Epidemiology of insulinoma
Insulinomas are the most frequent of all functioning pancreatic NETs, and constitutes ∼25% of all pancreatic NETs. The incidence of insulinoma was reported to be 2-4 patients per million population per year. The highest incidence is at age 40-60 years. Females are slightly more affected.

Symptoms of insulinoma
Due to episodic release of insulin from the tumors, the patients have attacks of hypoglycaemia typically before breakfast or after exercise. The symptoms are neurologic because of neuroglucopenia, including diplopia, blurred vision, confusion, abnormal behaviour and amnesia, sometimes also seizures and loss of consciousness. In addition counterregulatory production of catecholamines causes sweating, weakness, hunger, tremor, nausea, anxiety and palpitations. Insulinomas are usually sporadic and benign, but 5-10% may be associated with the hereditary MEN-1 syndrome, and can affect younger individuals. MEN1 patients often have multiple synchronous or asynchronous insulinoma, or insulinoma combined with other endocrine pancreatic tumour types. In nonfamilial patients insulinoma is rarely multiple.

Many patients with insulinomas have become obese, as they have learned to take frequent nightly meals to avoid hypoglycaemia, and this may complicate surgery.

Diagnosis of insulinoma
Diagnosis is verified by a supervised fasting test with demonstration of hypoglycaemia (serum glucose concentrations >45 mg/dl (<2.5 mM)), combined with inappropriately high serum insulin (this implies any detectable insulin during hypoglycaemia). Insulin/glucose
quotients are less relevant, since 20% of patients may have normal or minimally raised insulin values. Important is to show rise in C-peptide to exclude factitia caused by self-administration of insulin or peroral antidiabetic medication. The ratio of proinsulin to total immunoreactive insulin values is often higher in patients with insulinoma. Very high proinsulin/insulin ratio may indicate malignant insulinoma, but occur also with benign insulinoma.

Treatment of insulinoma
The basic treatment for insulinoma is surgery, which cure the patient with a benign sporadic insulinoma. Operation is often possible also in elderly persons, who may have considerable relief of severe symptoms or threatening mental disability. Surgery should generally not be
postponed since severe hypoglycaemic attacks may cause cerebral damage. Preoperative treatment with diazoxide (or somatostatin analogue) is not recommended; diazoxide may have severe side effects with fluid retention and oedema, that may complicate surgery. However, in cases where surgery is not possible, as well as in metastati malignant insulinoma diazoxide may be given.

Preoperative localization methods for insulinoma
The majority of insulinomas are small and benign, measuring from 5 mm to commonly around 1 cm, 90% have been <2 cm. Ectopic tumours have exceptionally occurred (<1%) in proximity to the pancreas or in the duodenal wall.

CT with contrast enhancement is performed routinely to rule out liver metastases and detect larger tumours (>4 cm) that indicate malignancy, but often fail to detect the small insulinomas.

Endoscopic ultrasound (EUS) is presently the most efficient method for preoperative localization with nearly 90% sensitivity for visualization of insulinomas; some isoechoic (6%) or pedunculated tumours may fail to be visualized. Insulinomas are typically hypoecogenic. EUS can reveal relation to the pancreatic duct, and if introduced into the horizontal duodenum can visualize also the uncinate process. False positive findings may be accessory spleens or lymph glands within the pancreas (Fig 1).

Fig. 1. Endoscopic ultrasound is the most important method for preoperative localization, can detect 90% of insulinoma.

Fig. 1. Endoscopic ultrasound is the most important method for preoperative localization, can detect 90% of insulinoma.


Selective arterial stimulation (SAS) test with calcium injection into the three major arteries supplying the pancreas (the gastroduodenal, superior mesenteric, and splenic arteries), together with hepatic vein sampling for insulin, can regionalize an insulinoma to the head, body or tail of the pancreas (Fig. 2). The SAS test may be used also before primary operation when other localization studies are negative, and is essential in reoperative cases. The test is performed with an initial angiogram that may visualize the typical tumour blush of the insulinoma. A SAS test demonstrating insulin secretion from multiple areas of the pancreas can support a diagnosis of multiple insulinoma (in MEN1 patients) or a diagnosis of nesidioblastosis.

