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Ana Emiliano, M.D. and Douglas Ball, M.D.
05-05-2010
- A neuroendocrine tumor of the pancreas which secretes insulin autonomously
- Unregulated insulin secretion leads to decreased hepatic glucose output and hypoglycemia (Rizza)
- A cause of endogenous hyperinsulinemic hypoglycemia
- Rare tumors, incidence of 4 per 1 million persons per year
- Most commonly solitary, benign and encapsulated (approximately 87% of the time)
- May originate anywhere in the pancreas, but rarely outside the pancreas unless metastatic
- 10% are malignant, a definition based on the presence of metastasis, found predominantly in liver and lymph nodes, sometimes bone and peritoneal tissue
- In a 20-year cohort at the Mayo Clinic, the median age at diagnosis for all insulinomas was 50, with a range of 17-89 years. (Placzkowski)
- Found in all ethnic groups
- Sporadic in more than 90% of cases
- Familial in 6-10% of cases, as part of multiple endocrine neoplasia type 1 (MEN-1) or Von-Hippel Lindau syndrome (VHL)
- MEN-1 is an autosomal dominant syndrome characterized by primary hyperparathyroidism, anterior pituitary adenomas and gastroenteropancreatic neuroendocrine tumors. Insulinomas occur in ~ 10% of MEN-1 patients, being the most commonly diagnosed gastroenteropancreatic neuroendocrine tumor in MEN-1, along with gastrinomas. >90% insulinomas benign, but more frequently multiple than in sporadic cases
- VHL is an autosomal dominant syndrome including CNS and retinal tumors, pheochromocytoma, islet cell tumors and renal cell carcinoma. VHL-associated insulinomas are frequently malignant.
- Document "Whipple's triad": neuroglycopenic symptoms with documented plasma glucose (PG) <60 mg/dL and symptom resolution with correction of hypoglycemia
- Requires biochemical demonstration of inappropriately high plasma insulin concentrations (>3 uU/mL) during hypoglycemia (PG <60 mg/dl) (Cryer). Sometimes represented as PG (mg/dl)/Insulin (uU/ml) >20
- In addition, an elevated plasma C-peptide level (>0.6 ng/mL), elevated plasma pro-insulin level ( >5 pmol/L) and a low plasma betahydroxybutyrate level (<2.7 mmol/L) occurring concomitantly with the hypoglycemia suggest endogenous hyperinsulinemia. (Cryer)
- Without outpatient documentation of hyperinsulinemic hypoglycemia, a 72-hour supervised fast is recommended (See Table below for specific instructions). >97% of all patients with insulinoma develop hypoglycemia and neuroglycopenic symptoms within 48-72 hours of a supervised fast (Hirschberg)
- Exclude factitious hypoglycemia: screen urine for sulfonylureas. Measure plasma C-peptide: if suppressed in the setting of increased insulin and hypoglycemia, this suggests exogenous insulin administration.
- Other causes of hyperinsulinemic hypoglycemia: hyperinsulinism of infancy, dumping syndrome and insulin autoimmune syndrome, among others.
- Having established clinical and biochemical confirmation of likely insulinoma, localization of the pancreatic tumor is done using ultrasound, CT or interventional radiology.
- Transabdominal ultrasound and CT of the abdomen has a rate of detection of approximately 70% (Mathur, Boukhman).
- Endoscopic ultrasound has variable sensitivity, 40-93%, depending on the operator (Anderson, Nikfarjam).
- Selective arterial calcium stimulation test with hepatic venous sampling (relies on calcium as secretagogue for insulin from tumor) has sensitivity of 80-94% (Guettier, Mathur).
- Most patients with insulinoma present clinically with fasting hypoglycemia (<70 mg/dl) (Service).
- About 6% of insulinomas, usually males, present with postprandial hypoglycemia (Placzkowski).
- About 20% of insulinomas present with both fasting and postprandial hypoglycemia.
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Hypoglycemia frequently manifests with neuroglycopenic as well as sympathoadrenergic symptoms.
- Metastatic disease, especially to liver, can cause severe, intractable hypoglycemia.
