Insulinoma

BASICS

DESCRIPTION

Tumors of the pancreatic β cells of the islets of Langerhans; pancreatic β cells secrete both insulin and C-peptide.
Most common functional (insulin-producing) tumor of the pancreas
Usually very small, with 90% <2 cm; suspect malignant insulinoma if tumor is >4 cm.
90% are located within the pancreas (1).
Usually single and benign; only 10% malignant; only 10% multiple tumors (2)
The malignant potential is not as clinically important as the functional ability to secrete insulin, which leads to symptomatic hypoglycemia (2).
Hypoglycemic episodes are irregular, recurrent, and tend to increase in frequency and severity over time.
Synonym(s): β-cell tumor; β-cell adenoma; nesidioblastoma

EPIDEMIOLOGY

Incidence

3 to 4 cases per 1 million person-years
Predominant age
- Rare: <20 years
- 20% of patients are of adults aged <40 years.
- 40% of patients are aged 40 to 60 years.
- 40% of patients are aged >60 years.
Predominant sex: female > male (3)

Prevalence

The prevalence of insulinoma is 0.4% (4).
5-10% of insulinomas are malignant (5).

Genetics

5-10% are due to multiple endocrine neoplasia type 1 (MEN1) syndrome; these typically occur in the 3rd decade of life (6).
Mutations in DAXX and ATRX have been identified in 43% of pancreatic endocrine tumors (7).

RISK FACTORS

Age >40 years
4-7% associated with MEN1 syndrome (2)

COMMONLY ASSOCIATED CONDITIONS

MEN1 syndrome (2)

DIAGNOSIS

Patients may have learned to avoid hypoglycemia by eating frequent meals, sometimes with resulting weight gain.

HISTORY

Symptoms are typically vague and periodic which can result in a delay in diagnosis of, on average, 18 months (3,8).
Symptoms are often worsened with fasting or exercise but can occur postprandially (3,8).
Symptoms (3)[B],(6,8)[C]:
- Confusion
- Visual disturbances
- Diaphoresis
- Fatigue, drowsiness
- Weakness
- Tremulousness
- Hunger
- Behavioral changes
- Seizures
- Amnesia
- Headache
- Paresthesias
- Palpitations
- Dysarthria
- Weight gain, or more rarely, weight loss

PHYSICAL EXAM

Nonspecific findings seen when having a hypoglycemic episode, such as diaphoresis or tremor

DIFFERENTIAL DIAGNOSIS

Medications:
- Inappropriate insulin or oral hypoglycemic administration
- β-Blockers
- Salicylates
- Quinine
Reactive hypoglycemia
Functional hypoglycemia
Adrenocortical insufficiency
Hypopituitarism
Significant liver disease
Nesidioblastosis
Hirata disease or insulin autoimmune syndrome (IAS) (9)
Tumor-induced hypoglycemia
- Ectopic tumor insulin secretion by bronchial carcinoid or gastrointestinal stromal tumor (5)
- Large sarcomas
- Hepatocellular carcinoma

