What is an insulinoma?
Insulinoma is a tumor of the pancreas that produces excessive amounts of insulin. Insulinomas are more common in women. The tumors are usually small (less than 2cm) and more than 90% of all insulinomas are benign (non-cancerous).
Insulinomas produce excessive amounts of insulin and this causes low blood sugar. The typical symptoms that patients complain about are related to the development of low bloods sugar and include tiredness, weakness, tremulous and hunger. Many patients have to eat frequently to prevent symptoms from the low blood sugar. Some patients may develop psychiatric symptoms because of the low blood sugar.
Workup
Laboratory Studies
- Failure of endogenous insulin secretion to be suppressed by hypoglycemia is the hallmark of an insulinoma. Thus, the finding of inappropriately elevated levels of insulin in the face of hypoglycemia is the key to diagnosis. Considering the reference range, the fasting plasma levels of insulin, C-peptide, and, to a lesser degree, proinsulin need not be elevated in insulinoma patients in absolute terms.
- The biochemical diagnosis is established in 95% of patients during prolonged fasting (up to 72 h) when the following parameters are found:
- Serum insulin levels of 10 µU/mL or more (normal <6 µU/mL)
- Glucose levels of less than 40 mg/dL
- C-peptide levels exceeding 2.5 ng/mL (normal <2 ng/mL)
- Proinsulin levels greater than 25% (or up to 90%) that of immunoreactive insulin
- Screening for sulfonylurea negative
- Stimulation tests no longer are recommended. The intravenous application of tolbutamide, glucagon, or calcium can be hazardous, as they may induce prolonged and refractory hypoglycemia.
- Prolonged (ie, 72 h) supervised fast in hospitalized patients provides the most reliable results.
- The calculation of ratios of insulin (µU/mL) to plasma glucose (mg/dL) is diagnostic.
- Healthy patients maintain a rate of less than 0.25. Obese patients may have a slightly higher rate.
- In patients with insulinoma, the ratio rises during fasting.
- In a study from the Netherlands, a positive Whipple triad on a prolonged fasting test, in combination with an insulin/C-peptide ratio <1, had a sensitivity of 88.9% and a specificity of 100% for the diagnosis of insulinoma.
Imaging Studies
- Start imaging studies only after the diagnosis has been confirmed biochemically, because 80% of insulinomas are less than 2 cm in size and may not be visible by CT scan or transabdominal ultrasonography.
- Successful preoperative tumor localization is achieved in about 60% of patients.14
- Some experienced surgeons perform only transabdominal ultrasound preoperatively.
- Other surgeons argue that the preoperative localization of insulinomas is not necessary at all because surgical exploration and intraoperative ultrasonography identify more than 90% of tumors.15
- Thus, the extent to which one attempts to define the anatomy of the beta cell lesion before surgery is a matter of judgment.
- Helical or multislice CT scan has 82-94% sensitivity. In one study, dual-phase helical CT proved more sensitive than single-phase for detection of insulinoma; in addition, image acquisition in the arterial phase proved more helpful than acquisition during the portal-venous phase.16
- MRI with gadolinium can be helpful in detecting a tumor in 85% of cases. One case report suggests that diffusion-weighted MRI can be useful for detecting and localizing small insulinomas, especially for those with no hypervascular pattern.17
- The accuracy of selective arteriography is 82%, although affected by a false-positive rate of 5%. Many experts see it as the best overall preoperative localization procedure.
- Arteriography with catheterization of small arterial branches of the celiac system combined with calcium injections (which stimulate insulin release from neoplastic tissue but not from normal islets), and simultaneous measurements of hepatic vein insulin during each selective calcium injection localizes tumors in 47% of patients.
- The sensitivity of somatostatin receptor scintigraphy is 60%, although many insulinomas lack somatostatin receptor subtype 2 for successful identification.
- Endoscopic ultrasonography detects 77% of insulinomas in the pancreas.18,19,20 The yield can be higher if it is done in combination with CT scan. A majority of sporadic insulinomas will be detected and localized by a combination of these two investigative means.
- Real-time transabdominal high-resolution ultrasonography has 50% sensitivity.
- Intraoperative transabdominal high-resolution ultrasonography with the transducer wrapped in a sterile rubber glove and passed over the exposed pancreatic surface detects more than 90% of insulinomas.
