Pancreatic insulinoma: current issues and trends

Athens, Greece

Pancreatic insulinoma: current issues and trends

Dennis Vaidakis, John Karoubalis, Theodora Pappa, George Piaditis and George N Zografos

Athens, Greece

BACKGROUND: Although insulinomas are very rare tumors, they are the most common pancreatic neuroendocrine neoplasms. The incidence in general population is 1-4 per 1 000 000 yearly but the incidence is higher in autopsy studies. The malignancy of insulinomas is difficult to be predicted on the basis of their histological features, and the current WHO classification has been re-evaluated. This review aimed to summarize classical knowledge with current trends in the diagnosis and treatment of insulinomas.

DATA SOURCES: A Medline search using terms "insulinoma", "treatment" and "neuroendocrine tumors" was conducted. Additional references were sourced from key articles.

RESULTS: Surgery is the treatment of choice for insulinoma and has an extremely high success rate. Medical treatment is also available but only for patients who are unable or unwilling to undergo surgical treatment. Preoperative localization is necessary for planning the surgical approach. Many methods exist for localization of an insulinoma and can be invasive and non-invasive. The combination of biphasic thin section helical CT and endoscopic ultrasonography (EUS) has an almost 100% sensitivity in localizing insulinomas. Laparoscopic ultrasound is mandatory to localize intraoperatively these tumors. EUS-guided fine needle tattoing is an alternative method of localization in case of lack of laparoscopic ultrasound.

CONCLUSION: Laparoscopic resection for benign insulinomas is the procedure of choice, whereas pancreatectomy is reserved for large, potentially malignant tumors.

(Hepatobiliary Pancreat Dis Int 2010; 9: 234-241)

insulinoma; pancreas; neuroendocrine tumor; diagnosis; treatment

Introduction

Pancreatic endocrine tumors are clinically classified as functioning or nonfunctioning according to the presence of symptoms of hormone hypersecretion.[1]Fasting hypoglycemia in healthy, well nourished adults is rare and is most commonly due to an adenoma of the islet of Langerhans, called insulinoma.[2]Although rare, insulinomas are the most common functional pancreatic neuroendocrine neoplasms,[3]with specific problems in their diagnosis, localization and treatment. Rarely, insulinoma may be associated with the syndrome of multiple endocrine neoplasia type 1 (MEN-1).[3]Surgery is the treatment of choice and has an extremely high success rate.[4]Improvements in minimally invasive techniques have facilitated the laparoscopic resection of these tumors.[5]

Historical data

Hypoglycemia was first recognized in the 19th century.[6]In 1869, the German pathologist Paul Langerhans discovered regions within the pancreas producing hormones, the islets of Langerhans.[7]Nicholls first described the findings of an autopsy of an islet cell tumor in 1902.[8]In 1922 Banting and Best discovered insulin and in 1923 Campbell and Fletcher were the first to describe the hypoglycemic complex as an etiology of insulin excess.[9]

The first resection of an insulinoma was performed in 1927, when WJ Mayo removed an insulin-secreting tumor from a physician and injected its extracts into rabbits that subsequently developed hypoglycemia.[10]In 1938, Whipple reported a triad, considered pathognomonic for insulinoma: neurologic symptoms of hypoglycemia, blood glucose levels less than 50 mg/dl and immediate alleviation of symptoms after glucose ingestion.[11]In 1954, Wermer[12]described a family with MEN-1 syndrome (often associated with gastrinomas and less frequently with insulinomas). In 1993, Gagner et al[13]reported the first successful laparoscopic distal pancreatectomy and pancreatoduodenectomy. A successful laparoscopic resection for pancreatic insulinoma was made in 1996.[13]Since then, an increasing number of reports of successfullaparoscopic resection for pancreatic insulinomas have been published in English literature.

