Surg Clin N Am 84 (2004) 775–785 Surgical treatment of insulinomas Emily Finlayson, MDb, Orlo H. Clark, MDa,b,* a Department of Surgery, University of California, San Francisco, 513 Parnassus Avenue S-320 San Francisco, CA 94143-0104, USA b Department of Surgery, University of California, San Francisco Comprehensive Cancer Center at Mount Zion Medical Center, 1600 Divisadero Street, Hellman Building, Room C3-47 San Francisco, California 94143-1674, USA Insulinoma, with an annual incidence of 1 to 4 per million, is the most common islet cell tumor . Most patients present with sporadic disease, and the median age at presentation in this population is 47 years. The vast majority of insulinomas in patients with nonfamilial disease are small (90% less than >2 cm), solitary (90%), and benign (90%). Unlike other pancreatic neuroendocrine tumors, they arise with equal frequency throughout the gland. They occur twice as often in women. Nearly 10% of tumors are associated with multiple endocrine neoplasia (MEN) type 1. In this context, multiple islet cell tumors are usually present. Although it has been over 7 decades since the ﬁrst surgical cure of insulinoma , diagnosis, localization, and surgical therapy remain challenging and controversial. Recent advances in preoperative and intraoperative radiologic localization have improved the ability to identify insulinomas preoperatively and intraoperatively, and have resulted in superior surgical cure rates [3,4]. In addition, the emergence of laparoscopic approaches for benign pancreatic lesions may oﬀer a less invasive option for selected patients with insulinomas. In this article, we discuss clinical presentation and diagnosis of insulinomas, controversies in preoperative and intraoperative localization, and the role of the laparoscopic approach. Diagnosis Clinical presentation Patients with insulinoma present with symptoms of hypoglycemia—lightheadedness, altered mental status, and abnormal behavior. Symptoms * Corresponding author. E-mail address: [email protected] (O.H. Clark). 0039-6109/04/$ - see front matter Ó 2004 Elsevier Inc. All rights reserved. doi:10.1016/j.suc.2004.02.004 776 E. Finlayson, O.H. Clark / Surg Clin N Am 84 (2004) 775–785 generally occur after a fast—in the morning, after skipping a meal, or after exercise. Because symptoms of insulinoma are primarily behavioral, patients are often misdiagnosed and deﬁnitive diagnosis is delayed. In our institution, the duration of symptoms before diagnosis ranged from 1 hour to 34 years, with a mean of 3.8 years . Diagnostic tests Traditionally, the diagnosis of insulinoma is suggested by the presence of Whipple’s triad—serum glucose \45 when symptomatic, symptoms of hypoglycemia with fasting, and symptom relief with glucose. Additional laboratory tests can help conﬁrm the diagnosis. Serum insulin levels greater or equal to 6 microunit/mL and a plasma insulin-to-glucose greater than 0.3 are diagnostic of insulinoma. In patients with borderline-fasting insulin levels, measurement of proinsulin levels is useful. Proinsulin levels in patients are substantially elevated—ranging from 30 to 2300 pmol/L . In addition, the molar ratio of proinsulin to insulin is higher in patients with insulinoma—1:6 in healthy subjects versus 1:1 in patients with insulinoma. Measurement of C-peptide levels is useful in conﬁrming the diagnosis of insulinoma. C-peptide, which is secreted in equimolar amounts as insulin by beta cells, is an accurate marker for endogenous insulin secretion. C-peptide levels of 2 nmol/L or greater suggest the presence of an insulinoma. Normal C-peptide levels in the setting of elevated blood glucose levels and hyperinsulinemia raise the question of accidental or surreptitious use of insulin or sulfonylureas. This etiology of hypoglycemia and hyperinsulimenia should be entertained in all patients, and especially in patients with access to hypoglycemic medications, such as health-care workers and family members of people with diabetes mellitus. Measurement of plasma or urine sulfonylureas excludes this diagnosis. Determination of plasma insulin and glucose levels is most reliably obtained through an observed, in-patient fast. Patients are fasted, and plasma levels of