DIAGNOSTIC TESTS & INTERPRETATION

Diagnosis is made based on low serum glucose with inappropriately elevated serum insulin and C-peptide, after excluding other possible diagnoses (3)[C].
Whipple described the key features of hypoglycemia in insulinoma: low serum glucose in the setting of symptoms of hypoglycemia which resolve with the administration of glucose (8)[C].
Glucose < 3.0 mmol/L, insulin >8 pmol/L, and C-peptide >0.2 nmol/L have 100% sensitivity and 89% specificity (10).
To make the diagnosis, perform a 72-hour supervised fast (8,11)[C]:
- 99% of patients with an insulinoma will develop symptomatic hypoglycemia during a 72-hour fast (8)[C].
- Monitor the blood glucose levels at regular intervals (11)[C].
- If the patient develops hypoglycemia (serum glucose <55 mg/dL), screen for oral hypoglycemic agents (as sulfonylureas produce glucose, C-peptide and insulin levels indistinguishable from an insulinoma) (11)[C].
- Detection of C-peptide and insulin in the setting of symptomatic hypoglycemia demonstrates an exogenous source of insulin (8)[C].
- High serum insulin without elevated C-peptide is suspicious for exogenous insulin administration (11)[C].
- Hypoglycemia is likely caused by insulin or insulin-like growth factor if the patient has undetectable serum ketones and/or a strong response to IV glucagon (8)[C].
- An end of (48-hour) fast proinsulinoma concentration ≥27 pmol/L had 100% sensitivity and specificity in a small case control series (12)[B].
Consider provocative testing:
- IV calcium gluconate (15 mg/kg of elemental calcium) over 4 hours to determine insulin and glucose levels
- Tolbutamide bolus (1 g after overnight fast); determine insulin and glucose levels at 150 minutes.
- C-peptide suppression with 0.1 U/kg of regular insulin; determine C-peptide and glucose levels.
Malignant tumors may secrete β-human chorionic gonadotropin (β-hCG).
There is debate regarding the value of preoperative localization after the diagnosis is confirmed by lab results. Historically, noninvasive imaging had poor sensitivity for localization of insulinomas. However, sensitivity has improved with advances in imaging technology and was recently reported at 80%. Noninvasive imaging options include US, CT, and MRI (3,6)[C].
Endoscopic US has sensitivity of 75-86% for intrapancreatic insulinomas and is routinely performed during insulinoma resections for localization and to identify possible metastases (6)[C].
Adding endoscopic US to CT increases sensitivity to nearly 100% (8)[C].
Angiography can be used in difficult to localize cases due to the high vascularity of insulinomas (6)[C].
Intraoperative US is useful in the detection of occult insulinomas, which are typically <1 cm (1)[C].
After diagnosing insulinoma, exclude MEN1 by testing for primary hyperparathyroidism and pituitary tumors (6)[C].

Diagnostic Procedures/Other
Intraoperative palpation and intraoperative US are more sensitive than preoperative imaging. Palpation and intraoperative US are used to confirm preoperative localization and to look for multiple small tumors (13).
Test Interpretation

Metastases found in liver or regional lymph nodes (distant metastases rare)
Tumors are evenly distributed throughout pancreas (1/3 in head, 1/3 in body, 1/3 in tail).

TREATMENT

GENERAL MEASURES

Definitive treatment is surgical removal, usually by enucleation (5)[C].
Medications can be used to help stabilize blood sugars in patients awaiting surgery, those with metastatic disease, or in patients for whom surgery is not an option (5,6,8)[C].
Observe closely for severe hypoglycemic symptoms.
Keep a ready glucose source available.

MEDICATION

First Line

Medical management is reserved for patients with metastatic disease or for whom surgery is not an option (8)[C].
Recommend small, frequent meals (6,14)[C].
Diazoxide inhibits secretion of insulin: 200 to 600 mg PO daily (8)[C].
Octreotide acetate (long-acting analogue of somatostatin). Insulinomas do not commonly express somatostatin receptors (5)[C].
Verapamil (6)[C]
PO or IV glucose or dextrose; IM or SC glucagon (8)[C]

Second Line

Lutetium-177 octreotate (radiolabeled somatostatin analog which has higher affinity for receptors than octreotide) (14)[C]
Everolimus (mTOR receptor antagonist) (14,15)[C]
Corticosteroids inhibit insulin production and increase peripheral insulin resistance: up to 60 mg PO daily (14)[C].
Chemotherapy for metastatic disease (14)[C]
- Streptozocin with doxorubicin
- Fluorouracil
- Dacarbazine

SURGERY/OTHER PROCEDURES

Surgical resection is the treatment of choice (5)[C].
Enucleation for small lesions <2 cm
Deep-seated or invasive tumor: partial pancreatectomy
Cure rates of 75-98% after surgery
Mechanical ablative techniques (hepatic arterial embolization for refractory metastases)
Some small tumors in body and tail, remote from the pancreatic duct, can be managed with laparoscopic pancreatectomy or enucleation; higher risk of pancreatic effusion; long-term results of this approach are not yet known.

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring
Watch for recurrence of hypoglycemic symptoms.

DIET

Frequent high-carbohydrate meals and snacks

PROGNOSIS

Excellent, if tumor is solitary, benign, and completely resected
Disease-specific survival at 5, 10, and 15 years has been reported as 100%, 100%, and 93% following resection (3)[B].
Most recurrences occur in the first 5 years.
Recurrence rate is 8% in benign disease and 63% in malignant disease (3)[B].
Malignant insulinomas may metastasize to liver, lymph nodes, or lungs; 29% 10-year survival for metastatic malignant insulinoma
Up to 25% of MEN1-associated insulinomas are malignant.