- Performing a preoperative study to localize the tumor followed by intraoperative ultrasonography and a physical examination is not unreasonable.
- Insulinomas have been shown to have a very high density of glucagon-like peptide-1 receptors (GLP-1R), and radiolabeling with an111 In-labeled GLP-1R agonist (111 In-DOTA-exendin-4) has successfully been used to localize small insulinomas both preoperatively and, with the use of a gamma probe, intraoperativel
Surgical Care
Because in Insulinoma resection achieves cure in 90% of patients, it is currently the therapy of choice.- Preoperative management
- Administer diazoxide on the day of surgery in patients who respond to it. Diazoxide reduces the need for glucose supplements and the risk of hypoglycemia.
- Monitor blood glucose level throughout surgery.
- Infuse 10% dextrose in water at a rate of at least 100 mL/h.
- A preoperative trial with diazoxide is indicated to determine whether the patient is a responder. (Five to 10% of patients do not respond.) This information helps determine the intraoperative strategy if the tumor is not localized.
- In MEN 1, hypercalcemia must be corrected first by parathyroidectomy before insulinoma resection.24
- Successful tumor location
- Fully expose the pancreas, including a wide Kocher maneuver to allow complete bimanual palpation.
- A large study from Spain showed laparoscopic surgery to be safe and effective in benign and malignant tumor resection. It led to a shorter hospital stay compared to open resection.5
- Laparoscopic enucleation techniques, also in combination with preservation of the spleen for distal pancreatic tumors, have been described recently.25
- Because of the small likelihood that a tumor that presents without metastatic spread is malignant, insulinomas may be removed by enucleation. Care should be taken to achieve total tumor capsule removal to prevent tumor recurrence. If enucleation is not possible, a larger pancreatic resection including pancreaticoduodenectomy may be necessary. This should only rarely be required. When metastatic insulinoma is found on a patient's initial presentation, the organ spread is to liver and sometimes to bone.
- Avoid total pancreatectomy because of its high morbidity and mortality rates.
- Major resections, such as the Whipple procedure, may become necessary when the tumor is found in the pancreatic head and local excision is not possible.
- Resect all gross disease when multiple tumors or metastases are present.
- If insulinoma is associated with MEN 1, the management strategy is modified because tumors are often multiple, diffusely spread in the pancreas, and of small size. Definite cure by surgery is rare.
- Subtotal pancreatectomy with enucleation of tumors from the pancreatic head and uncinate processus often is recommended over simple enucleation because of frequent multiple tumors in MEN 1.
- Intraoperative serum insulin measurements recently have been employed to ensure complete tumor removal. This may be important, particularly in patients with MEN 1 who harbor multiple insulinomas.
- Tumor is found to be metastatic at surgery in about 5-10% of patients. It would be extremely uncommon for metastases to develop in a case in which only a solitary lesion was found on initial presentation.
- If the patient is responsive to diazoxide, continue it, while more invasive imaging studies are performed before repetitive surgery is considered.
- If the patient is not responsive (5-10%) or if drug intolerance is present and ectopic disease is excluded, a blind distal two-thirds pancreatectomy may be performed. (This procedure has only a 25% success rate.)
- Most authorities recommend serial sectioning during resection.
- Tumors that are not found at surgery normally are located in the pancreatic head (54%), body (20%), and tail (14%).
- Metastatic disease found
- Even when metastases are found, surgical excision is often feasible before any medical, chemotherapeutic, or other interventional therapy is considered.
- Resect all gross disease, including wedge resections of hepatic metastases.
- Avoid ligation of the hepatic artery in case further regional infusion therapy becomes necessary.
What is an insulinoma?
Insulinoma is a tumor of the pancreas that produces excessive amounts of insulin. Insulinomas are more common in women. The tumors are usually small (less than 2cm) and more than 90% of all insulinomas are benign (non-cancerous).
Insulinomas produce excessive amounts of insulin and this causes low blood sugar. The typical symptoms that patients complain about are related to the development of low bloods sugar and include tiredness, weakness, tremulous and hunger. Many patients have to eat frequently to prevent symptoms from the low blood sugar. Some patients may develop psychiatric symptoms because of the low blood sugar.
