Clinical Radiology (2005) 60, 1039–1050 REVIEW Multimodality preoperative imaging of pancreatic insulinomas G. McAuleya, H. Delaneya, J. Colvillea, I. Lyburnb, D. Worsleyc, P. Govendera, W.C. Torreggiania,* Departments of Radiology aThe Adelaide and Meath Hospital incorporating The National Children’s Hospital, Tallaght, Dublin 24, Ireland; bCheltenham Hospital, Cheltenham, UK; and cNuclear Medicine, Vancouver General Hospital, Vancouver, BC, Canada Received 23 December 2004; received in revised form 29 May 2005; accepted 1 June 2005 KEYWORDS Insulinomas; Islet cell tumour; Hypoglycaemia; CT; MRI; Octreotide Pancreatic insulinomas are rare tumours of the islet cells of the pancreas, which account for the majority of functional neuroendocrine tumours of the pancreas. There is often a typical history of recurrent hypoglycaemic collapse and dizzy spells. Insulinomas are usually solitary, and the vast majority are intra-pancreatic in location. They are characteristically small with approximately 66% being less than 2 cm at presentation. Insulinomas continue to pose a diagnostic challenge to physicians, surgeons and radiologists alike. The role of imaging is to detect and provide precise anatomical localization and staging of tumours prior to surgery. Due to their small size at clinical presentation, they are notoriously difficult to localize radiologically, and specifically designed protocols are necessary to aid detection. In this review, we describe the current “state of the art” imaging protocols that may be used in the preoperative localization of insulinomas. Q 2005 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. Introduction Pancreatic insulinomas are a rare tumour of the islet cells of the pancreas. They account for the majority of functional neuroendocrine tumours of the pancreas (Table 1). The incidence is about one case per 250,000 patient-years, and there is a slight female predominance with a female-to-male ratio of 3:2.1 The median age at diagnosis is about 50 years, except when patients with insulinoma have associated multiple endocrine neoplasia type 1 (MEN 1), in whom the median age drops to the mid 20s. Insulinomas are characteristically small with approximately 66% being less than 2 cm at presentation.2 Even though these tumours tend to * Guarantor and correspondent: W.C. Torreggiani, Department of Radiology, Adelaide and Meath Hospital, Tallaght, Dublin 24, Ireland. Tel.: C353 14143700; fax: C353 14143805. E-mail address: william.torreggiani@amnch.ie (W.C. Torreggiani). be small, the functionality of these lesions causes their early presentation. There is often a typical history of recurrent hypoglycaemic collapse and dizzy spells. These symptoms combined with biochemical evidence of fasting hyperinsulinaemia often allow the diagnosis to be made. Insulinomas are usually solitary (95%) and the vast majority (98%) are intra-pancreatic in location. Most insulinomas are benign (90%) with metastatic disease being rare.3 They are generally very vascular lesions, may be cystic, and may rarely calcify. Insulinomas are the most common cause of hypoglycaemia resulting from endogenous hyperinsulinism. Insulinomas continue to pose a diagnostic challenge to physicians, surgeons and radiologists alike. The role of imaging is to detect and provide precise anatomical localization and staging of tumours prior to surgery. Due to their small size at clinical presentation, they are notoriously difficult to localize radiologically, and specifically designed protocols are necessary to aid 0009-9260/$ - see front matter Q 2005 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.crad.2005.06.005 1040 Table 1 G. McAuley et al. Neuroendocrine tumours Non-functioning islet cell tumours (60%) Functioning islet cell tumours (40%) No hormone excretion Often large Present late Greater than 50% malignant Hormone excretion Often small Present early Include: insulinoma (55%), gastrinoma (36%), vipoma (5%), glucagonoma (3%), somatostatinoma (1%) detection. In this review, we present an overview of the imaging of insulinomas in current day practice and describe the options available for preoperative localization. Clinical presentation The symptoms and features of patients with insulinomas are largely related to excessive release of insulin into the bloodstream from the tumour. Up to 85% of patients present with diplopia, blurred vision, palpitations, or weakness.4 Other symptoms include abnormal behaviour, confusion and amnesia. Grand mal seizures occur in 12% of patients. Hunger may be a prominent symptom and weight gain occurs in about 30% of patients. Symptoms caused by mass effects of local tumour mass are very rare as tumours are usually less than 2 cm in size at presentation. Symptoms