Insulinoma
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.
Previous
Next Section: Pathophysiology
Epidemiology

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.
  
• 
  

Insulinoma Clinical Presentation

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.
Previous
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.
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
    
  
  </li>
  
• 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.
    
  
  </li>
  
• 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
    
  </li>
  

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.
    
  
  </li>
  
• 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.
Previous
Next Section: Imaging Studies

Staging

A recent TNM staging system has not been validated yet for insulinoma tumors.
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.
    
  
  </li>
  
• 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]
    
  
  </li>
  
• 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.
    
  
  </li>
  
• 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%).
    
  
  </li>
  
• 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
    
  </li>
  

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 Summary

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.
Next
Hyperglycemic agents

Class Summary

Inhibit insulin release from the tumor.View full drug information
Diazoxide (Proglycem, Hyperstat)

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

Diuretics

Class Summary

Used to counteract edema and hyperkalemia secondary to diazoxide and to potentiate its hyperglycemic effect.View full drug information
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.
Somatostatin analogs

Class Summary

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. View full drug information
Octreotide acetate (Sandostatin)

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

Class Summary

These agents inhibit cell growth and proliferation.View full drug information
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.

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
    
  
  </li>
  
• 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.
    
  </li>