Workup
Laboratory Studies
- Failure of endogenous insulin secretion to be suppressed by hypoglycemia is the hallmark of an insulinoma. Thus, the finding of inappropriately elevated levels of insulin in the face of hypoglycemia is the key to diagnosis. Considering the reference range, the fasting plasma levels of insulin, C-peptide, and, to a lesser degree, proinsulin need not be elevated in insulinoma patients in absolute terms.
- The biochemical diagnosis is established in 95% of patients during prolonged fasting (up to 72 h) when the following parameters are found:
- Serum insulin levels of 10 µU/mL or more (normal <6 µU/mL)
- Glucose levels of less than 40 mg/dL
- C-peptide levels exceeding 2.5 ng/mL (normal <2 ng/mL)
- Proinsulin levels greater than 25% (or up to 90%) that of immunoreactive insulin
- Screening for sulfonylurea negative
- Stimulation tests no longer are recommended. The intravenous application of tolbutamide, glucagon, or calcium can be hazardous, as they may induce prolonged and refractory hypoglycemia.
- Prolonged (ie, 72 h) supervised fast in hospitalized patients provides the most reliable results.
- The calculation of ratios of insulin (µU/mL) to plasma glucose (mg/dL) is diagnostic.
- Healthy patients maintain a rate of less than 0.25. Obese patients may have a slightly higher rate.
- In patients with insulinoma, the ratio rises during fasting.
- In a study from the Netherlands, a positive Whipple triad on a prolonged fasting test, in combination with an insulin/C-peptide ratio <1, had a sensitivity of 88.9% and a specificity of 100% for the diagnosis of insulinoma.
Imaging Studies
- Start imaging studies only after the diagnosis has been confirmed biochemically, because 80% of insulinomas are less than 2 cm in size and may not be visible by CT scan or transabdominal ultrasonography.
- Successful preoperative tumor localization is achieved in about 60% of patients.14
- Some experienced surgeons perform only transabdominal ultrasound preoperatively.
- Other surgeons argue that the preoperative localization of insulinomas is not necessary at all because surgical exploration and intraoperative ultrasonography identify more than 90% of tumors.15
- Thus, the extent to which one attempts to define the anatomy of the beta cell lesion before surgery is a matter of judgment.
- Helical or multislice CT scan has 82-94% sensitivity. In one study, dual-phase helical CT proved more sensitive than single-phase for detection of insulinoma; in addition, image acquisition in the arterial phase proved more helpful than acquisition during the portal-venous phase.16
- MRI with gadolinium can be helpful in detecting a tumor in 85% of cases. One case report suggests that diffusion-weighted MRI can be useful for detecting and localizing small insulinomas, especially for those with no hypervascular pattern.17
- The accuracy of selective arteriography is 82%, although affected by a false-positive rate of 5%. Many experts see it as the best overall preoperative localization procedure.
- Arteriography with catheterization of small arterial branches of the celiac system combined with calcium injections (which stimulate insulin release from neoplastic tissue but not from normal islets), and simultaneous measurements of hepatic vein insulin during each selective calcium injection localizes tumors in 47% of patients.
- The sensitivity of somatostatin receptor scintigraphy is 60%, although many insulinomas lack somatostatin receptor subtype 2 for successful identification.
- Endoscopic ultrasonography detects 77% of insulinomas in the pancreas.18,19,20 The yield can be higher if it is done in combination with CT scan. A majority of sporadic insulinomas will be detected and localized by a combination of these two investigative means.
- Real-time transabdominal high-resolution ultrasonography has 50% sensitivity.
- Intraoperative transabdominal high-resolution ultrasonography with the transducer wrapped in a sterile rubber glove and passed over the exposed pancreatic surface detects more than 90% of insulinomas.
- Performing a preoperative study to localize the tumor followed by intraoperative ultrasonography and a physical examination is not unreasonable.
- Insulinomas have been shown to have a very high density of glucagon-like peptide-1 receptors (GLP-1R), and radiolabeling with an111 In-labeled GLP-1R agonist (111 In-DOTA-exendin-4) has successfully been used to localize small insulinomas both preoperatively and, with the use of a gamma probe, intraoperativel
- Administer diazoxide on the day of surgery in patients who respond to it. Diazoxide reduces the need for glucose supplements and the risk of hypoglycemia.