Epidemiology

The incidence of insulinomas in the general population is estimated 1-4 per 1 000 000 yearly.[14]The incidence has been reported higher in autopsy studies (0.8% to 10%), suggesting that these tumors frequently remain undiagnosed.[15,16]The median age of patients at presentation is approximately 47 years, and females show a slight predominance over males (59%). Insulinomas comprise 70% to 80% of all functional neuroendocrine pancreatic tumors.[14]The majority are solitary, benign lesions occurring in a sporadic setting;[17]they are also single, small, and hypervascular, with 90% measuring less than 2 cm and 30% measuring less than 1 cm in diameter. Approximately 10% are multiple, 10% are malignant, and 16% are associated with MEN-1 syndrome.[18]Malignant insulinomas tend to occur more frequently in MEN-1 patients. The incidence of insulinomas in patients with diabetes mellitus (DM) is the same with the general population.[14]Approximately 60 years were required to obtain accurate epidemiological data regarding insulinomas because of the rarity of these tumors.[5]

Malignant insulinoma

It is difficult to predict the malignant nature of an insulinoma on the basis of its histological features.[19]The current WHO classification criteria involve the presence of metastases, gross invasion, tumor size, percentage of mitoses, proliferative index and vascular invasion.[20]However, metastases are generally considered the only definitive characteristic of malignancy. Out of all insulinomas, 5%-10% are malignant.[3]The differential diagnosis between malignant and benign insulinomas is usually very difficult and is based on intraoperative evidence (metastases in the liver, regional nodes or local invasion), whereas in some patients the metastases are frequently found along with the recurrence of a hypoglycemic episode.[20]It is important to discover alternative ways of estimating the malignant potential of insulinomas and not solely rely on histopathological examination.[21]The combination of medical and surgical therapeutic approaches must be considered for the treatment of malignant insulinomas.[22]Intravenous streptozotocin chemotherapy could be administered according to published protocols (500 mg/m2streptozotocin on 5 consecutive days and repeated every 6-8 weeks) and additional chemotherapy could be used according to the stage of the disease.[23]

Clinical findings and symptoms

Insulinoma should be included in the differential diagnosis of fasting hypoglycemia in a healthyappearing person.[24]Clinical manifestations of an insulinoma can mimick central nervous system disorders, like epilepsy and psychiatric disturbances.[24]On the other hand, obesity can be the result of an over-attempt to relieve symptoms of hypoglycemia in longstanding cases.[25]

The clinical symptoms of insulinoma are the subsequent development of symptoms of hypoglycemia.[26]The leading symptoms establishing the diagnosis of endogenous hyperinsulinism comprise the Whipple's triad. This includes: 1) symptoms of neuroglycopenia, 2) documented hypoglycemia (plasma glucose levels＜50 mg/dl), and 3) symptoms relief (often within 5-10 minutes) following glucose administration. Patients with the above symptoms warrant further evaluation.[26]

Symptoms can be divided into either adrenergic, resulting from the catecholaminergic response (anxiety, tremor, nausea, hunger, sweating and palpitations) or neuroglycopenic (headache, lethargy, dizziness, diplopia, blurred vision, amnesia, seizures and in more severe cases confusion or coma). Hypoglycemic symptoms tend to occur with plasma glucose concentrations at or below 50 mg/dl with central nervous system disturbances becoming apparent when plasma glucose falls below 45 mg/dl. It is very frequent for some patients to develop hypoglycemic unawareness, as a result of central nervous system adaptation to chronic hypoglycemia.[27]The result of hypoglycemic unawareness is the absence of symptoms in these patients with critically low glucose levels.[28]Clinical hypoglycemic disorders have also been divided in two categories: those occurring in healthy-appearing subjects and in patients with a known illness.[29]Because several diseases manifest with the same symptoms as hypoglycemia, plasma glucose concentrations must always be measured at the time of the episodes.[5]

Diagnostic tests

Laboratory findings

Blood glucose levels are tightly regulated with a negative feedback system between 70 and 110 mg/dl. Following food ingestion, blood glucose levels increase and stimulate insulin production. On the contrary, whenblood glucose levels decrease, insulin production is reduced. In β-cell adenomas the production of insulin is not dependent on blood glucose levels.[27]The critical diagnostic test for insulinoma is to measure elevated serum insulin levels in the presence of hypoglycemia.

