eMedicine Specialties > Oncology > Carcinomas of Endocrine Organs

Insulinoma

Zonera Ashraf Ali, MD, Consulting Staff, Main Line Oncology Hematology Associates, Lankenau Cancer Center
Klaus Radebold, MD, PhD, Research Associate, Department of Surgery, Yale University School of Medicine

Updated: Nov 3, 2009

Introduction

Background

Insulinomas are the most common cause of hypoglycemia resulting from endogenous hyperinsulinism. 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%).¹

CT scan image with oral and intravenous contrast in a patient with biochemical evidence of insulinoma. The 3-cm contrast-enhancing neoplasm (arrow) is seen in the tail of the pancreas (P) posterior to the stomach (S) (Yeo, 1993).

Endoscopic ultrasonography in a patient with an insulinoma. The hypoechoic neoplasm (arrows) is seen in the body of the pancreas anterior to the splenic vein (SV) (Rosch, 1992).

In 1927, Wilder established the association between hyperinsulinism and a functional islet cell tumor.² 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.

Pathophysiology

An insulinoma is a neuroendocrine tumor, deriving mainly from pancreatic islet cells, that secretes insulin. Some insulinomas also secrete other 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.

About 90% of insulinomas are benign. Approximately 10% of insulinomas are malignant (metastases are present). Approximately 10% of patients have multiple insulinomas; of patients with multiple insulinomas, 50% have multiple endocrine neoplasia type 1 (MEN 1). Insulinomas are associated with MEN 1 in 5% of patients. On the other hand, 21% of patients with MEN 1 develop insulinomas. Because of the association of insulinomas with MEN 1, consideration should be given to screening family members of insulinoma patients for MEN 1.

Frequency

United States

Insulinomas are the most common pancreatic endocrine tumors. The incidence is 3-10 cases per million people per year.³ These make up 55% of neuroendocrine tumors, as stated in Background.

International

Exact data for international incidence of insulinomas 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.⁴ A 10-year single-institution study from Spain of 49 consecutive patients who underwent laparoscopic surgery for neuroendocrine pancreatic tumors included 23 cases of insulinoma.⁵ 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.

Race

Insulinomas have been reported in persons of all races. No racial predilection appears to exist.

Sex

The male-to-female ratio for insulinomas 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). The age range for peak incidence of insulinoma is between 30 and 60 years.

Clinical

History

• About 85% of patients present with symptoms of hypoglycemia that include 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).⁶ Symptoms may occur most frequently at night or in the early morning hours.
• 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. Because of hyperinsulinism, many patients may be overweight.
• A case report of a patient with type 2 diabetes who developed recurrent hypoglycemia was published from France.⁷
• Symptoms caused by effects of local tumor mass are very rare in insulinoma.

Physical

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

• Presence of symptoms of hypoglycemia 
• Documented low blood sugar at the time symptoms are present
• Reversal of symptoms by glucose administration.

Most patients with insulinoma have normal physical examination findings.

Causes

The genetic changes in neuroendocrine tumors are under investigation.⁸

• 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.

One study showed k -ras mutation to be present in 23% of insulinomas.

Differential Diagnoses

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).⁹ 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.¹⁰ 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.⁶

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.¹¹

Noninsulinoma pancreatogenic hypoglycemia syndrome (NIPHS) is a condition in which pancreatic islet hyperplasia is present.¹² 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

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.¹³
• 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.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, intraoperatively.²¹

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 histologic 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.

Staging

A recent TNM staging system has not been validated yet for insulinoma tumors.

Treatment

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.²³

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.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.

Consultations

Consult with the anesthetist to plan for precise preoperative and intraoperative blood glucose monitoring. The approach should be multidisciplinary, with an endocrinologist, surgeon, and anesthesiologist.

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

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.

Hyperglycemic agents

Inhibit insulin release from the tumor.

Diazoxide (Proglycem, Hyperstat)

Produces an increase in blood glucose within 1 h by inhibition of insulin release from the insulinoma.

Dosing

Adult

3-8 mg/kg/d PO divided q8h

Pediatric

Administer as in adults

Interactions

May displace other substances (coumarin, bilirubin) because it highly binds to proteins; diphenylhydantoin may lose control on seizures

Contraindications

Documented hypersensitivity; functional hypoglycemia

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Initiate only under close clinical supervision; prolonged treatment requires regular monitoring of the urine for sugar and ketones; monitor blood sugar levels for dose adjustments
The plasma half-life is prolonged in impaired renal function; the antihypertensive effect of other drugs may be enhanced; dose reduction of coumarin or its derivatives may be necessary

Diuretics

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

Hydrochlorothiazide (Microzide, HydroDIURIL, Esidrix)

Inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium and water as well as potassium and hydrogen ions.