- Hyperphagia with weight gain can occur in patients with insulinoma (Nikfarjam).
- In estimated 20% of patients with insulinoma, symptoms are misattributed to psychiatric or neurologic disorders.
- Resection of the insulinoma is the treatment of choice.
- Palpation of the pancreas and intraoperative ultrasound detect insulinoma in the 83-98% of cases.
- Distal pancreatectomy, enucleation, and pancreaticoduodenectomy most common surgical procedures (Nikfarjam)
- Tumor resection is usually curative, as most insulinomas are benign (Boukhman).
- Laparoscopic surgery is possible for small, solitary insulinomas.
- For resectable liver metastasis, surgical resection of the metastasis and the primary tumor is recommended.
- For unresectable metastatic disease of the liver, treatment options include chemoembolization, radiofrequency ablation and cryoablation.
- Indications: 1) severe, life-threatening hypoglycemia due to unresectable metastases;2) patient not a surgical candidate;3) insulinoma not identified at surgery
- Frequent carbohydrate-containing meals is the background for all medical therapy.
- Diazoxide is a first-line agent, acting by inhibiting insulin release via stimulation of alpha-adrenergic receptors. Initial dose: 150-200 mg in 2-3 divided doses, maximum dose 1200 mg daily.
- Octreotide, a somatostatin analog, inhibits insulin secretion. Unpredictable clinical response, depending on the density of somatostatin-2 receptors on the insulinoma, which is highly variable
- Verapamil, propranolol, phenytoin, glucagon and glucocorticoids (please see steroid-induced hyperglycemia) also used to alleviate symptoms
- See Table below for further details on symptom control and adverse effects.
- ~ 6% of patients re-experience hypoglycemia within 6 months of initial surgery. Additional localization procedures and repeat surgery are recommended.
- For patients with sporadic insulinoma, the recurrence rate was 5% at 10 years and 7% at 20 years (Service).
- Recurrence rates are higher in MEN-1: 20% at 10 and 20 years (Service).
- Recurrence within 4 years usually due to regrowth of an incompletely resected tumor.
- Prognosis favorable in benign insulinoma (Nikfarjam). With malignant insulinoma, 25-35% 5-year survival.
- Follow-up of malignant insulinomas includes close monitoring with history and physical examination, neuroendocrine tumor markers (insulin, chromogranin A) and imaging 3 and 6 months after initial resection, then every 6-12 months for at least 3 years post surgery.
- Insulinoma should be considered in the differential for hypoglycemia, particularly in individuals who continue to have unexplained fasting hypoglycemia with high endogenous insulin levels.
- The medical workup, sometimes including a supervised fast, is the most important step in diagnosing an insulinoma.
- Establish hyperinsulinemic hypoglycemia before proceeding with localization or surgery.
- Given biochemical evidence of hyperinsulinemic hypoglycemia, preoperative localization of tumor avoids need for blind pancreatic exploration
- Careful removal of the tumor, with the capsule, by an experienced surgeon, prevents local recurrence
- Because insulinomas can occur throughout the pancreas, a blind partial pancreatectomy is not advisable.
- There is limited experience with hepatic transplantation for unresectable liver metastasis, and questionable survival benefit.
- Conventional cytotoxic chemotherapy has not proved effective for malignant insulinoma. Novel therapies are under investigation, such as small molecule tyrosine kinase inhibitors and inhibitors of the mammalian target of rapamycin (mTOR).
- Depending on degree of pancreatic resection, surgery for insulinoma may rarely result in diabetes although this is unusual (Please see post-pancreatectomy diabetes).
- Cryer PE, Axelrod L, Grossman AB, et al.;
Evaluation and management of adult hypoglycemic disorders: an Endocrine Society Clinical Practice Guideline.;
J Clin Endocrinol Metab;
2009; Vol.
94; pp.
709-28;
ISSN:
1945-7197;
PUBMED: 19088155
Rating:
Basis for recommendation
Comments:Expert Endocrine Society consensus on the evaluation and management of hypoglycemic disorders in adults.
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