterson ME, Matus RE. Insulin-secreting tumor: diagnosis and medical and surgical management in 55 dogs. J Am Vet Med Assoc 1986;188:60-64. 
9. Matthiesen DT, Mullen HS. Problems and complications associated with endocrine surgery in the dog and cat. Prob Vet Med 1990;2:627-667.
10. Caplan ER, Peterson ME, Mullen HS, et al. Diagnosis and treatment of insulin-secreting pancreatic islet cell tumors in ferrets: 57 cases (1986-1994). J Am Vet Med Assoc 1996;209:1741-1745. 
11. Chen S. Pancreatic endocrinopathies in ferrets. Vet Clin North Am Exot Anim Pract 2008;11:107-123.
12. Tobin RL, Nelson RW, Lucroy MD, et al. Outcome of surgical versus medical treatment of dogs with beta cell neoplasia: 39 cases (1990-1997). J Am Vet Med Assoc 1999;215:226-230. 
13. Wouters EG, Buishand FO, Kik M, et al. Use of a bipolar vessel-sealing device in resection of canine insulinoma. J Small Anim Pract 2011;52:139-145.