AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Background

In 1927, Wilder established the association between hyperinsulinism and a functional islet cell tumor. In 1929, Graham achieved the first surgical cure of an islet cell adenoma. Insulinomas can be difficult to diagnose. It was not uncommon for patients to have been misdiagnosed with psychiatric illnesses or seizure disorders before insulinoma was recognized.

In a large single-center series of 125 patients with neuroendocrine tumors, insulinomas constituted the majority of cases (55%), followed by gastrinomas (36%), VIPomas (vasoactive intestinal polypeptide tumor) (5%), and glucagonomas (3%).

Insulinomas are the most common cause of hypoglycemia resulting from endogenous hyperinsulinism.

Pathophysiology

An insulinoma is a neuroendocrine tumor deriving mainly from pancreatic islet cells that produce excessive amounts of insulin. About 90% of insulinomas are benign. In healthy individuals, insulin and C-peptide are secreted in equimolar quantities because they derive from the same inactive precursor, proinsulin. Normally, less than 20% of proinsulin is released directly into the circulation.

Some insulinomas secrete additional hormones, such as gastrin, 5-hydroxyindolic acid, adrenocorticotropic hormone (ACTH), glucagon, human chorionic gonadotropin, and somatostatin. The tumor may secrete insulin in short bursts, causing wide fluctuations in blood levels.

Approximately 10% of insulinomas are malignant (metastases are present), and 10% are multiple, particularly in patients with multiple endocrine neoplasia type 1 (MEN 1). Of patients with multiple insulinomas, 50% have MEN 1. Insulinomas are associated with MEN 1 in 5% of patients. On the other hand, 21% of patients with MEN 1 develop insulinomas.

Frequency

United States

Insulinomas are the most common pancreatic endocrine tumor. The incidence is 4 cases per million people per year. These make up 55% of neuroendocrine tumors, as stated above in Background.

International

Exact data are not available. One source from Northern Ireland reported an annual incidence of 1 case per million persons. A study from Iran found 68 cases in a time span of 20 years in a university in Tehran. These reports may be an underestimate.

Mortality/Morbidity

• The postoperative morbidity rate in a recently published series was 14%, mainly due to local complications, such as fistula formation after pancreatic resections. The postoperative mortality rate in another series of 117 insulinoma patients was 7.7%.
• The median survival in metastatic disease to the liver ranges from 16-26 months.

Sex

The male-to-female ratio is 2:3.

Age

• The median age at diagnosis is about 47 years, except in insulinoma patients with MEN 1, in whom the median age is the mid 20s.
• In one series, patients with benign disease were younger (mean age of 38 y) than those with metastases (mean age of 52 y).

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

• Symptoms caused by effects of local tumor mass are very rare.
• About 85% of patients present with symptoms of hypoglycemia with diplopia, blurred vision, palpitations, or weakness.
• Other symptoms include confusion, abnormal behavior, unconsciousness, or amnesia.
• About 12% of patients have grand mal seizures.
• Adrenergic symptoms (hypoglycemia causes adrenalin release) include weakness, sweating, tachycardia, palpitations, and hunger.
• Symptoms may be present from 1 week to as long as several decades prior to the diagnosis (1 mo to 30 y, median 24 mo, as found in a large series of 59 patients).
• Hypoglycemia usually occurs several hours after a meal.
• In severe cases, symptoms may develop in the postprandial period. Symptoms can be aggravated by exercise, alcohol, hypocaloric diet, and treatment with sulfonylureas.
• Weight gain occurs in 20-40% of patients.

Physical

Insulinomas are characterized clinically by the Whipple triad (which occurred in 75% of 67 insulinoma patients as reported recently).

• Episodic hypoglycemia
• Central nervous system (CNS) dysfunction temporally related to hypoglycemia (confusion, anxiety, stupor, convulsions, coma)
• Dramatic reversal of CNS abnormalities by glucose administration

Causes

The genetic changes in neuroendocrine tumors are under investigation.

