eMedicine Specialties > Oncology > Carcinomas of Endocrine Organs

Insulinoma: Differential Diagnoses & Workup

Author: Zonera Ashraf Ali, MD, Consulting Staff, Main Line Oncology Hematology Associates, Lankenau Cancer Center
Coauthor(s): Klaus Radebold, MD, PhD, Research Associate, Department of Surgery, Yale University School of Medicine
Contributor Information and Disclosures

Updated: Nov 3, 2009

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.

More on Insulinoma

Overview: Insulinoma
Differential Diagnoses & Workup: Insulinoma
Treatment & Medication: Insulinoma
Follow-up: Insulinoma
Multimedia: Insulinoma
References
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Further Reading

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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

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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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