Insulinoma: a rare neuroendocrine pancreatic tumor

Prevalence
Since 1927 and until today more than 3000 cases have been described. Conclusively, this is an extremely rare disease, met in almost all ages, mainly though between the 3rd and 7th decade of life, with a mean age of 50 years (5). The disease may insult both males and females, being more common among women by 60%. Concerning the different types of insulinoma, in 80 % of cases a benign single tumor is observed, an 11% constitutes multiple benign tumors, a 6% represents single malignant tumors and the remaining 3% are multiple malignant tumors or islet hyperplasia (nesidioblastosis) (5). It is worth mentioning that a histological differentiation between benign and malignant insulinomas is not easy. The diagnosis of a malignant insulinoma, after excluding the case of a big size of the tumor (>6 cm), is achieved by detection of metastasis in the local lymph nodes, the liver or other distal organs. A percentage of 4-10% of insulinomas has been proven to be part of MEN-1 syndrome (6,7). In most of these cases there are multiple tumors, 25% of them being malignant.

Clinical features
Insulinomas present hypoglycemic symptoms, grouped into two categories: neuroglycopenic and from the autonomic nervous system ones (8,9). Neuroglycopenic symptoms appear due to insulin hypersecretion and the resultant insufficient offer of glucose to the CNS, where glucose constitutes the main source of energy. They include vision disorders (59%), weakness (32%), epileptic crises (23%), vertigo, irritability, speech disorders, memory or even permanent neurologic damages with poor prognosis (8). The symptoms from the autonomic nervous system result from catecholamine release and represent sweating (43%), tremor (23%), tachycardia and feelings of hunger and fear (10). The most characteristic element is the manifestation of symptoms mainly during periods of fast, usually in the morning before breakfast intake. This fact may vaguely help an initial differentiation between insulinoma patients and those with noninsulinoma pancreatogenous hypoglycemia syndrome (NIPHS), who manifest postprandial symptoms (2). In the majority of cases the hypoglycemic episodes are initially sporadic, with intervals free of symptoms during weeks or months (11). This fact may usually lead to a wrong diagnosis. In most patients with insulinoma neuroglycopenic symptoms exist for several years before the establishment of a correct diagnosis, during which, plenty of hospitalizations from neurologists and psychiatrists are mentioned. Many patients manage to handle hypoglycemia on their own, by increasing carbohydrate intake leading to progressive weight gain and obesity. In these cases the clinical manifestation of insulinoma may become more obvious when the patient decreases food intake, because of an effort to lose weight (definitive diagnosis!!) (11,12).

Diagnosis
Since the moment that a clinical suspicion for insulinoma is raised, the patient should be inserted in the hospital and be subjected to a period of fast during which blood levels of glucose and insulin are measured every 6 hours. Normally a relatively stable value of glucose and a decreased insulin level should be present during this test. Though, among patients with insulinoma a significantly low value of blood glucose is observed, while insulin levels remain elevated (1,2,13). The fast is continued for 72 hours or until glycopenic symptoms appear. At this point, there has to be a measurement of glucose, insulin, C-peptide and pro-insulin level has to be conducted, and the fasting period is terminated. About 2/3 of patients with insulinoma will present hypoglycemic symptoms before 24 hours of fast, and the remaining will become symptomatic within 72 hours (14-16). The test results include the following (17):
- Glucose diminishes to hypoglycemic levels (<40 mg/dl).
- Insulin maintains inappropriately high levels (>5 mU/ml).
- The insulin (in IU) to glucose (in mg/dl) ratio is bigger than 0,3.
- The C-peptide level is elevated (>1,7ng/ml).
- Pro-insulin levels are increased. Normally pro-insulin represents the 10-15% and rarely over 22% of total insulin. When these levels exceed 40% of total, there are enough indications of malignancy.
In a few cases stimulation and suppression tests may be needed for the diagnosis of insulinoma. Stimulation tests include administration of tolbutamide, calcium, glucagon or leukine, and subsequent detection of high plasma insulin levels. The C-peptide suppression test refers to administration of pork or fish insulin, which normally suppresses endogenous insulin release. On the contrary, in patients with insulinoma, it will not have any impact on insulin secretion, indicated by persistently elevated levels of C-peptide (18).