• The gene of MEN, an autosomal dominant disease, is called MEN1 and maps to band 11q13. MEN1 is thought to function as a tumor suppressor gene.
• New data suggest that the MEN1 gene also is involved in the pathogenesis of at least one third of sporadic neuroendocrine tumors.
• Researchers were able to detect loss of heterozygosity in band 11q13 in DNA samples from resected insulinoma tissue by using fluorescent microsatellite analysis.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Factitious hypoglycemia can occur in patients who have psychiatric disturbances or a need for attention and access to insulin or sulfonylurea drugs (eg, medical staff). The triad of hypoglycemia, high immunoreactive insulin levels, and suppressed plasma C-peptide immunoreactivity is pathognomonic of exogenous origin. Insulin-induced hypoglycemia can be detected by a ratio of insulin to C-peptide that is greater than 1.0.

Hypoglycemia can occur after inadvertent ingestion of sulfonylurea due to patient or pharmacist error.

Autoimmune hypoglycemia is a rare disorder caused by the interaction of endogenous antibodies with insulin or the insulin receptor. The condition is more common in Japan than in the United States or Europe. The syndrome may produce severe neuroglycopenic symptoms, making immunosuppressive therapy occasionally necessary.

Nesidioblastosis is defined as hyperplasia of the islet cells causing hyperinsulinemic hypoglycemia. It is a predominantly neonatal disorder, although cases in adults have been reported recently.

Noninsulinoma pancreatogenic hypoglycemia syndrome (NIPHS) is a condition in which pancreatic islet hyperplasia is present. This is manifested with postprandial neuroglycopenia, a negative normal fasting test, negative pancreatic imaging results, and positive intra-arterial calcium stimulation of serum insulin.

Familial persistent hyperinsulinemia is manifested with inappropriately high insulin secretions seen in families with mutations in the glucokinase enzymes, glutamate dehydrogenase and short-chain3-hydroxyacyl1-CoA dehydrogenase.

Other causes for hypoglycemia include liver disease, endocrine deficiencies, extrapancreatic insulin-producing tumors (an insulin-secreting small-cell carcinoma of the cervix recently has been described), and pentamidine-induced hypoglycemia.

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• The presence of hypoglycemia in the face of inappropriately elevated levels of insulin 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 by inducing prolonged and refractory hypoglycemia.
• Failure of endogenous insulin secretion to be suppressed in the presence of hypoglycemia is the hallmark of an insulinoma.
• 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.
• The presence of MEN 1 must be evaluated by excluding the following:
• • Hyperprolactinemia due to a pituitary adenoma
  • Hyperparathyroidism due to parathyroid hyperplasia
  • Hypergastrinemia due to a gastrinoma

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.
• • 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.
  • Thus, the extent to which one attempts to define the anatomy of the beta cell lesion before surgery is a matter of judgment.
• CT scan has 44% sensitivity.
• When performed with gadolinium, MRI has 57% sensitivity.
• 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.
• 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.

Other Tests

• Preoperative portal venous sampling is obsolete as a routine investigation because of a high complication rate (10%), but it may be used when all other imaging procedures fail and surgical exploration findings are negative.
• Localization with anti-insulin labeled with iodine 131 was achieved in 50% of patients, with a 37.5% false-positive rate. Therefore, it is not recommended.
• Recently, endoscopic ultrasound-guided fine-needle aspiration biopsy has been described in an insulinoma. It is a technique combining endoscopic ultrasonography with local tumor biopsy and may be indicated when the tissue diagnosis must be established preoperatively.
• Laparoscopic ultrasonography with eventual tumor biopsy may be used in rare cases when other localization techniques failed.

Histologic Findings

Insulinomas are solitary tumors in 90% of patients. In MEN 1 syndrome, multiple microinsulinomas and macroinsulinomas are found, although hypoglycemia may be caused by a single tumor. The tumors are distributed evenly throughout the pancreas. Tumor size does not relate to the severity of clinical symptoms. Ectopic insulinomas may be found in the ligament of Treitz.

No histological criteria are available to distinguish benign from malignant insulinomas. Malignant tumors are usually larger (average size 6.2 cm), and a third of them have metastasized to the liver. Insulinoma tumor cells contain less insulin and secretory granules than normal B cells but higher levels of proinsulin. Atypical granules, or even agranular cells, are frequent. The clinical response to diazoxide and somatostatin correlates with the frequency and type of granules.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

• 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.
• • 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.