may be present from 1 week to as long as several decades before the diagnosis. Hypoglycaemia usually occurs several hours after a meal. In severe cases, symptoms may develop in the postprandial period. Symptoms can be aggravated by exercise, alcohol and a low calorie diet. Biochemical presentation The presence of hypoglycaemia in the face of inappropriately elevated levels of insulin is the key to diagnosis of an insulinoma.5 The calculation of an abnormal ratio of insulin to plasma glucose is diagnostic. During a monitored fast, a low blood glucose level and high serum insulin level enable diagnosis to be made. In healthy individuals, the islet cells of the pancreas secrete equal amounts of insulin and C-peptide into the bloodstream. These molecules are derived from the same inactive precursor, proinsulin.6 Normally, less than 20% of proinsulin is released directly into the circulation. Factitious insulin administration can be ruled out by demonstrating elevated C-peptide levels, which are found exclusively with endogenous insulin hypersecretion. Whipple’s triad is a useful combination of findings that occur during fasting which help establish the diagnosis in most patients.6 During prolonged fasting (up to 72 h) Whipple’s triad consists of: (a) patient symptoms occurring during the fast; (b) symptoms occur in the presence of hypoglycaemia; and (c) ingestion of carbohydrates relieves the symptoms. The combination of these findings allows an accurate diagnosis of insulinoma in most cases. Radiological diagnosis Overview Imaging to localize insulinomas should only take place once the diagnosis has been confirmed biochemically.7 It must be remembered that the role of imaging is not to diagnose insulinomas, but to identify and localize the tumour.8 As tumours are usually less than 2 cm in size, they may be invisible on conventional imaging and specific dedicated sequences need to be employed to detect small lesions. Two fundamental features of these tumours aid radiological detection: (a) most insulinomas are vascular and are best visualized in arterial phase imaging. Tailoring computed tomography (CT) and magnetic resonance imaging (MRI) sequences to optimize this factor is essential in maximizing visualization. (b) As insulinomas are functional neuroendocrine tumours, this factor can be used by employing functional imaging with radiolabelled somatostatin analogues such as octreotide. The majority of insulinomas contain somatostatin receptors subtype 2 to which octreotide binds thus enabling detection. Although ectopic insulinomas do occur and may be found in the stomach and duodenum, they are extremely rare and account for less than 1% of cases. For this reason, attempts to localize an insulinoma radiologically should be focussed specifically on the pancreas. No histological criteria are available to distinguish benign from malignant insulinomas. Malignant tumours are usually larger (average size 6.2 cm), and one third would have metastasized to the liver. Insulinoma tumour cells contain less insulin and secretory granules than normal B cells Multimodality preoperative imaging of pancreatic insulinomas 1041 Figure 1 Insulinoma in a patient with Von Hippel-Lindau disease. (a) Longitudinal ultrasound demonstrates a 1.5 cm area of low echogenicity within the pancreatic head. (b) On colour Doppler interrogation, the mass shows evidence of typical hypervascularity. but higher levels of proinsulin. Atypical granules, or even agranular cells, are frequent. Thus, the extent to which one attempts to define the anatomy of the beta cell lesion before surgery is a matter of judgment. Successful preoperative tumour localization is achieved in about 60% of patients. Traditionally, intra-operative ultrasound imaging with manual palpation was the gold standard for localizing insulinoma once a biochemical diagnosis had been confirmed. With a sensitivity of over 80% for intra-operative detection, the value of preoperative imaging has been questioned in the past.9 However, preoperative imaging enables more accurate surgery, which may spare the patient an unnecessary total pancreatectomy and its associated morbidities, and facilitates the detection of metastases. Furthermore, it avoids prolonging the duration of surgery and potential intra-operative damage to major structures such as the splenic vein. With recent advances in non-invasive imaging giving a detection rate fast approaching that of intra-operative imaging, the present consensus is generally that preoperative localization is worthwhile. When evaluating patients for insulinoma, it should be noted that insulinomas have some specific associations that may need to be addressed. Insulinomas may occur as part of the MEN 1 syndrome. This association needs to be evaluated by excluding the hyperprolactinaemia due to a pituitary adenoma and hyperparathyroidism due to parathyroid hyperplasia. In addition, insulinomas may occur as part of the Von Hippel Lindau syndrome, and these patients need to be assessed for the presence of renal and other pancreatic masses as well as neurological manifestations. 