COMPLICATIONS

From surgery

Pancreatitis
Pancreatic leaks
Fistulas (4)
Peritonitis
Abscess
Pseudocysts

REFERENCES

11 Shin LK, Brant-Zawadzki G, Kamaya A, et al. Intraoperative ultrasound of the pancreas. Ultrasound Q. 2009;25(1):39-48.22 Patel S, Narwari M, Parekh D, et al. Insulinoma: case report and review of diagnostic and treatment modalities. J Assoc Physicians India. 2013;61(6):423-426.33 Nikfarjam M, Warshaw AL, Axelrod L, et al. Improved contemporary surgical management of insulinomas: a 25-year experience at the Massachusetts General Hospital. Ann Surg. 2008;247(1):165-172.44 Mehrabi A, Fischer L, Hafezi M, et al. A systematic review of localization, surgical treatment options, and outcome of insulinoma. Pancreas. 2014;43(5):675-686.55 Iglesias P, D ez JJ. Management of endocrine disease: a clinical update on tumor-induced hypoglycemia. Eur J Endocrinol. 2014;170(4):R147-R157.66 Abood GJ, Go A, Malhotra D, et al. The surgical and systemic management of neuroendocrine tumors of the pancreas. Surg Clin North Am. 2009;89(1):249-266.77 Heaphy CM, de Wilde RF, Jiao Y, et al. Altered telomeres in tumors with ATRX and DAXX mutations. Science. 2011;333(6041):425.88 Vaidya A, Kaiser UB, Levy BD, et al. Clinical problem-solving. Lying low. N Engl J Med. 2011;364(9):871-875.99 Wong SL, Priestman A, Holmes DT. Recurrent hypoglycemia from insulin autoimmune syndrome. J Gen Intern Med. 2013;29(1):250-254.1010 Ahn CH, Kim LK, Lee JE, et al. Clinical implications of various criteria for the biochemical diagnosis of insulinoma. Endocrinol Metab (Seoul). 2014;29(4):498-504.1111 Pallais JC, Blake MA, Deshpande V. Case records of the Massachusetts General Hospital. Case 33-2012: A 34-year-old woman with episodic paresthesias and altered mental status after childbirth. N Engl J Med. 2012;367(17):1637-1646.1212 Guettier JM, Lungu A, Goodling A, et al. The role of proinsulin and insulin in the diagnosis of insulinoma: a critical evaluation of the Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2013;98(12):4752-4758.1313 Borazan E, Aytekin A, Yilmaz L, et al. Multifocal insulinoma in pancreas and effect of intraoperative ultrasonography. Case Rep Surg. 2015;2015:375124.1414 Ong GS, Henley DE, Hurley D, et al. Therapies for the medical management of persistent hypoglycaemia in two cases of inoperable malignant insulinoma. Eur J Endocrinol. 2010;162(5):1001-1008.1515 Kulke MH, Bergsland EK, Yao JC. Glycemic control in patients with insulinoma treated with everolimus. N Engl J Med. 2009;360(2):195-197.

CODES

ICD10

D13.7 Benign neoplasm of endocrine pancreas
C25.4 Malignant neoplasm of endocrine pancreas
D37.8 Neoplasm of uncertain behavior of oth digestive organs

ICD9

211.7 Benign neoplasm of islets of Langerhans
157.4 Malignant neoplasm of islets of langerhans
235.5 Neoplasm of uncertain behavior of other and unspecified digestive organs

SNOMED

Insulinoma (disorder)
Benign tumor of endocrine pancreas
Primary malignant neoplasm of islets of Langerhans

CLINICAL PEARLS

80% of patients with MEN1 syndrome have insulinomas.
10% of insulinomas are associated with MEN1 syndrome and tend to be multiple tumors presenting at an earlier age.
The distribution of insulinomas in the pancreas is 1/3 in head, 1/3 in body, and 1/3 in tail.
Conduct a C-peptide test if a patient is suspected of self-administering insulin or oral hypoglycemics to mimic symptoms of insulinoma. Proinsulin levels are not elevated with self-administered hypoglycemic agents.

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