glucose, insulin, and c-peptide are measured every 6 hours. When plasma glucose levels fall to 40 mg/dL or symptoms of hypoglycemia develop, the fast is terminated. A substantial proportion of patients—33%—become hypoglycemic within 12 hours, 65% within 24 hours, 84% within 36 hours, 93% within 48 hours, and 99% within 72 hours . Increasingly, outpatient overnight fasts with next-day testing in an ambulatory center are replacing inpatient 72-hour fasts. Up to 40% of patients have positive fasts in this setting . The remaining patients will require hospital admission for the completion of the study. Although a 72-hour fast is diagnostic in the majority of patients with insulinoma, additional tests are available to conﬁrm the diagnosis. The Cpeptide suppression test involves the infusion of exogenous insulin to suppress endogenous insulin secretion. In healthy subjects, when hypoglycemia is induced by exogenous insulin, endogenous insulin (measured as C-peptide E. Finlayson, O.H. Clark / Surg Clin N Am 84 (2004) 775–785 777 secretion) is suppressed by 50% to 70%. Elevated C-peptide after insulin infusion suggests the presence of insulinoma. Tolbutamine, a secretagogue that stimulates insulin secretion from insulinomas, can also be used to test for the presence of an insulinoma. In a tolbutamide tolerance test, plasma glucose levels less than 47 mg/dL or insulin levels greater than 20 microU/mL suggest the diagnosis of insulinoma. Preoperative localization Noninvasive imaging Results of noninvasive localization studies for insulinoma are often disappointing. Because of their small size (generally about 1 cm), transabdominal ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI) often fail to demonstrate the tumor. Transabdominal ultrasound is highly operator-dependent, and tumor localization rates vary widely, from 13% to 67% . In published series, CT scanning successfully localizes insulinomas in 17% to 73% of patients [4,5,8–15]. Even lower localization rates for have been demonstrated for MRI: 7% to 45% [4,5,8,11,16]. Although both MRI and CT scanning are of limited value for localization, these imaging studies give essential information about the presence or absence of metastatic disease, and also identify patients with large malignant tumors, which helps with preoperative planning. Somatostatin receptor scintigraphy is often useful for localizing many other pancreatic endocrine tumors; however, it usually fails to demonstrate insulinomas . Because most insulinomas do not express type 2 somatostatin receptors, only about 30% bind octreotide. Invasive imaging When preoperative noninvasive studies fail to localize tumors in patients with the biochemical diagnosis of insulinoma, invasive studies are often more successful. Endoscopic ultrasound (EUS) is rapidly becoming the diagnostic modality of choice for tumor localization. Numerous studies have reported superior localization rates with EUS [14,16–19]. With reported localization rates of 70% to 90%, many advocate it as the study of choice for identiﬁcation of insulinomas; however, because of the anatomic relationship between the stomach and the pancreas, the sensitivity of EUS varies by tumor location. In Schumaker et al’s series, localization rates were substantially lower for tumors in the distal pancreas—37% for insulinomas of the distal pancreas versus 83% for insulinomas in the pancreatic head . An additional limitation is that EUS is highly operator-dependent and is not yet widely available. Most published series are conducted at referral centers. Whether EUS is as successful in all hands is unknown. Historically, selective pancreatic angiography was the study of choice for localizing insulinomas. Reported localization rates for angiography, 778 E. Finlayson, O.H. Clark / Surg Clin N Am 84 (2004) 775–785 however, vary widely, ranging from 27% to 80% [9,11,19,21–28]. Because of its cost, invasiveness, and relatively low sensitivity, arteriography is no longer a ﬁrst-line localization study for insulinoma. It still has a role, however, in selected patients with persistent or recurrent disease in whom other localizing studies have been equivocal or negative. Regional localization of insulinomas can be facilitated by transhepatic