Insulinoma is the most common functional neuroendocrine tumor of the pancreas that secretes insulin. Its prevalence in the general population is approximately 1–4 cases per million. Insulinoma can occur at any age, with around 90% being benign tumors and 90% being solitary tumors. Ectopic insulinomas outside the pancreas account for less than 1%, and about 82% of tumors have a diameter smaller than 2 cm. Clinical symptoms do not correlate with tumor size.
Clinical Manifestations
The clinical symptoms of insulinoma are diverse and complex, potentially related to the severity of hypoglycemia. Symptoms can include autonomic manifestations (e.g., palpitations, sweating, trembling) and neuroglycopenic symptoms (e.g., cognitive impairment, amnesia, psychiatric symptoms, seizure-like episodes). Some patients may experience weight gain. During hypoglycemic episodes, increased heart rate and elevated blood pressure may occur. Diagnosis involves confirming Whipple's triad through intravenous blood glucose testing, along with relevant hormone measurements and functional tests. Tumor localization is assessed using imaging studies and selective arterial calcium stimulation with venous sampling (ASVS).
Diagnosis and Differential Diagnosis
The diagnosis of insulinoma includes qualitative and localization diagnostics.
Qualitative Diagnosis
Whipple's Triad
Determining whether symptoms are caused by hypoglycemia is critical, and the classic Whipple's triad is highly significant for diagnosis:
- Symptoms of hypoglycemia.
- Blood glucose levels below 2.8 mmol/L during episodes.
- Rapid symptom resolution after oral or intravenous glucose administration.
Based on Whipple's triad, most patients can be definitively diagnosed with hypoglycemia-related conditions.
Plasma Insulin and Proinsulin Levels
Under normal conditions, fasting insulin levels are very low. Measuring insulin levels and blood glucose during fasting or symptomatic episodes, and calculating their ratio, is valuable for diagnosing insulinoma. A ratio of insulin (IU/ml) to blood glucose (mg/dl) greater than 0.3 is strongly indicative of insulinoma.
Proinsulin measurements are also helpful in the diagnosis of insulinoma, as almost all insulinoma patients have elevated proinsulin levels. The proinsulin-to-insulin ratio is also higher than normal. The normal insulin-to-proinsulin ratio is 6:1 to 10:1, whereas in insulinoma patients it can reach 1:1. In malignant insulinomas, the elevation of both proinsulin levels and ratio is even more pronounced.
72-Hour Fasting Test
The fasting test is a simple and reliable diagnostic procedure. Nearly all insulinoma patients experience hypoglycemic episodes within 72 hours.
Procedure
The 72-hour fasting test is usually initiated after dinner. Throughout the test, a precise record of symptoms and signs is maintained, along with laboratory testing.
- Record the start time of fasting accurately.
- Discontinue all non-essential medications.
- Allow the patient to drink water.
- Collect blood samples every 6 hours to measure glucose, insulin, and C-peptide levels. As blood glucose levels drop below 3.3 mmol/L (60 mg/dL), blood sampling frequency is increased to every 1–2 hours. Rapid blood glucose monitoring via fingerstick is often used to track glucose changes, but decisions to terminate the test must be based on venous blood glucose results.
Termination Criteria and Duration
The fasting test is terminated upon meeting any of the following criteria:
- Blood glucose concentration ≤2.5 mmol/L (45 mg/dL).
- The patient develops symptoms or signs of hypoglycemia.
- Fasting has continued for 72 hours.
- Blood glucose concentration falls below 3.1 mmol/L (55 mg/dL) with previously confirmed Whipple's triad.
At the end of the fasting test, the following steps are performed:
- Blood samples are collected to measure glucose, insulin, C-peptide, and beta-hydroxybutyrate levels.
- The patient is instructed to eat or is given intravenous glucose.
If no hypoglycemic symptoms or signs are observed, nor is hypoglycemia detected during the 72-hour fasting test, the result is considered normal.
Localization Diagnosis
After the qualitative diagnosis of insulinoma, localization diagnosis becomes critical for the success of surgery. CT, MRI, and transabdominal ultrasound can detect most insulinomas. Transabdominal ultrasound is commonly used as an initial diagnostic test. Negative imaging results do not exclude the presence of insulinoma. If the tumor is not detected on initial imaging, additional tests such as endoscopic ultrasound (which can also perform fine-needle aspiration biopsy of detected tumors) or selective arterial calcium stimulation testing may be required. Somatostatin receptor scintigraphy using isotopes can aid in tumor localization. Recent studies have shown that the majority of insulinomas highly express GLP-1 receptors, and GLP-1 receptor imaging technology has demonstrated ultrahigh sensitivity.
Invasive methods include percutaneous transhepatic portal venous sampling for insulin measurements (PTPC) or selective arterial calcium stimulation and venous sampling (ASVS). In ASVS, calcium ions stimulate insulin secretion from hyperactive pancreatic beta cells (in insulinoma or beta-cell hyperplasia) but do not stimulate insulin secretion from normal beta cells.
Based on this principle, calcium gluconate is selectively injected into the gastroduodenal artery, splenic artery, and superior mesenteric artery, after which hepatic vein blood is sampled to measure insulin levels. If hepatic vein insulin levels increase following calcium stimulation of a particular artery, this artery is identified as supplying blood directly to the insulinoma. This indicates the tumor’s location within the pancreatic region supplied by that artery, aiding surgical localization. The accuracy of this method can reach 90%.
When hypoglycemia with hyperinsulinemia is present but tumor localization remains unclear, differential diagnoses must include the following conditions:
- Persistent hyperinsulinemic hypoglycemia of infancy (PHHI), also known as familial hyperinsulinemia, congenital hyperinsulinism, or primary beta-cell hyperplasia.
- Non-insulinoma pancreatogenous hypoglycemia syndrome (NIPHS), seen in adults, often accompanied by pancreatic enlargement and beta-cell hyperplasia.
- Insulin autoimmune hypoglycemia, which occurs in individuals with autoantibodies against endogenous insulin or insulin receptors. Symptoms can appear in the postprandial, fasting, or both states. The presence of insulin autoantibodies or insulin receptor autoantibodies helps differentiate insulin autoimmune hypoglycemia from insulinoma.
Treatment
Surgical removal is the preferred treatment for insulinoma. For patients who are unsuitable for surgery, refuse surgery, or have unresectable metastatic lesions, medical management should be considered. Treatment options for preventing symptomatic hypoglycemia include the following:
- Diazoxide: Suppresses insulin secretion and is used to control hypoglycemia.
- Somatostatin analogs (e.g., octreotide, lanreotide): Control hypoglycemia by inhibiting insulin secretion but also suppress other hormones such as growth hormone, thyroid-stimulating hormone, and glucagon. Octreotide is a reasonable option for patients with persistent hypoglycemia unresponsive to diazoxide.
- Chemotherapy: For metastatic malignant insulinomas, chemotherapy agents such as streptozotocin, fluorouracil, and doxorubicin can be used. Combination chemotherapy has shown greater efficacy than monotherapy.
- Arterial Infusion or Embolization Therapy: For unresectable liver metastases, intra-arterial chemotherapy infusion or embolization therapy has demonstrated good outcomes.
With advancements in molecular biology and genetic pathway research, biological and targeted therapies have emerged as new potential treatment approaches, though their clinical value requires further exploration.
Prognosis
The overall survival rate of insulinoma patients is comparable to that of the general population. However, survival rates are significantly reduced in patients with malignant insulinomas or in elderly patients.