1042 G. McAuley et al. Figure 2 Endoscopic ultrasound demonstrates a well-defined rounded hypoechoic insulinoma within the body of the pancreas (arrow). The lesion was not clearly visible on trans-abdominal ultrasonography. Figure 3 Insulinoma of the pancreatic tail. (a) Arterial phase contrast-enhanced CT demonstrates marked enhancement of a 2 cm mass within the tail of the pancreas (arrow). (b) Pathological specimen demonstrates characteristic pale well-defined mass consistent with an insulinoma. Multimodality preoperative imaging of pancreatic insulinomas Figure 4 Multiphase CT in a patient with a large islet cell tumour of the pancreas. (a) Non contrast-enhanced CT demonstrates a 9 cm mass within the pancreatic head. (b) Arterial phase imaging demonstrates marked vascular enhancement of the lesion. Note that the mass enhances more than the adjacent pancreas helping to increase conspicuity of the lesion. (c) Portal venous phase imaging demonstrates persistent enhancement of the mass. There is minor dilatation of the pancreatic duct. (d) Equilibrium phase CT demonstrates washout from the mass with the mass now having similar attenuation to the remaining pancreas. 1043 1044 G. McAuley et al. Figure 5 Non-enhancing insulinoma. Arterial phase CT demonstrating atypical features of a non-enhancing mass in the tail of the pancreas (arrow). Abdominal ultrasound (Fig. 1) Abdominal ultrasound was one of the first imaging techniques available in this field, but has a poor to moderate detection rate, with figures ranging from 0–66%. One study quoted a sensitivity of 79%, but this has not been reproduced elsewhere.10 Accurate imaging is limited by the small size of the tumour, interference by other intra-abdominal organs, and obese patients. Tumours located in the body and tail of the pancreas are particularly difficult to visualize. Ultrasound is also operator dependent to a certain degree. Advantages include the possible detection of liver metastases, although rare. In addition, the employment of Doppler assessment may aid the investigation of the vascularity of these lesions. More importantly this investigation is safe, rapid, non-invasive and relatively inexpensive. It is readily available in most institutions. A recent case report described the use of contrast enhancement in abdominal ultrasound successfully detecting a small insulinoma for which CT, MRI and ultrasound had been negative.9 Further investigation is warranted to determine if this result is reproducible. If so, this could provide a feasible alternative to CT and MRI in the future. Endoscopic ultrasound (EUS; Fig. 2) The advent of EUS brought preoperative imaging to a new level comparable with that of intraoperative. Sensitivities of 80—90% have consistently been described, detecting tumours as small as 2 mm.11 It enables visualization of the pancreas with an accurate analysis of the relationship of the tumour to vital structures such as the biliary and pancreatic ducts. Local metastases and invasion may be detected. It also potentially facilitates a preoperative tissue diagnosis by means of fineneedle aspiration (FNA). The role of EUS in the evaluation of entero-pancreatic endocrine tumours has evolved in conjunction with advances in other imaging methods. The high spatial resolution of this technique enables the detection of very small lesions and their precise anatomical location. EUS is recommended for screening asymptomatic patients with genetically proven MEN1.12 EUS can be effectively used as a first-line investigation, with a sensitivity of 94% in these patients.13 The use of EUS therefore greatly enhances preoperative planning. Unfortunately, however, this is an invasive investigation and relatively operator dependent. It carries the attendant risks of upper gastroinestinal endoscopy, though no significant morbidity has been described. Cost, availability and expertise are further limitations. CT (Figs. 3—5) CT is safe, simple to perform and operator independent. CT imaging visualizes the exact location of tumour, its relationship to vital structures, and the presence of metastases. As insulinomas are highly vascular in the arterial phase, modern contrast-enhanced imaging has focused on this property to aid detection. Precise bolus timing is critical in optimizing visualization. However, initial results using CT to visualize insulinomas