portal venous sampling (PVS). In this procedure, the portal vein is catheterized percutaneously and the catheter is advanced into the small veins draining the pancreas. Plasma insulin levels are obtained from each region of the pancreas to determine the location of the tumor. Localization rates for PVS range from 67% to 100% [4,5,9,12,21,25–27]. Selective arterial calcium stimulation with hepatic-vein catherization (the Imamura-Doppman test) has largely replaced PVS. In this procedure, the splenic, superior mesenteric, and gastroduodenal arteries are selectively catheterized. Calcium—a secretagogue for insulinomas—is sequentially injected into each artery. Venous samples of insulin, glucose, and calcium are then obtained from the right hepatic vein after each calcium infusion to localize the tumor. This procedure has a higher sensitivity for regional localization of insulinomas than PVS—91% to 100% [11,12,28]. Both PVS and selective arterial calcium stimulation are invasive and expensive. For this reason these modalities, like arteriography, are now used primarily for patients with persistent or recurrent disease. Surgical approaches Operative technique Surgical cure rates in patients with the biochemical diagnosis of insulinoma range from 77% to 100% [4,26,29,30]. At surgical exploration, the abdomen is initially explored for evidence of metastatic disease. The lesser sac through the gastro-collic ligament is then entered to expose the anterior surface of the pancreas. To facilitate bimanual palpation of the head of the pancreas, a Kocher maneuver is performed to mobilize the duodenum and head of the pancreas. Intraoperative palpation has been shown to be a reliable method for localizing insulinomas—with successful identiﬁcation of 42% to 95% of tumors [4,5,9,12,27,31]. Perhaps the most sensitive technique for intraoperative tumor localization is intraoperative ultrasound (IOUS). In published series, it successfully localizes 75% to 100% of insulinomas [4,5,9,11,12,27,30–32]. Because the combination of palpation and IOUS is very eﬀective method of intraoperative tumor localization, many now argue that expensive, invasive preoperative localization studies are not necessary, and should only be used for patients with persistent or recurrent disease [30,32]. IOUS is also useful in determining the relationship between insulinomas, and their relationships to the pancreatic duct and vessels. Identiﬁcation of the pancreatic duct and E. Finlayson, O.H. Clark / Surg Clin N Am 84 (2004) 775–785 779 determination of its proximity to the tumor can guide safe enucleation of the tumor. This approach can minimize the likelihood of a postoperative pancreatic ﬁstula. Tumor enucleation, when feasible, is the technique of choice. Using Bovie electrocautery, the tumor is carefully dissected away from the normal pancreatic parenchyma. Various maneuvers can be used to decrease the risk of pancreatic leak. For small insulinomas, the pancreatic capsule can be closed over the defect. The application of ﬁbrin glue to the defect may also be another useful tool. There is recent evidence that the use of ﬁbrin glue can decrease the incidence of pancreatic ﬁstula after pancreatic surgery [33,34]. Although most insulinomas are solitary, steps should be taken intraoperatively to ensure that additional disease is not missed. As many as 20% of patients with hyperinsulinemia have multiple tumors or nesidioblastosis (Fig. 1A, B) [35,36]. The latter is rare in adults but more common in neonates. The entire pancreas should be mobilized and palpated. If available, IOUS should be used to inspect the length of the pancreas gland. Rapid immunoreactive insulin (IRI) assays can conﬁrm complete resection of insulinomas Fig. 1. (A) ‘‘Single insulinoma’’ (patient with sporadic islet cell tumor of pancreas). (B) Multiple islet cell tumors in patient with MEN1, hypoglycemia, and insulinoma. (Note: Should read MEN [the number one]). 