Dosing

Adult

25-50 mg/d PO

Pediatric

1 mg/lb/d PO divided bid

Interactions

Potentiation of orthostatic hypotension may occur with alcohol, barbiturates, or narcotics; dosage adjustments of the antidiabetic drug may be required; other antihypertensive drugs may cause additive effect or potentiation; discontinue thiazides before testing parathyroid function

Contraindications

Documented hypersensitivity; anuria

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Closely observe all patients for fluid or electrolyte imbalance; hypokalemia and hypomagnesemia may develop; thiazides may decrease urinary calcium excretion

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.

Octreotide acetate (Sandostatin)

Acts similarly to the natural hormone somatostatin and can suppress secretion of gastroenteropancreatic peptides including insulin.

Dosing

Adult

200-300 mcg/d IV/SC divided bid/qid (range 150-750 mcg) during initial 2 wk; adjust dose to individual; LAR long-acting preparation can be used once/mo

Pediatric

Not established; 3-40 mcg/kg/d IV/SC has been used

Interactions

Imbalances in fluid and electrolytes or glycemic states may occur, requiring adjustment of doses; has been associated with alterations in nutrient absorption; consider its effect on any orally administered drug

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Dose adjustments may be required to control symptoms; cholelithiasis may develop; may alter insulin requirements in diabetes mellitus; absorption of dietary fats may be altered
In severe renal failure, the half-life may be increased

Antineoplastic Agents

These agents inhibit cell growth and proliferation.

Streptozocin (Zanosar)

Used in fasting hypoglycemia caused by tumor. Has high affinity for neuroendocrine cells, inhibits cell proliferation, and is cytolytic. Interferes with normal function of DNA by alkylation and protein modification.

Dosing

Adult

500 mg/m² IV for 5 d q6wk

Pediatric

Not established

Interactions

Aminoglycosides, loop diuretics and doxorubicin may increase nephrotoxicity; phenytoin may decrease effects; use with caution with steroids as can cause hyperglycemia

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Severe nausea and vomiting is common; liver dysfunction can occur; renal toxicity is dose-related and cumulative; closely monitor renal, hepatic, and hematologic function

Follow-up

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.
• Streptozocin chemotherapy may be used for cytotoxic drug control of systemic disease. This chemotherapeutic agent appears to be toxic to cells producing insulin. Short-acting somatostatin analogues may be tried to control insulin release. 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.²⁶
• 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.²⁷
  • 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.

Inpatient & Outpatient Medications

• 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-fluorouracil. 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-fluorouracil, 33% of patients show complete response, with the median survival increasing to 26 months.
  • There is a single case report of successful control of intractable hypoglycemia in an elderly man with metastatic insulinoma through the use of oral rapamycin (sirolimus), 2 mg/d.²⁸
  • Patients may develop nonfunctioning metastatic disease to the liver up to 14 years after insulinoma resection.²⁹ Note that some insulinomas are indolent (depending on the tumor biology), resulting in prolonged survival.

Miscellaneous

Medicolegal 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.

Multimedia

Media file 1: CT scan image with oral and intravenous contrast in a patient with biochemical evidence of insulinoma. The 3-cm contrast-enhancing neoplasm (arrow) is seen in the tail of the pancreas (P) posterior to the stomach (S) (Yeo, 1993).

Media file 2: Endoscopic ultrasonography in a patient with an insulinoma. The hypoechoic neoplasm (arrows) is seen in the body of the pancreas anterior to the splenic vein (SV) (Rosch, 1992).

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Keywords

insulinoma, hyperinsulinism, endogenous hyperinsulinism, islet cell adenoma, pancreatic islet cell, neuroendocrine tumor, hypoglycemia, B-cell tumor of the pancreas, adenoma of the islets of Langerhans

Contributor Information and Disclosures

Author

Zonera Ashraf Ali, MD, Consulting Staff, Main Line Oncology Hematology Associates, Lankenau Cancer Center
Zonera Ashraf Ali, MD is a member of the following medical societies: American Society of Clinical Oncology and American Society of Hematology
Disclosure: Nothing to disclose.

Coauthor(s)

Klaus Radebold, MD, PhD, Research Associate, Department of Surgery, Yale University School of Medicine
Klaus Radebold, MD, PhD is a member of the following medical societies: American Gastroenterological Association and New York Academy of Sciences
Disclosure: Nothing to disclose.

Medical Editor

Pradyumna D Phatak, MBBS, MD,, Chair, Division of Hematology and Medical Oncology, Rochester General Hospital; Clinical Professor of Oncology, Roswell Park Cancer Institute
Pradyumna D Phatak, MBBS, MD, is a member of the following medical societies: American Society of Hematology
Disclosure: Novartis Honoraria Speaking and teaching

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD, Clinical Professor of Medicine, Division of Hematology/Medical Oncology, Department of Internal Medicine, University of Arizona College of Medicine at Tucson; Consulting Staff, Arizona Cancer Center
Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research
Disclosure: GlobeImmune Salary Consulting; Amplimed Consulting fee Consulting; FibroGen Consulting fee Consulting

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