Fasting tests for insulinoma

Fasting is the principal maneuver in the diagnosis of insulinoma.[30]Fasting serves two purposes: first, identifying the relation between hypoglycemia and the patient's symptoms, and second, exhibiting inappropriately elevated insulin concentrations with low blood glucose levels.

One of the major diagnostic tests is the 72-hour fasting test,[30]which is considered as the gold standard for the diagnosis of insulinoma. The name of the test is rather a misnomer because it rarely takes 72 hours upon completion. A proposed protocol for the test is the following and requires hospitalization: during the fasting period the patient is allowed to drink calorie free fluids and physical activity should be encouraged. Blood glucose levels should be measured every 6 hours; when they fall to 60 mg/dl, they should be measured every 1 or 2 hours. When plasma glucose levels are 40-45 mg/dl and the patient has symptoms of hypoglycemia, blood sample should be drawn and sent to the laboratory for measurement of glucose, insulin, C-peptide, β-hydroxybutyrate and sulfonylurea. Some authors propose that after completion of the 72-hour fasting period, 1 mg of glucagon should be injected intravenously and plasma glucose measured after 10, 20 and 30 minutes.[30]

It would be desirable to modify the diagnostic test as described in textbooks and protocols to be conducted over a less extended period[31]and some suggest the 48-hour fasting test.[32]The basic steps of the 48-hour testing protocol are similar to those of the 72-hour test; the difference is that when glucose levels fall to 40-45 mg/dl without symptoms of hypoglycemia, the patient should be instructed to undergo light exercise (i.e. a short walk) for 15-30 minutes and afterwards plasma glucose measurements should be repeated. In order to replace the 72-hour with the 48-hour fast more clinical studies are necessary.[32]

Ancillary tests

Intravenous secretin test for insulinoma

In patients harboring an insulinoma, insulin production by normal pancreatic β cells is significantly suppressed. Following intravenous injection of secretin (2 units/kg of body weight), plasma insulin rises more than 200% in normal individuals, whereas in patients with insulinoma, the secretin stimulation test does not cause a rise in plasma insulin due to the unresponsiveness of insulinoma cells to secretin.[33]

C-peptide inhibition test with hog insulin

After proinsulin cleavage, insulin and C-peptide are secreted. Infusion of hog insulin for 1 hour leads to the decrease of plasma C-peptide levels in healthy subjects, but no such decrease is observed in insulinoma patients. Insulin release from insulinoma cells is not inhibited by the administration of exogenous insulin, whereas insulin secretion from normal β-cells is inhibited by the increased plasma insulin.[34]

Differential diagnosis

In the emergency ward two thirds of the patients with hypoglycemia have DM and nearly one fourth are septic.[35,36]Drugs, mainly insulin, are the most common cause of hypoglycemia in hospitalized patients.[37]Critical illness, renal or hepatic failure and sepsis are also common, whereas hypoglycemia due to hypocortisolism is an uncommon etiology.[38]Clinical manifestations of hypoglycemia vary among patients.[39,40]

The causes of hypoglycemia in healthy appearing patients include insulinoma, non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS), insulin factitial hypoglycemia, strenuous exercise, and ketotic hypoglycemia,[41]with insulinomas being the large majority of these cases. Although it requires several days of hospitalization, the diagnosis of insulinoma can be established according to the following criteria:[42]1) blood glucose levels near or below 45 mg/dl with hypoglycemic symptoms; 2) inappropriately high insulin levels (for some author over 6 μIU/ml); 3) elevated C-peptide levels (over 0.2 nmol/L); and 4) absence of sulfonylurea in toxicological examination.

