Insulinoma

CPT Randall S. Hall, MC USA* COL James F. Hanley, MC USA*

COL William Georgitis, MC USAt LTC Peter R. McNally, MC USA*

A 23-year-old male was referred to our hospital for evaluation of new-onset seizures. Signs and symptoms of neuroglycopenia, including weakness, dizziness, and confusion, appeared during fasting and resolved promptly with intravenous dextrose administration. Insulin, proinsulin, and C-peptide levels were consistent with a diagnosis of insulinoma. Screening tests for multiple endocrine neoplasia type 1 and surreptitious sulfonylurea uses were negative. Preoperative localization of the insulinoma by transabdominal ultrasonography, computed tomography, and indium-111 octreoscanning were unsuccessful. Endoscopic ultrasonography (EUS) identified a 6to 7-mm tumor at the juncture of the head and body of the pancreas. Surgical exploration confirmed the preoperative localization, and an 8-mm tumor was simply enucleated. The patient has been free of symptoms for IS months since surgery. This report describes the utility of EUS to localize a solitary pancreatic insulinoma and provides a comparison of EUS and other preoperative localization techniques.

Introduction nsulinomas are rare, with a reported prevalence of 1 per 1.25 million. 1,2 Whipple's triad of neuroglycopenic symptoms during periods of hypoglycemia that resolve with glucose leads to their clinical recognition.3 The diagnosis is confirmed by documenting inappropriate hyperinsulinemia during hypoglycemia. Surreptitious use of hypoglycemic medications must also be excluded. Insulinomas are often less than 1 cm in diameter.4 Such small tumors are difficult to localize using noninvasive techniques such as abdominal ultrasonography, computed tomography, and nuclear scanning.5 The majority of insulinomas are solitary and confined to the pancreas. Their location is equally distributed between the head, body, and tail of the gland. Although some specialized centers report very high rate of interoperative localization by palpation or with intraoperative ultrasonography,6-8 many surgeons prefer to have accurate preoperative localization.9 Successful preoperative localization shortens operative time, alleviates the need for intraoperative pancreatic biopsies and unnecessary pancreatic resections, and helps to reduce the incidence of pancreatic fistulae.9 Successful localization of an 8-mm pancreatic insulinoma by the new technique of endoscopic ultrasonography (EUS) is described in this report, accompanied by a brief review of the currently available preoperative imaging modalities. Case Report A 23-year-old Puerto Rican active duty serviceman was referred for evaluation of new-onset seizures. Two tonic-clonic seizures occurred within 1 week. The first was witnessed by the patient's wife and the second by emergency personnel. After the second seizure, a postictal blood glucose of 39 mg/dl led to treatment with intravenous dextrose. In retrospect, the patient realized that he had a habit of snacking during the day to avoid symptoms of weakness, dizziness, and poor concentration. To reduce weight gained gradually over 2 years, he began to diet with Slimfast on New Year's Day.

There was no past medical history of ulcer disease, nephrolithiasis, or medication use. Family history was negative for endocrine neoplasia. Physical examination was remarkable for an anxious, somewhat inattentive, well-developed male standing 70 inches tall and weighing 190 pounds. Serum sulfonylurea levels and insulin antibodies were undetectable. During a formal fast, Whipple's triad was observed. The patient described a sense of detachment and appeared mildly confused. Serum glucose was 34 mg/dl. Signs and symptoms reversed quickly with intravenous glucose and feeding. The immunoreactive insulin level was 28 mUI/ml (normal = 0-22 mUI/ml), and the serum C-peptide level of 6.9 ng/ml (normal = 1.0-3.0 ng/ml) and proinsulin level of 3.63 ng/ml (normal

Transabdominal ultrasonography, computed tomography, and indium- Ill octreoscan imaging failed to localize the tumor. Endoscopic ultrasonography was performed with a UM-20 echoendoscope (Olympus, Lake Success, NY) using a water-filled balloon and water-filled lumen techniques. The retroperitoneum was examined from the transduodenal and transgastric positions. Scanning was conducted at 7.5 and 12 MHz. A solitary 7-mm lesion with a 4-mm anechoic center and a 3-mm hyperechoic rim was identified at the juncture of the body and the head of the pancreas (Fig. 1). Selective visceral angiography was performed to confirm the EUS findings; a hypervascular blush in the area of the pancreas was seen on the first injection but was absent on subsequent injections, so this was considered an equivocal examination. The patient was taken to a computed tomography suite for simultaneous computed tomography and angiography. This study confirmed the EUS findings, identifying an 8-mm hypervascular lesion in the same region of the pancreas (Fig. 2).

