What is an insulinoma?

What is an Insulinoma

An insulinoma is a rare functional neuroendocrine tumor of the pancreas that secretes excessive insulin, causing recurrent hypoglycemia with neuroglycopenic symptoms such as confusion, lethargy, and seizures. 1, 2

Epidemiology and Pathology

• Insulinomas have an annual incidence of approximately 1-5 cases per million people, making them rare but the most common functional pancreatic neuroendocrine tumor 3, 4
• Approximately 90% of insulinomas are benign, solitary, and sporadic, while 10% are associated with multiple endocrine neoplasia type 1 syndrome 1, 3
• These tumors typically pursue an indolent course and can be cured surgically in 90% of cases 1, 2

Clinical Presentation

Patients present with Whipple's triad: hypoglycemic symptoms (particularly neuroglycopenic symptoms like confusion, altered sensorium, and seizures), documented low plasma glucose levels, and symptom resolution after glucose administration 3, 5

• Symptoms characteristically occur during fasting states, particularly in the morning 2
• Patients may experience weight gain due to frequent eating to avoid hypoglycemia 2
• Adrenergic symptoms include palpitations, diaphoresis, and dizziness 3

Common Diagnostic Pitfall

Diagnosis is frequently delayed because nonspecific symptoms are often misattributed to neurological or psychiatric conditions, sometimes for years 3, 6

Diagnostic Approach

The supervised 48-72 hour fasting test is the first-line diagnostic test, continued until hypoglycemia occurs or the time limit is reached 2

At termination of the fast, diagnostic criteria include:

• Plasma glucose <40-45 mg/dL 2
• Insulin level >3 mcIU/mL 1, 2
• C-peptide ≥0.6 ng/mL 1, 2
• Proinsulin levels ≥5 pmol/L 1, 2
• Insulin-to-glucose ratio ≥0.3 2

The elevated C-peptide is critical as it differentiates endogenous hyperinsulinemia (insulinoma) from exogenous insulin administration 2

Localization Studies

• Endoscopic ultrasound (EUS) is the preferred initial localization method with approximately 82% sensitivity 2
• Multiphase contrast-enhanced CT or MRI should be performed to rule out metastatic disease 1, 2
• For difficult cases, selective arterial calcium stimulation test (Imamura-Doppman procedure) can be considered 2
• Important caveat: Somatostatin scintigraphy is less useful for insulinomas than other pancreatic NETs because insulinomas are less consistently octreotide-avid 1

Treatment Approach

Preoperative Management

Glucose stabilization is essential before surgery using:

• Dietary management as first-line 1, 2
• Diazoxide as first-line medical therapy for managing hypoglycemia 2, 7
• Everolimus as an alternative option 1, 2

Critical Warning About Somatostatin Analogs

Octreotide and lanreotide should be used with extreme caution or avoided in insulinoma patients because they suppress counterregulatory hormones (growth hormone, glucagon, catecholamines), which can precipitously worsen hypoglycemia and result in fatal complications 1, 2

• Somatostatin analogs should generally not be used in patients with negative somatostatin scintigraphy 1

Surgical Management

Surgical resection is the optimal and definitive treatment for locoregional insulinomas with a 90% cure rate 1, 2, 4

Surgical options depend on tumor location:

• Enucleation is the procedure of choice for exophytic or peripheral insulinomas 2, 4
• Distal pancreatectomy with splenic preservation for tumors in the body/tail that cannot be enucleated 2
• Pancreatoduodenectomy for tumors in the pancreatic head that are deep, invasive, or close to the main pancreatic duct 2
• Laparoscopic approaches are safe for selected patients and may result in shorter hospital stays 2, 5

Contraindications to Surgery

Surgery should be avoided in patients with life-limiting comorbidities, high surgical risk, or widely metastatic disease 1

Malignant Insulinomas

While rare, approximately 10% of insulinomas are malignant 3. For metastatic high-grade insulinomas, a multimodal approach including chemotherapy (carboplatin/etoposide or dacarbazine), everolimus, and liver-directed therapies may be necessary 7