Localization

The treatment of choice for patients with insulinoma is surgical removal of the tumor.[5]Preoperative localization is necessary to plan the surgical approach.[43]Traditionally, blind distal pancreatectomy used to be the standard surgical procedure when a tumor could not be visualized and/or palpated intraoperatively. However, with the advance in localization techniques, blind resections for small and benign insulinomas have been abandoned.[44]Non-invasive imaging techniques like ultrasonography (US), computerized tomography (CT) and magnetic resonance imaging (MRI) can be helpful in localization of tumors larger than 1 cm,but fail to capture small insulinomas.[45,46]Invasive techniques like selective arteriography, transhepatic portal-venous sampling (THPVS), endoscopic US (EUS), and intraoperative US have better results in localization of insulinomas, but they have certain disadvantages.[47]Some authors[48]believe that the preoperative localization can be bypassed, because a relatively high percentage of insulinomas can be identified by an experienced surgeon during the operation. However, some studies showed that in 10%-27% of patients without preoperative localization the insulinoma could not be detected intraoperatively. As a result, preoperative localization is necessary for the successful surgical treatment of insulinomas. Localization of the tumor has helped reduce the degree of pancreatic trauma intraoperatively and determine the operation filed.[42]

Although all methods can facilitate localization of an insulinoma, it is neither practical nor necessary to be applied in every patient. By weighing the advantages and the disadvantages of the localization methods, a feasible and practical plan can be made to refer as a guide for proper treatment.

Preoperative transabdominal US

Like several abdominal disorders, transabdominal US yields the widest range of success and failure of all preoperative localization tests. It is noninvasive, free of radiation exposure, readily available, relatively inexpensive, and anatomically precise. Key major drawbacks include its extreme dependence on operator expertise and limitations based on the patient's habitus, that is usually unfavorable since many insulinoma patients are overweight or obese.[49]

CT scan

CT scan has many advantages since it can be easily performed, is non-invasive and the images are easily interpretable for the surgeon. Insulinomas typically appear as well-defined, rounded, homogeneously masses of the pancreas. Because the majority of insulinomas are usually smaller than 2 cm, dynamic CT scan should be performed;[50]the sensitivity of the dynamic CT scan in the detection of insulinoma ranges from 30% to 66%.[51,52]Atypical CT scan imaging of insulinomas includes hypoattenuating masses on enhanced CT or intraarterial dynamic CT, cystic masses, and calcified masses.[53]

MRI

The latest studies have demonstrated that MRI is superior to other preoperative imaging techniques in identifying small pancreatic insulinomas.[54]Its sensitivity ranges from 85% to 95%, in the detection of insulinomas and the determination of the presence of metastases.[54]Using conventional sequences, small insulinomas usually have a low signal on T1-weighted sequences and a high signal on T2-weighted sequences.[55]Some insulinomas containing fibrous tissue may show low signal intensity on both T1- and T2-weighted images.[55]An improvement in MRI technique is the use of diffusion weighted MRI (DWI-MRI) for abdominal imaging.[56]DWI is an MRI technique that detects changes in the molecular diffusion of water in biologic tissues and the valuable role of DWI in the detection of pancreatic tumors has been reported in several studies.[57]

Positron emission tomography (PET)

The results of 18 F-fluorodeoxyglucose (18 F-FDG) PET imaging for insulinomas are not very promising, maybe due to the low proliferative potential of these tumor cells. Positive results have been shown using 11 C-5-hydroxy-L-tryptophan (C-5-HTP), 18-3, 4-Dihydroxy-6-fluoro-DL-phenylananine (F-DOPA), and 67 Ga-DOTA-DPhe 1-Tyr 3-octreotide (67 Ga-DOTATOC) due to selective uptake in tumor tissue compared to surrounding tissue. These techniques produce very good tumor visibility and can be used for the examination of both the thorax and abdomen. However, lack of general availability of PET scanning and high cost limit its use.[44]