At surgical exploration, a palpable defect was evident on the ventral surface of the pancreas at the junction of the body and the head of the pancreas. At surgery, the lesion was enucleated. Immunohistochemical reactions of the surgical specimen were positive for insulin, chromogranin, synaptophysin, and focal keratin. There was no reactivity with somatostatin (octreotide), serotonin, glucagon, or gastrin. These findings support the diagnosis of insulinoma based on the clinical presentation and immunohistochemical findings. After a somewhat prolonged postoperative course caused by postoperative pancreatitis, the patient has been without episodes of hypoglycemia for 18 months. Discussion Insulinomas represent the most common type of functional pancreatic islet tumors and were first reported by Wilder in 1927.3 Confirmation of inappropriate elevation of serum insulin in the face of symptomatic hypoglycemia establishes the diagnosis. Surreptitious oral sulfonylurea use and self-administration of insulin must also be excluded by drug screens, insulin antibodies, and proinsulin and C-peptide levels. Hypothalamicadrenal dysfunction can be excluded as a cause for hypoglycemia by documenting an appropriate increase in serum cortisol during fasting.

Roughly 10% of insulinomas arise in the context of MEN-1.10 Hyperinsulinemia is caused by diffuse islet cell hyperplasia and can be associated with other neoplasms of the parathyroid, pancreas, and pituitary. It is important to screen all patients with endocrine pancreatic tumors carefully to determine if the tumor is sporadic or part of MEN-1. More than 95% of MEN-1 patients develop hyperparathyroidism during their lifetimes. Hypercalcemia is the most prevalent presenting feature of the syndrome. Therefore, the best screening test for MEN-1 is to evaluate the parathyroid gland for hyperactivity. A normal serum calcium level with a normal intact parathyroid hormone assay excludes hyperparathyroidism and makes the diagnosis of MEN- 1 unlikely. If the patient has a strong family history of MEN-1-related disease, it may be prudent to obtain a serum prolactin level and a 24-hour urine collection for free cortisol and 17-hydroxysteroid levels or to perform a magnetic resonance scan of the pituitary. 10-12 Our patient, in retrospect, recalled episodes of weakness, dizziness, and confusion relieved by eating. During a 2-year period, he had gained 10 pounds despite extensive physical training. Seventy-two percent of insulinoma patients relate a history of weight gain.lz The Slimfast weight-reduction diet probably was a contributing factor in precipitating his first hypoglycemic seizure.

As in our patient, 80% of insulinomas are solitary. Seventy percent are smaller than 1.5 cm, making them difficult to detect.413.14 Although 90% of insulinomas are benign, it is important to screen for nodal or hepatic metastasis from malignant insulinomas.15 Nesidioblastosis is a rare cause of hypoglycemia seen in only 5 to 10% of patients with exogenous hyperinsulinism. This disorder is characterized by diffuse proliferation of insulin-producing cells of the pancreas.'. 7 These multifocal tumors are best managed by subtotal pancreatectomy when localized to the body and/or the tail of the pancreas.ls