were disappointing, with reported sensitivities as Multimodality preoperative imaging of pancreatic insulinomas 1045 Figure 6 Multi-sequence MRI of a patient with a 3 cm insulinoma of the tail of the pancreas. (a) Axial T2-weighted MR image demonstrates a 3 cm mass within the tail of the pancreas. The mass is predominantly of high signal compared with the rest of the pancreas. (b) Axial T1-weighted breath-hold fast gradient imaging without contrast demonstrates the lesion to be isointense to the pancreas. (c) Axial gadolinium-enhanced late arterial phase breath-hold T1 fast gradient imaging demonstrates marked heterogeneous enhancement of the pancreatic tail mass. (d) Coronal gadolinium-enhanced T1-weighted fast gradient imaging eloquently demonstrate the relationship of the mass (arrow) to its surrounding structures. 1046 G. McAuley et al. Figure 7 (a) Arterial phase CT demonstrates a subtle enhancing mass in the head of the pancreas in a patient with clinical and biochemical features of insulinoma (arrow). (b) Selective coeliac artery angiogram shows an area of corresponding blush radiating from a branch of the distal gastroduodenal artery (arrow). low as 21%.14 The small size of the tumour and the difficulty in distinguishing from normal parenchyma are the major obstacles in CT imaging. Novel techniques with rapid phase contrast-enhanced imaging have made a significant impact in identifying theses lesions. The sensitivity of CT in the detection of insulinomas has improved consistently in the last two decades. With experience and advances in technology, the sensitivities of detection rates of insulinoma are over 80%. Much investigation has gone into determining the optimal phase for detection and the consensus shows that the use of CT in the early phases is the most sensitive.15,16 Rapid injection of high concentration contrast medium during the early arterial phase enables the operator to capture the tumour blush.17 However, there are conflicting opinions as to whether the early arterial or portal venous phase is best, and a recent study described promising results with the early pancreatic phase. Much of the evidence seems to support the early arterial phase. Technical advances have improved the quality of CT, with a recent study using dual-phase, thinsection multidetector CT visualizing 94.4% of insulinomas as compared with 28.6% with sequential CT.17 Another study using multiphasic, helical CT detected 63% of tumours prospectively and 83% retrospectively. The false-negative results were due to unusual tumour appearances and close proximity to vessels.18 CT is currently accepted as the first-line investigation.19 Multimodality preoperative imaging of pancreatic insulinomas 1047 Figure 8 Small pancreatic insulinoma. Twenty-four hour anterior and posterior whole images from an In-111 octreotide study demonstrate uptake within the pancreas in keeping with a small insulinoma. Note normal high uptake within the spleen. MRI (Fig. 6) Currently there is strong evidence emerging for the use of MRI in imaging insulinoma.20 Like CT, it is safe, non-invasive, rapid and facilitates the detection of metastases. Limitations include the standard contra-indications to MRI. More specifically, there are difficulties with motion artefact, low signal-to-noise ratio, and poor contrast of tumour against normal parenchyma. An early study demonstrated a sensitivity of only 7%,18 but the most recent literature reports sensitivities of over 90%.14,21 The use of fat-suppressed, T1-weighted imaging with spin-echo has been suggested to image the pancreas in previous studies.21,22 However modern MRI systems now allow rapid tri-phasic, breath-held T1 rapid gadolinium-enhanced sequences. These sequences help to significantly reduce motion artefact and enable accurate assessment of the pancreas in both arterial and venous phases. In addition, MRI enables accurate assessment of the tumour location in terms of resectability and major vessel involvement.23 Lymphadenopathy and metastatic disease may also be detected. Sensitivities have now been described of up to 92%.21,24 MRI has all the advantages of CT and recent evidence suggests that it may be the more sensitive tool. Drawbacks include cost, specific contra-indications and more limited availability as compared with CT. In current practice MRI is a second-line investigation, but potentially could take over from CT in the future as it becomes more widely available and expertise improves. Selective arteriography and hepatic venography (Fig. 7) Selective arteriography of the coeliac axis and pancreatic arterial supply is felt by some experts to be the best overall preoperative localization procedure. Sensitivities of up to 66% have been