Insulinoma

Background

• An insulinoma is a rare, functioning pancreatic neuroendocrine tumor that secretes insulin, resulting in a syndrome of hypoglycemia, especially while fasting or during exercise.
• Most insulinomas are sporadic but about 5%-10% are reported to be associated with multiple endocrine neoplasia type 1 (MEN1).
• Most insulinomas are solitary tumors (reported in about 90% of cases); however, patients with MEN1 are more likely to have multiple tumors.
• Fewer than 10% of insulinomas are reported to be malignant.

Evaluation

• Suspect insulinoma in patients without alternate explanations for hypoglycemia, such as insulin and sulfonylureas use, who present with hypoglycemia, specifically evaluating for the presence of the pathognomic Whipple triad which includes all of the following:
  • signs and symptoms suggestive of hypoglycemia
  • plasma glucose levels < 54 mg/dL (3 mmol/L) measured at the time of symptoms
  • symptom resolution following administration of glucose and correction of hypoglycemia
• In patients who present with the Whipple triad, the gold standard for diagnosis of insulinoma is the 72-hour fasting test (reported to diagnose > 95% of patients with insulinoma).
  • A definitive diagnosis of insulinoma can be made in patients with positive results on the 72-hour fasting test, defined as:
    • plasma glucose levels < 45 mg/dL (2.5 mmol/L) with signs or symptoms of hypoglycemia
    • plasma glucose levels < 54 mg/dL (3 mmol/L) without signs or symptoms of hypoglycemia if Whipple triad has been previously documented
  • Some patients may be diagnosable without a formal fast if spontaneous hypoglycemia can be documented on outpatient laboratory testing.
• Perform blood tests to confirm a diagnosis of inappropriate endogenous hyperinsulinemia (such as due to insulinoma) in patients with signs and symptoms of hypoglycemia.
  • Blood tests will show significant hypoglycemia without appropriate suppression in physiological insulin secretion.
  • If this cannot be captured spontaneously in the outpatient setting, blood tests are performed as part of the 72-hour fasting test to diagnose suspected insulinoma.
  • Blood test findings in patients with insulinoma include all of the following:
    • documented blood glucose levels < 55 mg/dL (3 mmol/L)
    • insulin levels ≥ 3 microunits/mL (18 pmol/L) when blood sugar is low
    • C-peptide levels ≥ 0.6 ng/mL (0.2 nmol/L)
    • proinsulin levels ≥ 5 pmol/L
    • negative sulfonylurea screening test in plasma and/or urine
    • beta-hydroxybutyrate levels ≤ 2.7 mmol/L (rarely, some patients with insulinoma may have beta-hydroxybutyrate levels > 2.7 mmol/L, especially if they have had previous partial pancreatectomy and are being evaluated for recurrence)
• Perform preoperative imaging studies in all patients with pancreatic neuroendocrine tumors (including suspected insulinoma) to localize the tumor within the pancreas.
  • Noninvasive techniques are typically used for initial imaging in patients with insulinoma, including any of the following:
    • three-phase contrast-enhanced computed tomography (CT) scan of the abdomen (most commonly used imaging method)
    • magnetic resonance imaging (MRI) (less widely available than CT but can detect smaller tumors)
    • transabdominal ultrasound (widely available but less sensitive than CT or MRI)
  • Endoscopic ultrasound is reported to have the highest diagnostic accuracy for insulinomas and can be used if unclear results with noninvasive techniques.
• Consider endoscopic ultrasound-guided fine needle aspiration biopsy in select patients with suspected insulinoma and unclear results on 72-hour fasting test and/or imaging studies.
• If the tumor cannot be located preoperative, bi-digital palpation of the pancreas during surgical exploration can localize the tumor in most patients. Selective arterial calcium stimulation test (SACST) can also be performed.
• Malignancy of insulinomas is diagnosed not with histology but by evidence of invasion of surrounding organs or presence of metastases.

Management

• Advise patients with insulinoma that dietary adjustments are necessary to help prevent hypoglycemia associated with prolonged periods of fasting. Examples include:
  • eating small meals frequently throughout the day, late at night (before bedtime), and early morning, such as 3:00 am if necessary
  • consuming carbohydrates that are slowly absorbed throughout the day, such as complex starches, whole grain bread, skin-on potatoes, and brown rice
  • consuming carbohydrates that are rapidly absorbed during hypoglycemic episodes, such as fruit juices with the addition of additional glucose or sucrose if need to ensure rapid return to normoglycemia
• Perform surgery for all patients in whom the tumor can be localized and without contraindications. Surgery is the only potentially curative treatment for patients with insulinoma.
  • Contraindications to surgery may include severe comorbidities, high anesthetic risk, older age, or nonresectable recurrent disease after initial surgery.
  • Surgery can be performed via laparoscopic or open techniques.
    • Laparoscopic surgery is preferred for patients with a single, non-malignant insulinoma that has been localized via imaging studies. In most cases, enucleation of the insulinoma is sufficient in these patients, while others will require more extensive resection.
    • Open surgery is typically preferred for patients with malignancy or insulinoma associated with multiple endocrine neoplasia type 1 (MEN 1) due to the increased likelihood of multiple tumors, especially if tumors have not been localized via imaging studies.
      • During open surgery, the pancreas can be fully examined and bi-digitally palpated, which is reported to localize up to 70% of insulinomas.
      • Findings associated with malignancy during surgical exploration include hard tumors, infiltration and puckering of surrounding tissue, and/or pancreatic duct dilatation.
• Medications are often necessary to help control hypoglycemic symptoms and tumor growth prior to surgery, in patients with metastatic disease, and in patients who are not eligible for surgery.
  • Diazoxide is a nondiuretic benzothiazide analog that is often used in patients with insulinoma to control glucose and symptoms of hypoglycemia.
    • The typical dose is 50-300 mg/day orally, which can be increased up to 600 mg/day. In patients with malignant insulinomas, higher doses may be used if tolerated.
    • Adverse effects include edema (particularly at higher doses), weight gain, nausea, renal impairment, and hirsutism.
    • Patients taking diazoxide may require addition of a diuretic (such as hydrochlorothiazide) to manage edema and sodium retention.
  • Somatostatin analogues (SSAs) suppress insulin and the release of glucagon via activation of somatostatin receptor 2 (SSTR), and can be used as:
    • first-line treatment in patients with malignant insulinomas (due to their antiproliferative effect)
    • second-line treatment in patients with insulinoma and symptoms refractory to diazoxide
• Additional considerations for management of metastatic disease:
  • In patients with malignant insulinomas, surgery is rarely curative and management often requires long-term antihormonal and antitumor medications for control of symptoms and tumor growth.
  • Chemotherapy, in addition to medications for glucose and tumor control and surgery for tumor removal when possible, is indicated in patients with malignant insulinomas, especially those with a high tumor grade.
  • Molecular targeted chemotherapy (such as everolimus or sunitinib) can be used in patients with inoperable metastatic insulinomas refractory to traditional chemotherapy, or as an alternative to locoregional therapies and traditional chemotherapy.
  • Peptide receptors radionuclide therapy (PRRT) has been used for metastatic gastroenteropancreatic neuroendocrine tumors, including those with distant metastasis, and may help control hypoglycemia in some patients with insulinoma.