Intraoperative localization Intraoperative ultrasound (IOUS) is necessary to perform during surgery for insulinoma together with complete pancreatic exploration and careful palpation and visualization of the entire pancreatic gland at surgery. The IOUS should be performed by an experienced investigator, and will efficiently visualize the typically hypoechogenic insulinoma, and can detect a few mm large tumours (Fig.3,4). IOUS can demonstrate the surgical anatomy and guide the safest approach to the tumour to avoid injuries of the pancreatic duct during removal, and can also reveal tumour bilobation that has to be appreciated by the surgeon at enucleation.

Fig. 3. Typically hypoechogenic insulinoma.

Fig. 3. Typically hypoechogenic insulinoma.


Operation for insulinoma
Exposure of the pancreas is often achieved via bilateral subcostal incision. The head of the pancreas is mobilized to the aorta by a Kocher manoeuvre, and the ventral and dorsal surfaces of the pancreatic head are dissected, and the uncinate process freed from the porto-mesenteric vein. The distal pancreas is explored via the lesser sac, with incision of the retroperitoneum at the lower pancreatic border, and blunt dissection of the pancreatic body and tail to the mesenteric vein. The entire pancreas is bidigitally palpated and scanned with IOUS from the ventral and dorsal surfaces (Fig.4).

An insulinoma often appears brownish-red and possible to palpate as a firm discrete mass (Fig.5). Tumors deep within the pancreatic head and in the uncinate process are difficult to palpate, especially in patients with previous pancreatitis. Combination of IOUS and palpation increases sensitivity of insulinoma detection to nearly 100%, but requires complete surgical exploration by an experienced surgeon.

Insulinomas in the head of the pancreas may be safely enucleated with careful ligation of pancreatic duct tributaries. Some pancreatic head tumors adjacent to the pancreatic duct may be safer enucleated towards a catheter introduced by ERCP or duodenotomy.
Pancreaticoduodenectomy is only rarely required with large tumours and suspicion of malignancy. Also pancreatic tail tumors may be enucleated, but tail resection is chosen for distal tumors close to the duct to minimize the risk of pancreatic fistulation. Distal pancreatic resection is often made spleen-preserving with benign tumors, but this is avoided with large and therefore potentially malignant pancreatic NETs, since the splenic hilum is often a first site of metastases. Frozen section analysis can be used to verify successful insulinoma excision. If no insulinoma is found, blind pancreatic resections should not be done. In such case the abdomen should be closed, and the patient subjected to further investigation to verify the biochemical diagnosis, and once again exclude factitious insulin administration. Extensive localization procedures are applied before reoperation, often including the SAS intraarterial calcium injection test.

- differential diagnosis to insulinoma
Symptomatic hypoglycaemia has been reported in adult individuals without insulinoma, but with diffuse β-cell proliferation due to islet hypertrophy/nesidioblastosis. These patients typically have postprandial, rather than fasting-provoked hyperinsulinaemic hypoglycaemia,
and diagnosis can be confirmed by a meal test causing hypoglycaemia and inappropriate insulin and C-peptide levels. The diagnosis is supported if the SAS stimulation test shows insulin secretion from multiple areas of the pancreas.

Malignant insulinoma
Malignant insulinoma is seen in 5-10% of patients with endogenous hypoglycaemia. Hypoglycaemia may be severe, and some patients need continuous glucose infusion and cannot undergo a fasting test. High proinsulin/insulin ratio (>50%) may indicate malignant insulinoma, but occurs also with benign tumours. The diagnosis of malignancy requires demonstration of local invasion or metastases. The malignant insulinoma is generally large, >4 cm, many patients present with spread metastases. Aggressive attempts of resection of palliative debulking is considered and may give survival benefit. If malignancy is suspected (e.g. large tumour) distal pancreatic resection should include the spleen and peripancreatic lymph nodes. Patients with spread metastases in the liver, lungs and lymph nodes are often not available for tumour reduction, and survival depends merely on response to chemotherapy.

Some patients have larger, apparently dedifferentiated malignant insulinoma, with only slight insulin hypersecretion and less severe hypoglycaemia. These patients can benefit from surgical removal of large pancreatic tumours and can in absence of metastases experience long-term survival or cure.