- Monitor blood glucose level throughout surgery.
- Infuse 10% dextrose in water at a rate of at least 100 mL/h.
- A preoperative trial with diazoxide is indicated to determine whether the patient is a responder. (Five to 10% of patients do not respond.) This information helps determine the intraoperative strategy if the tumor is not localized.
- In MEN 1, hypercalcemia must be corrected first by parathyroidectomy before insulinoma resection.24
- Fully expose the pancreas, including a wide Kocher maneuver to allow complete bimanual palpation.
- A large study from Spain showed laparoscopic surgery to be safe and effective in benign and malignant tumor resection. It led to a shorter hospital stay compared to open resection.5
- Laparoscopic enucleation techniques, also in combination with preservation of the spleen for distal pancreatic tumors, have been described recently.25
- Because of the small likelihood that a tumor that presents without metastatic spread is malignant, insulinomas may be removed by enucleation. Care should be taken to achieve total tumor capsule removal to prevent tumor recurrence. If enucleation is not possible, a larger pancreatic resection including pancreaticoduodenectomy may be necessary. This should only rarely be required. When metastatic insulinoma is found on a patient's initial presentation, the organ spread is to liver and sometimes to bone.
- Avoid total pancreatectomy because of its high morbidity and mortality rates.
- Major resections, such as the Whipple procedure, may become necessary when the tumor is found in the pancreatic head and local excision is not possible.
- Resect all gross disease when multiple tumors or metastases are present.
- If insulinoma is associated with MEN 1, the management strategy is modified because tumors are often multiple, diffusely spread in the pancreas, and of small size. Definite cure by surgery is rare.
- Subtotal pancreatectomy with enucleation of tumors from the pancreatic head and uncinate processus often is recommended over simple enucleation because of frequent multiple tumors in MEN 1.
- Intraoperative serum insulin measurements recently have been employed to ensure complete tumor removal. This may be important, particularly in patients with MEN 1 who harbor multiple insulinomas.
- If the patient is responsive to diazoxide, continue it, while more invasive imaging studies are performed before repetitive surgery is considered.
- If the patient is not responsive (5-10%) or if drug intolerance is present and ectopic disease is excluded, a blind distal two-thirds pancreatectomy may be performed. (This procedure has only a 25% success rate.)
- Most authorities recommend serial sectioning during resection.
- Tumors that are not found at surgery normally are located in the pancreatic head (54%), body (20%), and tail (14%).
- Even when metastases are found, surgical excision is often feasible before any medical, chemotherapeutic, or other interventional therapy is considered.
- Resect all gross disease, including wedge resections of hepatic metastases.
- Avoid ligation of the hepatic artery in case further regional infusion therapy becomes necessary.
Medical Care
Medical therapy is indicated in patients with malignant insulinomas and in those who will not or cannot undergo surgery. These measures are designed to prevent hypoglycemia and, in patients with malignant tumors, to reduce the tumor burden. In malignant insulinomas, dietary therapy with frequent oral feedings or enteral feedings may control mild symptoms of hypoglycemia. A trial of glucagon may be attempted to control hypoglycemia.
- Diazoxide is related to the thiazide diuretics and reduces insulin secretion. Adverse effects include sodium retention, a tendency to congestive cardiac failure, and hirsutism.
- Prescribe hydrochlorothiazide to counteract the edema and hyperkalemia secondary to diazoxide and to potentate its hyperglycemic effect.
- Of patients with insulinoma, 50% may benefit from the somatostatin analogue octreotide to prevent hypoglycemia.22
- The effect of the therapy depends on the presence of somatostatin receptor subtype 2 on insulinoma tumor cells.
- As studies have shown, an OctreoScan is not a prerequisite before starting octreotide treatment. In patients with insulinoma and a negative scan finding, somatostatin decreased insulin levels significantly and lowered the incidence of hypoglycemic events.
- CT-guided radiofrequency ablation has been used successfully to treat insulinoma in an elderly patient whose hypoglycemia that was refractory to diazoxide, and who was not a candidate for surgery because of comorbidities and poor physical condition.
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