Surgical Care

Because 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.
• Successful tumor location
• • Fully expose the pancreas, including a wide Kocher maneuver to allow complete bimanual palpation.
  • Laparoscopic enucleation techniques, also in combination with preservation of the spleen for distal pancreatic tumors, have been described recently.
  • Simple enucleation is the procedure of choice in insulinomas in the pancreatic head.
  • 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.
• Tumor not localized at surgery (10% of patients)
• • 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.
• Intraoperative serum insulin measurements recently have been employed to assure complete tumor removal. This may be important, particularly in patients with MEN 1 who harbor multiple insulinomas.

Consultations

Consult with the anesthetist to plan for precise preoperative and intraoperative blood glucose monitoring.

Diet

• Because most tumors are not responsive to glucose, carbohydrate feedings every 2-3 hours can help maintain euglycemia, although obesity may develop.
• Glucagon should be available for emergency use.

Activity

Exercise may aggravate hypoglycemia in patients with insulinoma.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Diazoxide is the drug of choice because it inhibits insulin release from the tumor. Adverse effects must be treated with hydrochlorothiazide. In patients not responsive to or intolerant of diazoxide (10%), somatostatin may be indicated to prevent hypoglycemia.

Drug Category: Hyperglycemic agents

Inhibit insulin release from the tumor.

Drug Category: Diuretics

Used to counteract edema and hyperkalemia secondary to diazoxide and to potentiate its hyperglycemic effect.

Drug Category: Somatostatin analogs

May control symptoms by suppressing secretion of gastroenteropancreatic peptides including insulin. High-dose treatment also may lead to additional antiproliferative effects. However, long-term application of somatostatin may down-regulate receptor expression levels, resulting in decreased efficiency despite increasing doses. Both short- and long-acting depot preparations are available.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• After insulinoma resection, hyperglycemia may persist for 48-72 hours because of chronic down-regulation of insulin-receptors by the following:
• • Previously high circulating insulin levels secreted by the tumor
  • Suppression of normal pancreatic B cells
• Small subcutaneous doses of insulin every 3-6 hours may be necessary if plasma glucose level exceeds 300 mg/dL (16.7 mmol/L).
• Patients with major pancreatic resections may develop diabetes mellitus.
• In patients with unresectable metastatic disease to the liver, when systemic chemotherapy was unsuccessful, embolization of the hepatic artery and intraarterial chemotherapy may be indicated to control symptoms and hormone release, to inhibit tumor growth, and to improve survival.
• For insulinomas, some cases of sustained improvement in hypoglycemic attacks have been reported, particularly when streptozotocin has been used.
• New therapy is currently under investigation.
• • OctreoTher consists of a somatostatin peptide analogue, labeled with a beta-emitter (yttrium-90). By targeting somatostatin-receptor–positive tumors (imaged by scan), it may deliver a local tumoricidal dose of radiation.
  • OctreoTher binds to somatostatin receptor 2 and 3, has a mean path length of 5 mm, and a physical half-life of 64.1 hours.

In/Out Patient Meds

• Continue diazoxide and hydrochlorothiazide in patients who are not fit for surgery or when tumor resection was unsuccessful.

Transfer

• In advanced metastatic disease, the indications for chemotherapy or other interventional treatments must be emphasized in a multidisciplinary way and discussed with surgeons, specialists in chemoembolization, gastroenterologists, endocrinologists, and medical oncologists.

Complications

• Surgical complications (eg, pancreatic leakage) occur in about 14% of patients.
• Pseudocysts
• • Pancreatitis
  • Abscess
• Other complications
• • Intestinal obstruction
  • Pleural effusion
  • Hemorrhage
  • Fistula formation
• Permanent diabetes mellitus may occur in about 5% of patients, mainly in those with major pancreatic resections.

