What is the diagnostic and treatment approach for a patient suspected of having insulinoma?

Insulinoma Diagnosis

For suspected insulinoma, perform a supervised 48-72 hour fast with measurement of insulin (>3 mcIU/mL), C-peptide (≥0.6 ng/mL), and proinsulin (≥5 pmol/L) when glucose falls below 55 mg/dL, followed by endoscopic ultrasound for tumor localization. 1

Clinical Presentation

Patients typically present with neuroglycopenic symptoms including confusion, lethargy, and seizures, often occurring during fasting states, particularly in the morning. 1 Weight gain from frequent eating to prevent hypoglycemia is common. 1

Diagnostic Testing Algorithm

Step 1: Supervised Fast (First-Line Diagnostic Test)

• A 48-hour supervised fast is now the diagnostic standard, replacing the traditional 72-hour protocol, as 94.5% of insulinomas are diagnosed within 48 hours. 2
• The fast should continue until hypoglycemia occurs (glucose <55 mg/dL) or the time limit is reached. 1
• At the termination of the fast, measure simultaneously:
  • Insulin level (diagnostic if >3 mcIU/mL, typically >6 mcIU/mL) 3, 1
  • C-peptide (diagnostic if ≥0.6 ng/mL) 3, 1
  • Proinsulin (diagnostic if ≥5 pmol/L) 3, 1
  • Plasma glucose (should be <55 mg/dL) 3

Critical diagnostic nuance: Proinsulin should be measured routinely during the fast, as even mild elevations can independently indicate aberrant insulin secretion, particularly in cases where insulin and C-peptide may be paradoxically suppressed. 4 Proinsulin is elevated at the beginning of the fast in 90% of insulinoma patients. 2

Step 2: Tumor Localization

Endoscopic ultrasound (EUS) is the preferred initial localization method, with 82-93% sensitivity for detecting pancreatic neuroendocrine tumors. 3, 1, 5 EUS provides dual benefits: tumor localization and tissue sampling via fine needle aspiration. 1

Multiphasic CT or MRI should be performed to rule out metastatic disease, with sensitivities of 57-94% and 74-94% respectively. 1, 5 These cross-sectional studies are essential for surgical planning. 1

Step 3: Advanced Localization for Occult Tumors

If initial imaging is negative or equivocal:

• Selective arterial calcium stimulation with hepatic venous sampling (Imamura-Doppman procedure) achieves up to 90% success rate for localizing occult insulinomas. 3, 1, 5 This test should be reserved for persistent/recurrent insulinoma or when other localization tests are inconclusive. 3

• 68Ga-DOTATOC/DOTATATE PET/CT demonstrates the highest sensitivity (87-96%) for pancreatic neuroendocrine tumors when conventional imaging is negative. 1

Step 4: Intraoperative Localization

Intraoperative ultrasound (IOUS) is mandatory regardless of preoperative imaging success, improving sensitivity to 92-97% for identifying small lesions. 1, 5

Critical Pitfalls to Avoid

Do not rely on somatostatin receptor scintigraphy (SSRS) for insulinoma detection, as its sensitivity is only 50-60%, significantly lower than for other pancreatic NETs. 3, 1, 5 SSRS should only be performed if octreotide or lanreotide is being considered for metastatic disease treatment. 3

Avoid measuring chromogranin A in patients on proton pump inhibitors, as these medications cause spuriously elevated levels. 3, 1 Patients must be off proton pump inhibitors for at least 1 week before testing. 3

Elevated C-peptide levels (≥0.6 ng/mL) help differentiate endogenous hyperinsulinemia from exogenous insulin administration, which is critical for accurate diagnosis. 1

Treatment Approach

Preoperative Stabilization

Stabilize glucose levels with dietary management first, followed by diazoxide as first-line medical therapy for managing hypoglycemia. 1 Everolimus can be considered as an alternative for preoperative stabilization. 1

Somatostatin analogs (octreotide, lanreotide) must be used with extreme caution or avoided entirely, as they can suppress counterregulatory hormones and precipitously worsen hypoglycemia, potentially causing fatal complications. 3, 1

Surgical Management

Surgical resection is the optimal treatment for locoregional insulinomas, with a 90% cure rate. 3, 1 Surgical options depend on tumor location:

• Enucleation for exophytic or peripheral tumors, which can be performed laparoscopically for localized tumors in the body and tail. 1
• Distal pancreatectomy with splenic preservation for body/tail tumors that cannot be enucleated. 1
• Pancreatoduodenectomy for tumors in the pancreatic head that are deep, invasive, or close to the main pancreatic duct. 1

Laparoscopic procedures are safe for selected patients and may reduce hospital stays. 1