Angiography

Angiography combined with calcium stimulation and THPVS was previously considered the gold standard of insulinoma localization,[58]with a sensitivity ranging from 87.5% to 100%.[59,60]THPVS is the most accurate preoperative tool for the localization of insulinomas.[61]However, this method is both invasive and technically demanding, since it requires intra-arterial and intravenous catheterization and should be employed only upon high suspicion for insulinoma and failure of all non-invasive imaging tests to detect the lesion.[61]

EUS

EUS allows the positioning of a high frequency (7.5-10 MHz) transducer in close proximity to the pancreas and lesions as small as 5 mm as well as tumors located in the bowel can be detected.[62]Although there is a potential "blind-spot" at the splenic hilum, a high sensitivity has been obtained. A recent single-centre prospective study showed a sensitivity of 93% and a specificity of 95% in localization of intra-pancreatic lesions. EUS could detect all tumors visualized by everyother conventional technique, thus questioning the need for the rest imaging modalities.[62]

Intraoperative US (IOUS)

IOUS has been very useful in localizing small tumors. Additionally, it demonstrates the relevant operative anatomy, defining the relationship of the tumor to the pancreatic and bile duct and adjacent blood vessels. Intraoperative localization techniques, which include both careful palpation of the pancreas and the use of IOUS, remain the most reliable way to localize insulinomas and determine the indicated surgical procedure (enucleation versus middle pancreat-ectomy). Moreover, it is mandatory in patients, where multiple lesions are suspected.[63,64]Laparoscopic IOUS in experienced hands can identify over 85% of insulinomas.[64]

Somatostatin receptor scintigraphy

The main indication for111Indium-pentetreotide scintigraphy is the imaging of neuroendocrine tumors, like gastroenteropancreatic (GEP) tumors and sympathoadrenal system tumors, which usually have a high expression of somatostatin receptors. Because not all insulinomas express somatostatin receptor type 2,111Inpentetreotide scintigraphy is positive in only 46% of benign insulinomas.[65]

Treatment

Surgery is the treatment of choice for insulinoma and has an extremely high success rate.[5]Medical treatment is also available for the subgroup of patients, who are unable or unwilling to undergo surgical treatment, for preoperative control of blood glucose levels or for unresectable metastatic disease.[66]

Medical management

The medical treatment is designed to prevent prolonged periods of fasting with dietary management. The most effective drug for controlling hypoglycemia is diazoxide (50-300 mg/day, can be increased up to 600 mg/day), that suppresses insulin secretion by direct action on the beta cells and by enhancing glycogenolysis.[67]Other drugs useful in controlling hypoglycemia are verapamil, glucocorticoids, phenytoin and, in some cases, somatostatin analogues.[67]

Surgical management

After establishing the diagnosis and the proper localization of the tumor, surgical treatment should be planned.[68,69]The patient should be hospitalized at least one day before the operation and blood glucose levels should be monitored. Regarding preoperative management, an intravenous catheter is placed and 10% dextrose solution is infused to avoid hypoglycemia, particularly after midnight. Some authors[70,71]propose the administration of diazoxide in the day of the operation in order to reduce the need for glucose supplements as well as the risk of hypoglycemia. Consultation of the anesthesiologist to plan precise intraoperative blood glucose monitoring is necessary and blood glucose levels should not fall below 40-50 ml/dl.[42]

The majority of pancreatic insulinomas are small and may not be easily exposed during the surgical procedure, particularly if they are not located at the anterior surface of the gland.[72]Enucleation is the procedure of choice for all benign insulinomas. Intraparenchymal insulinomas and tumors located in the pancreatic head and the uncinate process can be missed and require extensive mobilization of the pancreatic head or body.

Traditionally, blind distal pancreatectomy has been considered the standard surgical procedure, when a tumor could be not visualized and/or palpated intraoperatively. However, with the advance in diagnostic and localization techniques blind resections for small and benign insulinomas have been abandoned.[72]Preservation of the pancreatic parenchyma is currently considered mandatory, because insulinomas are mainly benign tumors and most patients remain disease-free following successful excision even after a prolonged follow-up. Preoperative EUS and IOUS as well as careful surgical palpation have an almost 100% sensitivity in identifying eutopically localized (intra-pancreatic) small insulinomas.