Prognosis

• Approximately 90-95% of insulinomas are benign. Long-term cure with complete resolution of preoperative symptoms is expected after complete resection.
• Recurrence of benign insulinomas was observed in 5.4% of patients in a series of 120 patients over a period of 4-17 years. The same diagnostic and therapeutic approach was recommended, including surgical exploration and tumor resection.
• Indications for chemotherapy include progressive disease with an increase of greater than 25% of the main tumor masses in a follow-up period of 12 months, or tumor symptoms not treatable with other methods. Polychemotherapies have achieved better results than monochemotherapies.
• • The current medical treatment is based primarily on streptozotocin in combination with doxorubicin or 5-fluoruoracil. Streptozotocin alone may achieve partial response in 50% of patients and complete response in 20%. The median survival in one study was 16 months.
  • If streptozotocin is combined with 5-fluoruoracil, 33% of patients show complete response, with the median survival increasing to 26 months.
  • Patients may develop nonfunctioning metastatic disease to the liver up to 14 years after insulinoma resection. Note that some insulinomas are indolent (depending on the tumor biology), resulting in prolonged survival.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Monitor blood glucose levels carefully during surgery, especially when the insulinoma is being palpated and manipulated.
• Exclude factitious hypoglycemia before surgery, particularly in patients from the medical profession.
• Screen for MEN 1. When results are positive, the hypercalcemia must be corrected before abdominal surgery is performed.

Special Concerns

• In patients with insulinoma and MEN 1 syndrome, family members must be screened for the syndrome.
• A genetic test has not been developed yet but may be available in the near future.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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• Boukhman MP, Karam JM, Shaver J, et al. Localization of insulinomas. Arch Surg. Aug 1999;134(8):818-22; discussion 822-3. [Medline].
• Dexter SP, Martin IG, Leindler L, et al. Laparoscopic enucleation of a solitary pancreatic insulinoma. Surg Endosc. Apr 1999;13(4):406-8. [Medline].
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• Kuzin NM, Egorov AV, Kondrashin SA, et al. Preoperative and intraoperative topographic diagnosis of insulinomas. World J Surg. Jun 1998;22(6):593-7; discussion 597-8. [Medline].
• Larijani B, Aghakhani S, Lor SS, et al. Insulinoma in Iran: a 20-year review. Ann Saudi Med. Nov-Dec 2005;25(6):477-80.
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• Molven A, Matre GE, Duran M, et al. Familial hyperinsulinemic hypoglycemia caused by a defect in the SCHAD enzyme of mitochondrial fatty acid oxidation. Diabetes. Jan 2004;53(1):221-7.
• Moscetti L, Saltarelli R, Giuliani R, et al. Intra-arterial liver chemotherapy and hormone therapy in malignant insulinoma: case report and review of the literature. Tumori. Nov-Dec 2000;86(6):475-9. [Medline].
• Phan GQ, Yeo CJ, Hruban RH, et al. Surgical experience with pancreatic and peripancreatic neuroendocrine tumors: review of 125 patients. J Gastrointest Surg. Sep-Oct 1998;2(5):472-82. [Medline].
• Proye C, Malvaux P, Pattou F, et al. Noninvasive imaging of insulinomas and gastrinomas with endoscopic ultrasonography and somatostatin receptor scintigraphy. Surgery. Dec 1998;124(6):1134-43; discussion 1143-4. [Medline].
• Redmon JB, Nuttall FQ. Autoimmune hypoglycemia. Endocrinol Metab Clin North Am. Sep 1999;28(3):603-18, vii. [Medline].
• Rougier P, Mitry E. Chemotherapy in the treatment of neuroendocrine malignant tumors. Digestion. 2000;62 Suppl 1:73-8. [Medline].
• Ruszniewski P, Malka D. Hepatic arterial chemoembolization in the management of advanced digestive endocrine tumors. Digestion. 2000;62 Suppl 1:79-83. [Medline].
• Smith MC, Liu J, Chen T, et al. OctreoTher: ongoing early clinical development of a somatostatin- receptor-targeted radionuclide antineoplastic therapy. Digestion. 2000;62 Suppl 1:69-72. [Medline].
• Starke A, Saddig C, Kirch B, et al. Islet hyperplasia in adults: challenge to preoperatively diagnose non-insulinoma pancreatogenic hypoglycemia syndrome. World J Surg. May 2006;30(5):670-9.
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Article Last Updated: Jul 25, 2006