Localization
Since the diagnosis of insulinoma is defined, an effort at localizing the tumor will follow. The methods which can successfully achieve an accurate localization are:
1. Ultrasonography;
2. Computed tomography (19-22);
3. Computed tomography with intravenous infusion of contrast medium (22-25);
4. Selective pancreatic arteriography (26-27);
5. Scintigraphy with octreotide (1,28-29);
6. Endoscopic ultrasound (30-32);
7. Magnetic resonance, which presents similar accuracy with ultrasonography, but is less sensitive than computed tomography or arteriography, thus it should not be included in the routine imaging control for the detection of insulinoma (33).
Combining all the above imaging techniques will lead to an accurate localization of the tumor in 80% of cases. In the remaining patients, methods such as transhepatic catheterization of portal, superior mesenteric or splenic vein, for blood sampling at different levels and insulin measurement, may be demanded. This method does not lead to a definitive imaging of the tumor, though helps to regionalize it in the head, body or tail of the pancreas in 75%-100% of patients.
A new technique is selective arterial calcium infusion and measurement of insulin levels from hepatic venous blood samples (2,34,35). Small quantities of calcium can be directly administered through the gastroduodenal, splenic, hepatic, or superior mesenteric artery. When calcium is infused within the artery which is responsible for the blood perfusion of the tumor’s region, a sudden and significant rise of insulin levels will be observed 30 seconds after the calcium infusion. Finally, the intra-operative ultrasonography may be able to localize small insulinomas, which can not be detected by palpation, in a range of 83-90% (36-38). Certainly though, palpation constitutes a highly accurate intra-operative method for the detection and localization of insulinomas.

Treatment
The treatment of choice for insulinomas is surgical resection. These tumors are benign and small sized in almost every case, thus the main surgical difficulty is their accurate localization (1,2,39-42). Three methods can be used:
1. Visual exploration. Insulinomas are reddish-brown tumors, like cherries, because of their rich vascularization. Most of them though are not visible because they are located inside the pancreas;
2. Palpation. Insulinomas are hard and bulky tumors. Palpation may though be difficult:
- When another operation is preceded;
- In alcoholic patients;
- When the insulinoma is located at the pancreatic head, which has a bigger diameter.
3. Intraoperative ultrasonography, where the insulinoma appears as a hypoechoic region. Intraoperative ultrasonography can be very helpful in determining the position of the tumor related to the pancreatic duct, the superior mesenteric vein and other anatomical structures (43). As far as the type of operation is concerned, enucleation is preferred for insulinomas located in the head of the pancreas. Those located in the body and tail of the pancreas are enucleated or resected in terms of distal or subtotal pancreatectomy depending on the distance between the tumor and the pancreatic duct. Since the possibility of malignancy, even limited, still exists, a surgeon should assess local lymph nodes and liver for metastases (1,44). In case of infiltration of the regional lymph nodes, a fact which declares malignancy, a pancreato-jejunectomy, or total pancreatectomy with lympha-denectomy is performed (45). If there is a respectable metastatic tumor, it should be resected as well at the same time, or during a re-operation.
The advances in laparoscopic techniques have recently made laparoscopic intervention for the management of insulinoma more favorable (46-48). The first laparoscopic resection of insulinoma was reported in 1996 (49). Insulinomas localized in the body or the tail of the pancreas, are ideal for laparoscopic enucleation or distal pancreatectomy with or without splenectomy. A postoperative pancreas related complication rate in a multicenter European study is 31%, principally being pancreatic fistula (48). The use of laparoscopic ultrasound can render this procedure more feasible, effective and decrease the possibility of complications (48,50).
Postoperatively we should expect a rapid elevation of plasma glucose, immediately after resection. The patient may need small doses of intravenous insulin infusion for a few days until obtaining a new endocrine balance and the drain adjacent to the pancreas can be removed as soon as the patient tolerates a general diet, which is about seven days postoperatively (2). Vaccination against meningococcus, H. influenza and pneumoniococcus is indispensable for the patients who have undergone splenectomy to avoid sepsis.
When the tumor is not possible to be localized, as well as in cases where an operation is not indicated due to an advanced age or a bad general condition, the insulinoma is managed conservatively. The diet of the patient can be modified by increasing the frequency of meals and adding complex carbohydrates, like cornstarch, in order to decelerate the carbohydrate absorption. Slowly absorbed types of carbohydrates are also contained in bread, potatoes and rice.
The medical management includes (1,2,45,51-55):
1. Diazoxide, which is effective in 60% of patients, though presents side-effects, such as gastrointestinal disorders, hirsutism and water and sodium retention.
2. Calcium channel blockers,
3. Octreotide, which has proved to be effective in the management of hypoglycemia in infants with nesidioblastomas, though not so successful in adults with insulinoma; it may even worsen hypoglycemia because of suppression of glucagone and growth hormone (GH) secretion.
In general, medical management has proved insufficient and the best results have been achieved by surgical resection. The treatment of metastatic disease, finally, demands the use of streptozocin and 5-fluorouracil, as well as embolization of the hepatic artery (2,56-58).

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