The Pancreas And The Pea-Insulinoma

Gerard W. Frank, M.D. and Michael Yeh, M.D.
UCLA Departments of Medicine and Surgery

Case Report

This 46-year-old woman had been followed for borderline diabetes on no medications. While driving, she experienced lightheadedness and blurred vision. She was taken to hospital where blood glucose was 40 mg/dl and her hemoglobin was 4.0 mg/dl. She had been otherwise healthy with a prior history of heavy ethanol use. She did note heavy menstrual periods. Family medical history was unremarkable for endocrine abnormalities. Initial studies revealed elevated insulin and C-peptide levels. She remained hypoglycemic in spite of glucose infusion and administration of diazoxide. Abdominal CT and MRI were unremarkable, except for a somewhat radiodense liver. All other studies were within normal limits. She was transfused and transferred to UCLA. Repeat imaging of the abdomen revealed only a cystic appearing area in the pancreas. The patient underwent endoscopic ultrasound of the pancreas and a 1.5 cm nodule was noted. A fine needle biopsy was performed with non-diagnostic pathology. She also underwent a transcutaneous needle liver biopsy which was free of abnormal iron or copper deposition.

The patient was seen by Surgery and taken to the operating room. Intraoperative ultrasound showed a well-circumscribed 1.5 cm x 1.5 cm isoechoic nodule in the pancreatic body (Figure 1), which was excised (Figure 2). The intraoperative record of blood glucose demonstrated a rise after the excision (Figure 3). Microscopic examination revealed pathology consistent with an islet cell tumor (Figure 4). Stains for somatostatin receptors were not done. The patient had a persistent leak from her pancreatic drain at discharge and is following up with surgery.

Figure 1. Intraoperative ultrasound of pancreas

Discussion

Insulinomas are a relatively uncommon variety of neuroendocrine tumors, which arise from cells embryologically derived from the neural crest. Such tumors are found in various organs, may be benign or malignant, and may or may not secrete biologically active substances with clinical effects. Surgery has always been the preferred treatment of insulinomas^1,2,3,4. The presentation of insulinoma is invariably the result of hypoglycemia: diplopia, blurred vision, sweating, confusion, amnesia, grand mal convulsions. However, because of the nonspecific nature of these effects, the diagnosis is often delayed, even up to years. The most common misdiagnosis is a seizure disorder⁴. The incidence of insulinoma is uncommon, 99 cases having been seen at the NIH over a 30-year period¹ and 224 patients having been seen at the Mayo Clinic over 60 years². The female-to-male ratio has usually been reported to be about 60%-40%^1,2,3.

Figure 2. Gross specimen of tumor

Figure 4A. Low-power view of tumor.                              Figure 4B. Medium-power view of tumor.

Over the past few decades the diagnostic workup has evolved and improved. The older literature refers to Whipple's Triad: characteristic symptoms, appropriate laboratory studies and response to glucose. Previously, prolonged fast or the administration of intravenous tolbutamide were used to distinguish hypoglycemic patients with abnormal levels of insulin from normal subjects. Surreptitious administration of insulin could be confirmed by the presence of anti-insulin antibodies, but the absence of elevated C-peptide levels is probably more confirmatory. Other causes of hypoglycemia: panhypopituitarism, ketosis, nonpancreatic tumors, or gluconeogenic block are distinguished from insulinoma by suppressed insulin levels in the face of hypoglycemia (as with fasting)⁴.

Most insulinomas are small, solitary and benign. Rarely, they are seen with Multiple Endocrine Neoplasia, Type I (MEN-I), parathyroid tumors or hyperplasia and gastrinomas being the more common components of the syndrome⁴. Less than 10% of insulinomas are malignant. Solitary insulinomas may be found anywhere in the pancreas, with a slight preponderance in the head¹.

Methods of localization have also evolved and improved. Before the advent of CT-scanning, there were various surgical approaches to localize the tumor, e.g., step-wise excision of the pancreas starting at the tail and monitoring for a rise in blood glucose concentration. With current imaging techniques, this is no longer necessary¹. Because insulinomas and other neuroendocrine tumors often have receptors for somatostatin, octreotide scans are frequently used, particularly with malignant, metastatic tumors⁵. CT and MRI are also valuable, but the highest sensitivity appears to be with endoscopic ultrasound (up to 94% for tumors < 10 mm diameter) and allows for fine needle aspiration, as in this patient^1,6,7. Enhanced ability to detect metastases from neuroendocrine tumors has been achieved by targeting the somatostatin receptors using Gluc-Lys([(18)F]FP-TOCA) with PET/CT scanning⁸.

The current management of solitary tumors is enucleation. Multiple tumors may require pancreatectomy, or even a Kausch-Whipple operation⁵. The clinical course of malignant insulinoma is surprisingly variable. A median survival of 5 years after resection was reported in 1984⁹. There is a male predominance among the malignant forms of insulinoma. A series of patients with long term follow up showed that some patients with metastatic disease at presentation had prolonged survival without hypoglycemia (up to 25 years) and others developed metastatic disease (manifested by recurrent hypoglycemia) after a hiatus of greater than 4 years¹⁰.

With metastatic disease and persistent hypoglycemia, diazoxide has been the most effective agent¹¹. Other modalities: radical resection, embolization, chemotherapy, radioablation and somatostatin have not proven to be beneficial¹⁰. In the preoperative period, infusions of glucose, corticosteroids or diazoxide have been used to maintain blood glucose levels, all of which were also used in this patient. Diazoxide is chemically related to the thiazides, but has no diuretic properties. It has been used in the past as an acute vasodilator in hypertensive emergencies. It is known to inhibit insulin release, probably through a potassium channel mechanism¹².

Conclusion

In summary, this patient had a typical presentation of insulinoma and, fortunately, a prompt diagnosis.