described,25,26 however, there is a false-positive rate of 5%. Combining arteriography with CT has been tried but does not significantly increase sensitivity.10 Arteriography with catheterization of small arterial branches of the celiac system combined with calcium injections (which stimulate insulin release from neoplastic tissue but not from normal islets), and simultaneous measurements of 1048 G. McAuley et al. Figure 9 Large pancreatic insulinoma. Twenty-four hour anterior and posterior whole images from an In-111 octreotide study in a 67-year-old woman. CT (not shown) demonstrated a lobulated, enhancing tumour mass at the level of the coeliac artery measuring 5!3 cm. In this image, the tumour mass is In-111 octreotide avid and was confirmed to represent an insulinoma at pathology. hepatic vein insulin during each selective calcium injection localizes tumours in 47% of patients. In some studies up to 100% of insulinomas have been detected with transhepatic venous sampling.27 Otherwise sensitivities of 55—76% are described in most of the literature. Both arteriography and venography are relatively invasive techniques. In addition they are operator dependent and require a high level of expertise, as well as specialized facilities. They are also time-consuming, costly procedures, which carry a number of significant risks. Epigastric pain, transient haemobilia, hepatic haematoma, biliary leak and haemorrhage are among the potential complications. Another localization technique using preoperative portal venous sampling is now considered obsolete as a routine investigation because of a high complication rate (10%). It may be employed occasionally when all other imaging procedures fail and surgical exploration findings are negative. Functional imaging (Figs. 8—10) More recently, functional imaging with radiolabelled isotopes such as octreotide adds a further tool in the evaluation and detection of insulinomas.28 The sensitivity of somatostatin receptor scintigraphy is 60%, although some insulinomas lack somatostatin receptor subtype 2 for successful identification.29 Positron emission tomography plays only a limited role. It may detect the presence of a neuroendocrine tumour, and may have a limited role in the evaluation of operability of malignant lesions and the presence of metastatic disease. A further technique used in the past was tumour localization using iodine 13-labelled anti-insulin antibodies. Sensitivities of up to 50% were achieved. However, the procedure has largely been abandoned due to an unacceptably high false-positive rate of a 37.5%. Multimodality preoperative imaging of pancreatic insulinomas 1049 insulinomas, metastatic insulinomas, and in those who will not or cannot undergo surgery for other reasons. Medical therapy is designed to prevent hypoglycaemia, and in patients with malignant tumours, to reduce the tumour burden. Diazoxide is related to the thiazide diuretics and reduces insulin secretion. Octreotide prevents hypoglycaemia, provided insulinoma tumour cells have somatostatin receptors subtype 2 present. Conclusion Figure 10 Anterior positron emission tomography images of a patient with malignant islet cell tumour of the pancreas with extensive liver metastases. Treatment and prognosis In the vast majority of cases, surgical excision provides a cure and is the treatment of choice.30 Simple enucleation is the procedure of choice in insulinomas in the pancreatic head. Total pancreatectomy is usually avoided because of its high morbidity and mortality. As most tumours are benign, complete cure occurs in up to 90% of patients. Patients with malignant insulinoma have a much better prognosis compared with those with a pancreatic ductal malignancy, and pancreatic resection with regional lymph node dissection seems to be a rational procedure in such cases. If insulinoma is associated with MEN 1, the management strategy is modified because tumours are often multiple, diffusely spread in the pancreas, and of small size. Subtotal pancreatectomy with enucleation of tumours from the pancreatic head and uncinate process is often recommended over simple enucleation. The overall postoperative mortality is approximately 7.7%.31 The median survival from metastatic disease to the liver ranges from 16—26 months.31 Medical therapy with diazoxide or a somatostatin analogue such as octreotide is indicated in patients with unresectable malignant Insulinomas are rare islet cell functional neuroendocrine tumours of the pancreas. They typically present when they are small in size due to their symptomatic release of insulin causing hypoglycaemic effects. The diagnosis is therefore often suggested clinically with biochemical testing confirming the diagnosis. The role of imaging