780 E. Finlayson, O.H. Clark / Surg Clin N Am 84 (2004) 775–785 intraoperatively. For this test, serum insulin levels are drawn from the portal vein and a peripheral vein at the beginning of the procedure. Twenty minutes after resection of the tumor, repeat portal and systemic insulin levels are drawn. Insulin levels are expected to decrease to the normal range, and insulin/glucose ratios should be less than or equal to 0.4 within 20 minutes of successful insulinoma resection. Studies of the use of IRI measurement to predict operative cure have reported sensitivity of 84% to 100% and accuracy of 84% to 89% [35,37]. Blood sugar levels also begin to increase in most patients within 15 minutes of removal of an insulinoma. In very thin patients, the increase in blood sugar levels make take longer. Historically, blind distal pancreatectomy was the procedure of choice when insulinomas were not identiﬁed intraoperatively. It was thought that because insulinomas are distributed evenly throughout pancreas, a distal pancreatectomy would cure many patients with occult tumors. In a recent review of 17 patients referred to the National Institutes of Health (NIH) after failed blind distal pancreatectomy, 5 were diagnosed as having factitious hypoglycemia, and in the remaining 12 the tumor was localized in the pancreatic head . To preserve pancreatic function and reduce the risk of iatrogenic diabetes mellitus, patients in whom tumor localization is unsuccessful at operation should be carefully evaluated to be certain of the diagnosis, and in general should not undergo blind resection. Instead, these patients should be referred to an experienced endocrine endocrinologist or surgeon for conﬁrmation of the diagnosis and further localization studies. Laparoscopy Recent advances in laparoscopic technique and instrumentation have enabled surgeons to approach complex procedures laparoscopically. Over the past decade, there have been numerous case reports or small series of successful laparoscopic resections of insulinomas [38–47]. The pancreas is exposed in the standard fashion. Laparoscopic ultrasound can be used to identify nonvisible tumors and determine the relationship of the lesion to surrounding veins and the pancreatic duct. Laparoscopic ultrasound can be particularly helpful in identifying lesions of the tail that are often missed by endoscopic ultrasound . For superﬁcial ventral tumors, laparoscopic enucleation is undertaken with electrocautery or laparoscopic coagulating shears (Harmonic scalpel, Ethicon, Somerville, New Jersey). Small pancreatic feeder vessels can be either clipped or cut with the LigaSure device (Tyco, U.S. Surgical, Norwalk, Connecticut). Tumors located deep in the body or tail of the pancreas and those in close proximity to the pancreatic duct require distal pancreatectomy. In cases where visualization and ultrasound fail, a hand port can be used to allow palpation of the gland. Tumors situated very distally in the splenic hilum are especially diﬃcult to identify. Spleen-sparing distal pancreatectomy can be accomplished by careful division of the short gastric vessels and stapling of the pancreas. E. Finlayson, O.H. Clark / Surg Clin N Am 84 (2004) 775–785 781 Results of laparoscopic resection for insulinoma have been mixed. Tumors are sometimes diﬃcult to identify, because one cannot palpate the increased ﬁrmness of the tumor, and tumor color is often less helpful for identifying the tumor. Avoidance of laparotomy should translate into shorter recovery times. Hospital stays in reported series, however, are relatively long—ranging from 2 days to 14 days [38–45,47]. Mean operative time ranges from 1.7 hours to 5 hours [38–45,47]. Pancreatic ﬁstula rates are comparable to those for open procedures. Open insulinoma resection is associated with a pancreatic ﬁstula rate up to 43% . Fistula rates for laparoscopy ranged between 0% to 40% [40,44,47], with one patient requiring reoperation.  