The advantages of laparoscopic surgery are well established and the technique applied in many intraabdominal conditions. In 1996, Cushieri et al[73]reported the first series of laparoscopic distal pancreatectomy. Since then, few reports of laparoscopic pancreatic surgery have been published. Prior to the laparoscopic era, the division of the gastrocolic ligament was followed by careful intraoperative exploration both visually and by palpation. IOUS and surgical exploration were the ideal localizing strategy for pancreatic insulinomas. However, in the laparoscopic era, inspection and laparoscopic US are the usual localizing modality. In the absence of tacticle sense, experience with the laparoscopic US technique is mandatory, although these tumors are rare. On this ground, accuracy of the technique can only be achieved in centers with significant case load of neuroendocrine tumors.

EUS-guided fine needle preoperative tattoing ofinsulinoma with methylene blue and laparoscopic enucleation of the tumor has recently been suggested as an alternative preoperative localization technique.[74]It was first advocated in open surgery by Gress et al.[75]This technique requires an experienced endoscopist and a skilled surgeon in laparoscopic and pancreatic surgery.[76]

The most common complication of enucleation for pancreatic insulinomas is pancreatic leak. It presents either as pancreatic fistula or as an intra-abdominal collection, usually self-limited after few weeks.[77]The use of fibrin glue has been reported to decrease the leak rate.[78]

Pancreatoduodenectomy or distal pancreatectomy, rarely indicated for malignant tumors or failed enucleation of multiple insulinomas, has a higher complication rate. Although surgical mortality in pancreatoduodenectomy is less than 5%, postoperative morbidity remains high and is approximately 50% even in large series.[47]

Open and laparoscopic distal pancreatectomy, in the absence of pancreaticojejunostomy, are followed by a minimal mortality rate, but a significant rate of pancreatic fistula, ranging from 15% to 40%.[48]

After a successfully removal of an insulinoma the blood glucose level rapidly rises to 120-140 ml/dl, sometimes even while the patient is in the recovery room.[5]The intravenous glucose solution should be administered for an additional 24-hour period and during that time blood glucose levels may rise up to 180-230 mg/dl.[5]For a period of several days to several weeks the glucose levels may increase up to 200-400 mg/dl and in these cases small doses of insulin should be administered.[79]Blood glucose levels should be measured frequently during hospitalization and once daily after patient's discharge.[79]The drain can be removed, when a common diet can be tolerated and the drainage is minimal (usually at the seventh postoperative day).[80]After the complete removal of the tumor, a patient with insulinoma is considered cured, but periodic followup is important, especially for patients with malignant insulinomas and MEN-1 subjects.[80]

Conclusion

The combination of biphasic thin section helical CT scan and EUS has an almost 100% sensitivity in localizing insulinomas. Laparoscopic US is mandatory for intraoperative localization of these tumors. EUS-guided fine needle tattoing represents an alternative method, when laparoscopic US is not available. Laparoscopic resection of benign insulinomas is the procedure of choice, whereas pancreatectomies are reserved for the rare cases of large, potentially malignant tumors.

Funding: None.

Ethical approval: Not needed.

Contributors: VD wrote the main body of the article under the supervision of ZGN. KJ, PT and PG provided advice on medical aspects. ZGN is the guarantor.

Competing interest: No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.

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Received February 3, 2010

Accepted after revision May 1, 2010

Author Affiliations: Third Department of Surgery (Vaidakis D and Zografos GN), Department of Gastroenterology (Karoubalis J), and Department of Endocrinology (Pappa T and Piaditis G), Athens General Hospital, Athens 15237, Greece

George N Zografos, MD, Third Department of Surgery, Athens General Hospital, 10 K. Ourani Str., Athens 15237, Greece (Tel: +306944918944; Fax: +302107706915; Email: gnzografos@yahoo.com)

? 2010, Hepatobiliary Pancreat Dis Int. All rights reserved.