The equal distribution of insulinomas between the head, body, and tail of the pancreas4 precludes an empiric resection of only a portion of the gland. Although surgical palpation and intraoperative ultrasonography is reported to be the most sensitive localization technique,6-8 many surgeons appreciate preoperative localization to aid in planning a surgical approach.89 Knowing where the tumor lies helps minimize operative time and morbidity. Additionally, the accuracy of surgical palpation and intraoperative ultrasonography is highly dependent on surgical expertise. A series of more than 300 patients operated on for organic hypoglycemia by surgeons in France reported that 14% of tumors were undetectable at the time of surgery.6 This further supports the notion that preoperative localization of the tumor is important. Table I describes the advantages and disadvantages of radiologic localization techniques.5.19-27 Transabdominal ultrasonography is simple, noninvasive, readily available, and without radiation exposure. The scanning frequencies used (3-5 MHz) permit visualization of the retroperitoneal structure far from the transducer but at a loss of spatial resolution often necessary to detect these small tumors. Interference from intestinal gas and obesity diminish resolution, making detection of tumors difficult, especially in the region of the tail of the pancreas. The reported sensitivity of ultrasonography for insulinoma varies from 50 to 70%,19-zl,za with a false-negative rate as high as 25%.21 Localization by computed tomography has been extremely variable, with a lower sensitivity of detection than with ultrasonography, ranging from 15 to 77%514.19-2,28 Lesions smaller that 1 cm commonly fail to distort the contour of the pancreas, making a small insulinoma difficult to distinguish by computed tomography. The use of dynamic bolus injections to highlight these vascular tumors, fine-cut (3-5 mm) resolution through the region of the duodenal C-loop, and rapid-acquisition spiral computed tomography have been reported to improve the accuracy of computed tomography.5 Furthermore, computed tomography is very helpful in the evaluation of liver metastasis in cases of malignant insulinomas.5 With magnetic resonance scanning, insulinomas exhibit hypointense patterns on Tl -weighted images and a hyperintense pattern on T2-weighted images.25 Motion artifact limits the use of magnetic resonance for gastrointestinal tract imaging. Visceral angiography is 44 to 67% sensitive2l,24,29 and is considered best at detecting small liver metastases. Percutaneous transhepatic portal venous sampling allows for correct localization of insulinoma independent of tumor size in up to 94% of patients undiagnosed by traditional imaging techniques.21,24,29 However, this technique is highly invasive, tedious, and reliable in only a few specialized centers. Forty percent to 50% of / islet cell tumors of the pancreas contain somatostatin receptors.'9 The indium-111-labeled octreoscan is a very specific new imaging technique.25,26 In our patient, immunohistochemical stains of the tumor were negative for somatostatin, explaining why the octreoscan was negative. The absence of somatostatin receptors in half of insulinomas and the lack of spatial discrimination with nuclear scanning are detractions to the routine use of this new localization test. EUS is a relatively new technique. It is remarkably accurate in localizing pancreatic neuroendocrine tumors. EUS requires the availability of expensive echoendosonographic and processing equipment. Such equipment is found only in large hospitals or endoscopy units. The number of skilled endoscopists in the United States formally trained to perform and interpret EUS of the retroperitoneum is in the hundreds. Narcotic and benzodiazepine sedation is necessary to perform the endoluminal portion of the examination. With these drugs, the procedure is well tolerated and remarkably safe. Most gastroenterologists now consider EUS to be the most accurate, least expensive preoperative method of localizing neuroendocrine pancreatic tumors. The technical advantage of EUS imaging over transabdominal ultrasonography is attributable to the close proximity of the transducer to the target. This permits the use of high scanning frequencies, which provide much greater spatial resolution. Rosch et al. prospectively compared the accuracy of EUS and ultrasonography, computed tomography, and endoscopic retrograde cholangiopancreatography in the detection of pancreatic tumors.22 The sensitivity and specificity of EUS in localizing pancreatic tumors is 99 and 100%, respectively, compared with ultrasonography (67 and 40%, respectively) and computed tomography (77 and 53%, respectively) and is equal to endoscopic retrograde cholangiopancreatography (sensitivity of 90%).27 In a recent multicenter study, EUS was shown to be the most sensitive localization modality in accurate detection of pancreatic tumors (sensitivity of 82 versus 27%) and had a specificity of 95%.27 EUS accurately defines the size of tumors to within 2 mm of the excised lesion. Although not performed in our patient, EUS-guided fine-needle aspiration of pancreatic adenocarcinoma has been reported to be accurate and important in nonoperative staging.31 Treatment of solitary insulinomas requires surgery. If the tumor can be localized and is small, simple enucleation is preferred.3.32-24 If the insulinoma cannot be localized, stepwise distal pancreatectomy is performed until frozen sections of resected specimens accompanied by blood glucose measurements indicate that all of the tumor has been excised. If no tumor can be found or if multiple tumors are present, subtotal (70-80%) pancreatectomy may be performed to preserve digestive and endocrine function.27 Surgical complications occur predominantly with pancreatic resections.22,34 Two-thirds of the complications with simple tumor enucleation occur after removal of lesions in the pancreatic head. Mortality ranges from 0 to 5%,8'13'22'33'34 Pancreatic resections are associated with pancreatic fistulae in 6 to 12% of cases. Fistula formation carries a mortality of 10 to 20%.34 These mortality rates constitute the most compelling argument for accurate preoperative tumor localization.

EUS is a valuable method of localizing insulinomas. The technique requires specialized endoscopic skill, but it is both safe and effective in experienced hands. EUS should prove to be very helpful for localization of insulinomas undetectable by transabdominal ultrasonography or computed tomography, but it is not a satisfactory method for evaluating the liver in patients suspected to have metastatic disease.

The opinions and assertions contained herein are the private views of the authors and are not to be construed as official policy or reflecting the views of the Department of Defense.

This manuscript was received for review in December 1997. The revised manuscript was accepted for publication in April 1998.

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Divisions of *Internal Medicine, ;Endocrinology, and $Gastroenterology, Department of Medicine, Fitzsimons Army Medical Center, Aurora, CO 80045.

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