is predominantly used to identify the tumour and assess its location within the pancreas and relationship to other structures. The combination of modern imaging techniques has helped in the preoperative detection of these difficult lesions. In this review we have demonstrated the strengths and weaknesses of the various available imaging techniques in aiding tumour detection. In addition, we have emphasized the importance of technique optimization in lesion detection. Although insulinomas are rare, knowledge of the various radiological features of these tumours is essential as it is the radiologist who is mainly responsible for the preoperative detection of these lesions. Acknowledgements Courtesy of Dr Wai Lup Wong, Mount Vernon Hospital, London. References 1. Thompson NW, Eckhauser FE. Malignant islet-cell tumors of the pancreas. World J Surg 1984;8:940—51. 2. Kaplan EL, Lee CH. Recent advances in the diagnosis and treatment of insulinomas. Surg Clin North Am 1979;59: 119—29. 3. Pasieka JL, McLeod MK, Thompson NW, Burney RE. Surgical approach to insulinomas. Assessing the need for preoperative localization. Arch Surg 1992;127:442—7. 4. Dizon AM, Kowalyk S, Hoogwerf BJ. Neuroglycopenic and other symptoms in patients with insulinomas. Am J Med 1999;106:307—10. 5. De Herder WW. Insulinoma. Neuroendocrinology 2004; 80(Suppl 1):20—2. 1050 6. Katz LB, Aufses Jr AH, Rayfield E, Mitty H. Preoperative localization and intraoperative glucose monitoring in the management of patients with pancreatic insulinoma. Surg Gynecol Obstet 1986;163:509—12. 7. Vinik A, Strodel WE, Cho K, Eckhauser FE, Thompson N. Localization of hormonally active gastrointestinal tumors. In: Thompson NW, Vinik AI, editors. Endocrine surgery update. New York: Grune and Stratton; 1983. p. 293—300. 8. Mabrut JY, Lifante JC, Cherki S, Sin S, Berger N, Peix JL. Is preoperative localization of insulinomas necessary? Ann Chir 2001;126:850—6. 9. D’Onfrio M, Mansueto G, Vasori S, Falconi M. Contrastenhanced ultrasonographic detection of small pancreatic insulinoma. J Ultrasound Med 2003;22:413—7. 10. Angeli E, Vanzulli A, Castrucci M, Venturini M, Sironi S. Value of abdominal sonography and MR imaging at 0.5 T in preoperative detection of pancreatic insulinoma: A comparison with dynamic CT and angiography. Abdom Imaging 1997;22:295—303. 11. Pitre J, Soubrane O, Palazzo L. Endoscopic ultrasonography for the preoperative localization of insulinomas. Pancreas 1996;13:55—60. 12. Gouya H, Vignaux O, Augui J, et al. CT, endoscopic sonography, and a combined protocol for preoperative evaluation of pancreatic insulinomas. AJR Am J Roentgenol 2003;181:987—92. 13. McLean AM, Fairclough PD. Endoscopic ultrasound in the localisation of pancreatic islet cell tumours. Best Pract Res Clin Endocrinol Metab 2005;19:177—93. 14. Zimmer T, Stolzel U, Bader M, Koppenhagen K. Endoscopic ultrasonography and somatostatin receptor scintigraphy in the preoperative localisation of insulinomas and gastrinomas. Gut 1996;39:562—8. 15. Van Hoe L, Gryspeerdt S, Marchal G, Baert A. Helical CT for the preoperative localization of islet cell tumours of the pancreas: Value of arterial and parenchymal phase images. AJR Am J Roentgenol 1995;165:1437—9. 16. King AD, Ko GTC, Yeung VTF. Dual phase spiral CT in the detection of small insulinomas of the pancreas. 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Owen NJ, Sohaib SAA, Peppercorn PD, Monson JP. MRI of pancreatic neuroendocrine tumours. Br J Radiol 2001;74: 968—73. 24. Catalano C, Pavone P, Laghi A. Localization of pancreatic insulinoma with MR imaging at 0.5 T. Acta Radiol 1999;40: 644—8. 25. Vick C, Zech CJ, Hopfner S, Waggershauser T, Reiser M. Imaging of neuroendocrine tumours of the pancreas. Radiologe 2003;43:293—300. 26. Boukhman MP, Karam JM, Shaver J, Siperstein AE. Localization of insulinomas. Arch Surg 1999;134:818—22. 27. Kisker O, Bastian D, Frank M, Rothmund M. Diagnostic localization of insulinoma. Experiences with 25 patients with solitary tumours. Med Klin 1996;91:349—54. 28. Pereira PL, Wiskirchen J. Morphological and functional investigations of neuroendocrine tumours of the pancreas. Eur Radiol 2003;13:2133—46. 29. Mirallie E, Pattou F, Malvaux P, Filoche B. Value of endoscopic ultrasonography and somatostatin receptor scintigraphy in the preoperative localization of insulinomas and gastrinomas. Gastroenterol Clin Biol 2002;26:360—6. 30. Thompson NW. The surgical treatment of islet cell tumors of the pancreas. In: Dent TL, editor. Pancreatic disease. New York: Grune and Stratton; 1981. p. 108—13. 31. Yamauchi H, Miyagawa K, Maeda M, Matsuno S, Sato T. Surgical management of insulinoma: Diagnosis of tumor location and high incidence of malignancy. Jpn J Surg 1986; 16:8—15.