What is the definition, symptoms, investigations, and treatment of Insulinoma?

Insulinoma: Definition, Symptoms, Investigations, and Treatment

Definition

Insulinoma is a rare pancreatic neuroendocrine tumor that causes excessive insulin secretion, leading to recurrent hypoglycemia, with 90-95% being benign and solitary. 1, 2 The tumor occurs predominantly in the pancreas with an incidence of 1-4 per 1,000 yearly in the general population, though most cases are sporadic with approximately 10% associated with Multiple Endocrine Neoplasia type 1 (MEN1) syndrome. 3, 2

Clinical Presentation

Neuroglycopenic Symptoms

• Patients present with confusion, lethargy, and seizures due to brain glucose deprivation. 1
• Symptoms characteristically occur during fasting states, particularly in the morning hours. 1
• Weight gain is common as patients eat frequently to prevent hypoglycemic episodes. 1

Timing Pattern

• Hypoglycemic episodes typically manifest during periods of fasting or increased metabolic demand. 1

Diagnostic Investigations

Biochemical Diagnosis

The supervised 48-72 hour fast is the gold standard diagnostic test, performed until hypoglycemia occurs or the time limit is reached. 1 At the termination of the fast, the following criteria must be met:

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

The elevated C-peptide is critical for differentiating endogenous hyperinsulinemia (insulinoma) from exogenous insulin administration. 1

Tumor Localization Strategy

Begin with dual-phase multidetector CT or MRI (sensitivity 57-94% and 74-94% respectively) to rule out metastatic disease and provide initial localization. 1 These cross-sectional studies are essential for surgical planning but may miss small lesions.

Endoscopic ultrasound (EUS) should be performed in all cases, as it achieves 82-93% sensitivity and allows tissue sampling via fine needle aspiration. 1 EUS is particularly valuable for detecting small tumors that cross-sectional imaging misses, especially in MEN1 or VHL syndromes. 1

68Ga-DOTATOC/DOTATATE PET/CT demonstrates the highest sensitivity (87-96%) and should be considered when conventional imaging is negative. 1 However, avoid relying on somatostatin receptor scintigraphy (SSRS) alone, as its sensitivity for insulinomas is only 50-60%, significantly lower than for other pancreatic NETs. 1, 4

For truly occult cases where all non-invasive studies are negative, selective arterial calcium stimulation with hepatic venous sampling achieves up to 90% success rate for regionalization. 1 This invasive technique localizes the tumor to specific pancreatic arterial territories. 1

Intraoperative ultrasound (IOUS) is mandatory at the time of surgery regardless of preoperative imaging results, improving sensitivity to 92-97%. 1

Critical Diagnostic Pitfall

Proton pump inhibitors can cause spuriously elevated chromogranin A levels, complicating the diagnostic workup. 1

Treatment Approach

Preoperative Stabilization

Stabilize glucose levels with dietary management (frequent small meals) as the first-line approach before any intervention. 1

Diazoxide is the first-line medical therapy for managing hypoglycemia due to hyperinsulinism. 1, 5 The FDA-approved indication specifically includes hypoglycemia due to hyperinsulinism from inoperable islet cell adenoma or carcinoma. 5 Side effects include fluid retention and hirsutism, which are common but generally not troublesome. 4

Everolimus can be considered as an alternative for preoperative stabilization. 1

Somatostatin analogs (octreotide, lanreotide) should be used with extreme caution or avoided entirely in insulinoma patients, as they can suppress counterregulatory hormones (particularly glucagon) and precipitously worsen hypoglycemia, potentially resulting in fatal complications. 1, 4 Only 50% of insulinomas express type II somatostatin receptors, and the variable effects on blood glucose make these agents unpredictable. 4

For immediate effect in acute hypoglycemia, glucose infusion and intramuscular glucagon can be administered. 4 In urgent situations, steroids may be used. 4

Surgical Management

Surgical resection is the optimal treatment for locoregional insulinomas, with a cure rate of 90%. 1, 2 The surgical approach depends on tumor location, size, and relationship to critical structures:

Enucleation

• Primary treatment for exophytic or peripheral insulinomas 1
• Can be performed laparoscopically for localized tumors within the body and tail of the pancreas 1
• Preferred when technically feasible due to lower morbidity 2

Distal Pancreatectomy

• Indicated for tumors in the body/tail that cannot be enucleated 1
• Spleen preservation should be attempted when possible 1

Pancreatoduodenectomy

• Reserved for tumors in the head of the pancreas that are deep, invasive, or close to the main pancreatic duct 1

Laparoscopic Approach

• Laparoscopic procedures are safe for selected patients and may be associated with shorter hospital stays. 1
• Laparoscopic resection for benign insulinomas is the procedure of choice, whereas formal pancreatectomy is reserved for large, potentially malignant tumors. 3

Preoperative Vaccination

Administer preoperative trivalent vaccine (pneumococcus, haemophilus influenzae b, meningococcus group c) to all patients who might require splenectomy. 1

Medical Management for Non-Surgical Candidates

Patients with life-limiting comorbidities or high surgical risk may require long-term medical management with diazoxide for effective symptom control. 1, 4 Medical treatment is available but only for patients who are unable or unwilling to undergo surgical treatment. 3

Alternative Interventions

For patients who cannot undergo surgery due to tumor adherence to large vessels or prior multiple operations, embolization using spherical polyvinyl alcohol particles can result in tumor shrinkage and improvement in hypoglycemic episodes. 6

Malignant Disease

For the 5-10% of insulinomas that are malignant, more aggressive surgical resection may be necessary, and medical management becomes more critical for symptom control. 7