Evaluation and Treatment of Insulinoma

What is an insulinoma?

Patients with insulinomas present with episodic hypoglycemic events; with central nervous system dysfunction (confusion, anxiety, stupor, paralysis, seizures, coma). These symptoms reverse dramatically with the ingestion of carbohydrates or intravenous glucose infusion; a clinical situation otherwise known as Whipple´s triad.

Patients with insulinomas have complete loss of the feedback control over insulin secretion. Hypoglycemic events are intermittent in frequency. Patients refer being misdiagnosed and treated for psyquiatric or neurological disease, which explains the late diagnosis. Thus, individuals with insulinoma are overweight or obese, as they find symptoms are controlled with sugar or a diet rich in carbohydrates.

Lesions are unique in 80 to 90 % of cases, with the exception of MEN-1 patients (multiple lesions). Tumors are frequently less than 1 cm in size (47%), and almost always intrapancreatic (97%),  with an even distribution along the gland. They are benign in 85 to 90 % of patients.

Measurement of plasma glucose, insulin, C Peptide and proinsulin every six hours during a 72 hour fast is considered the gold standard diagnostic test for patients with insulinoma. Measurement intervals are shortened to every two hours if hypoglycemia of less than 60 mg/dL is documented. Fast is suspended and diagnosis confirmed with glucose levels of 45 mg/dL or less are documented, with an elevation in insulin (> 6 micromol/mL) and C-peptide (> 0.2 nmol/l) in the absence of elevated levels of plasmatic sulfonylureas.

What radiological tests are helpful before surgery in localizing these tumors?

Once biochemical diagnosis has been established, imaging studies are helpful in locating the hyper secreting lesion or lesions; and in designing the most appropriate approach when deciding to operate on these patients. Imaging studies help in the staging process as well, when facing a patient with malignant or advanced disease. This is specially true in patients with non functional tumors, who present with large lesions, with or with out local invasion to adjacent organs. Multiple lesions in younger patients may suggests the occurrence of a hereditary form of the disease.

Whilst biochemical diagnosis is pretty straight forward, insulinomas remain the most challenging of the PNETs to locate once diagnosis has been confirmed; and it is not infrequent that more than one location study has to be performed trying to locate the tumor involved.

CT SCAN

This study has been defined as the modality of choice in evaluating patients with PNETs. CT Scan provides information regarding the pancreatic parenchyma, as well as extension of these tumors outside the gland.

Four phases are analyzed: simple, arterial, portal and late venous. Whilst most PNETs can be detected and characterized in the arterial phase, portal phase may be also of great sensitivity. This latter has been described between 57 and 63 %, and may be improved when reducing the thickness when performing the study.

MAGNETIC RESONANCE IMAGING

Magnetic Resonance Imaging for PNETs performsT1, T2 and Dynamic 3D sequences with gadolinium infusion in arterial, venous and late phases. This late sequence is of help when evaluating a patient with a poorly differentiated lesion, and important mitotic activity; limiting radiation exposure and the risk for contrast related nephropathy. Its sensitivity is higher for hepatic metastatic lesions.

ENDOSCOPIC ULTRASOUND

Endoscopic ultrasound has greatly evolved and is capable of detecting small pancreatic lesions (2 to 5 mm) with a sensibility of 79 to 94 %, specially those located in the head of the pancreas. Insulinomas are almost always located in the pancreatic parenchyma, evenly distributed, and 2 cm in size on average in 90 % of cases.

When located outside the gland, endoscopic ultrasound can detect and biopsy these lesions. Suspicious adenopathies can also be evaluated and biopsied accordingly.

ARTERIOGRAPHY

Because of their elusive nature, insulinoma patients may require a selective arterial calcium stimulation test as an ultimate effort to localize the lesion when all other studies fail in locating the tumor. While considered the gold standard in the 1970s, success was achieved in only 50 % of patients. Insulin secretion is stimulated by calcium infusion in two of the main arteries feeding the pancreas. Insulin is measured along the different regions in an effort to regionalize insulin secretion accordingly to direct the surgeon towards a specific region during the intervention. The study is invasive, requires considerable expertise and is expensive.

INTROAOPERATIVE ULTRASOUND

Laparotomy and extensive exploration of the pancreatic gland in the search of an insulinoma with the help of an ultrasound probe has been reported to be successful in up to 95 % of cases. The presence of the radiologist may be necessary however, as an expert eye may be needed to better differentiate a lesion from the normal pancreatic parenchyma, as well as other anatomical structures. A blind pancreatic resection when all imaging studies are negative is not recommended

What are the treatment options for insulinoma, both the benign and the malignant?

The standard surgical approach for patients with insulinoma was a formal laparotomy with complete exploration of the gland. Accordingly, insulinomas could be enucleated (most lesions are hard and easily dissected from normal parenchyma), or a distal pancreatectomy with splenectomy be performed if the lesion was located to the left of the mesenteric vessels; versus a pancreatoduodenectomy (Whipple procedure) when the tumor was located on the head of the gland.

A more limited approach can be proposed however, as our understanding of the disease has improved (90 % of insulinomas are benign in nature); better imaging and location studies are available, and even the most radical of interventions can be performed using minimally invasive techniques.

Thus, enucleation can be performed laparoscopically even if the tumor is in close proximity to the pancreatic duct. Distal pancreatectomy with or without spleen resection is equally feasible using this techniques. Laparoscopic pancreatoduodenectomy for lesions located in the head has been described in large series, even in the presence of malignant lesions where extensive lymph node resection may be required.

Of note, complications for pancreatic resections performed via an open or laparoscopic approach may still occur in up to 50 % of patients. Pancreatic fistula remains the most important challenge in pancreatic surgery, occurring in up to 30 % of patients irrespective of the approach performed. However, most of the fistulas resolve spontaneously with drainage and medical treatment as the mainstay of management. Other complications may occur and are less complex in nature (respiratory, urologic), but can prolong hospital stay none the less.