These high ﬁstula rates underscore the need for intraoperative drain placement after laparoscopic resection to facilitate the diagnosis and treatment of pancreatic leaks. Finally, conversion to an open procedure is reported as high as 33% to 40% [39,44]. As with many emerging laparoscopic techniques, there is a necessary learning curve. In our experience with laparoscopic resection, which we have only used in patients who have their tumors identiﬁed preoperatively, the duration of hospitalization has been shorter by 1 to 3 days than after open procedures, and subsequent return to full activity is faster. Special circumstances Multiple endocrine neoplasia Over 75% of patients with multiple endocrine neoplasia (MEN) type 1 present with multiple insulinomas and other, often nonfunctioning islet cell tumors . For this reason, patients presenting with hypoglycemia and hyperinsulinemia should be carefully screened for MEN type 1. Patients with MEN type 1 often have a family history of endocrinopathy, hypercalcemia, or a history tumors of the parathyroid or pituitary. Because insulinomas in these patients are usually multicentric, local tumor resection often results in disease recurrence . Subtotal pancreatic resection with IOUS-guided enucleation of pancreatic head lesions is the procedure of choice for hyperinsulinemia in patients with MEN type 1 [49,50]. In contrast to gastrinomas, virtually all insulinomas (99%) are situated in the pancreas. Nesidioblastosis Nesidioblastosis is a rare but important cause of hypoglycemia and hyperinsulinemia in adults. Also known as endocrine cell dysplasia, islet cell hyperplasia, islet cell hypertrophy, islet hypertrophy, microadenomatosis, and neisidiodysplasia, it is characterized by diﬀuse hyperplasia of the pancreatic islet cells. Although it is the most common cause of hyperinsulinemia in neonates, and is not uncommon in young children, it is rarely diagnosed in adults. Preoperative studies can sometimes help in distinguishing nesidioblastosis from insulinoma. Negative preoperative diagnostic or 782 E. Finlayson, O.H. Clark / Surg Clin N Am 84 (2004) 775–785 intraoperative localization procedures should raise the suspicion of nesidioblastosis. In this situation, intra-arterial calcium angiogram can be used. If insulin levels rise after each selective calcium injection, multicentric insulinoma or nesidioblatosis are the likely diagnoses. Surgical management of adult-onset nesidioblastosis is controversial. In case reports of surgical management of adult nesidioblastosis, surgical approach included 70% to 95% distal pancreatectomy [51–56]. Although near-total pancreatectomy is associated with the chance for cure for hyperinsulinemia, it carries a high risk of subsequent development of insulin-dependent diabetes—up to 40%. This is also true in children immediately after near-total pancreatectomies or subsequently at adolescence. In the largest case series (n = 5), patients underwent 70% distal pancreatectomy . Of these patients, three remained asymptomatic and two had recurrent hypoglycemia. Summary Insulinoma should be included in the diﬀerential diagnosis of all patients presenting with hypoglycemia. A plasma insulin-to-glucose level greater than 0.3 and C-peptide levels of 2 nmol/L or greater suggest the presence of an insulinoma. CT scan of the abdomen is useful as a initial imaging study to exclude metastatic disease and for identifying uncommon large islet cell tumors, but has poor sensitivity for localizing most insulinomas. Transgastric endoscopic ultrasound has emerged as the most sensitive preoperative localizing technique. The combination of palpation and intraoperative ultrasound identiﬁes nearly all tumors at the time of operation, and gives vital information about surrounding structures. If no tumor is found intraoperatively, blind distal pancreatectomy should not be performed, and the patient should be referred to an experienced endocrinologist or endocrine surgeon for conﬁrmation of the diagnosis and further localization studies. Laparoscopy is emerging as a viable alternative to open tumor resection. Successful resection—both enucleation and distal pancreatectomy—has been reported over the past decade. Intraoperative use of laparoscopic ultrasound can facilitate localization and guide safe resection. References  Service FJ, McMahon MM, O’Brien PC, et al. Functioning insulinomas-incidence, recurrence, and long-term survival of patients: a 60-year study. Mayo Clin Proc 1991;66(7): 711–9.  Howland G, Campbell WR, Maltby EJ, L, et al. Carcinoma of the islands of the pancreas, hyperisulinism hypoglycemia. JAMA 1927;89:348.  Huai J, Zhang W, Niu H. Localization and surgical treatment of pancreatic insulinomas guided by intraoperative ultrasound. 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