bubble_chart Overview

Insulinoma, also known as endogenous hyperinsulinemia, is a tumor of pancreatic islet B cells, accounting for 70-75% of pancreatic islet cell tumors. Most are benign, with malignant cases making up 10-16%. Nicholis first discovered insulinoma during an autopsy in 1902. The clinical manifestations include excessive insulin or hypoglycemia syndrome. In 1920, Roscose Graham successfully treated "spontaneous hypoglycemia" by removing an insulinoma. The exact incidence of the disease is unclear, but some foreign authors report an incidence of 1/800 to 1/1000, while data from Mayo Clinic shows 1/234. Over 500 cases have been documented in Chinese literature. Insulinoma can occur at any age but is most common in young and middle-aged adults, with about 74.6% of patients aged 20-59. It is more prevalent in males than females, with a male-to-female ratio of 1.4-2.1.

bubble_chart Pathological Changes

Most insulinomas are solitary, accounting for approximately 91.4%, with a minority being multiple. The tumors are generally small, with diameters ranging from 1 to 2.5 cm in about 82% of cases. They are located in the head of the pancreas in 17.7% of cases, the body in 35%, and the tail in 36%, while the incidence of ectopic insulinomas is less than 1%.

Gross examination reveals that insulinomas have a smooth surface, appearing round or oval, occasionally irregular. They are typically pink or dark red, with clear boundaries and a slightly firm texture. The tumor cells contain insulin, with approximately 10–30 IU per gram of tumor tissue, and up to 100 IU in some cases (normal pancreatic tissue contains 1.7 IU of insulin per gram). Microscopic observation shows that the tumor cells are polygonal with indistinct cell boundaries and sparse, translucent cytoplasm. The nuclei are round or oval, uniform in size, with fine and evenly distributed chromatin, and nucleoli are generally not easily visible. The tumor cells are arranged in clusters, closely associated with capillaries, forming small nodules or islands. They may also be arranged in glandular patterns, forming rosette-like structures, with columnar cells and basally located nuclei; red-stained secretions are sometimes seen within the glandular lumens. The tumor cells can also be distributed in sheets. Under electron microscopy, the secretory granules of the tumor cells exhibit characteristics of B granules. Insulinomas can be benign or malignant, and it is sometimes difficult to determine based solely on cellular morphology. The most reliable indicator is the presence or absence of metastasis.

The clinical symptoms caused by insulinomas are related to elevated blood insulin levels, but more importantly, they result from the lack of normal physiological feedback regulation of insulin secretion, rather than simply excessive insulin secretion. Under physiological conditions, normal blood glucose levels are maintained by the regulation of insulin and glucagon. When blood glucose levels drop, glucagon secretion increases, while insulin secretion is suppressed. When blood glucose falls to 1.94 mmol/L, insulin secretion almost completely stops. However, in individuals with insulinomas, this normal physiological feedback mechanism is entirely lost, and the tumor cells continue to secrete insulin, leading to hypoglycemia. The metabolic activity of human brain cells relies almost exclusively on glucose and cannot utilize glycogen for energy. Therefore, when blood glucose levels drop, brain cell metabolism is the first to be affected, resulting in central nervous system symptoms such as drowsiness, confusion, and even unconsciousness.

bubble_chart Clinical Manifestations

The typical clinical manifestations of insulinoma are: ① Paroxysmal episodes of hypoglycemia or unconsciousness, along with neuropsychiatric symptoms; ② Blood glucose levels below 2.78 mmol/L during episodes; ③ Immediate relief of symptoms after oral or intravenous glucose administration. These three criteria are known as Whipple's triad or the insulinoma triad. Hypoglycemic symptoms often occur in the early morning, during fasting, after exertion, or under emotional stress, with intervals ranging from days to weeks or even months between episodes. However, not all patients exhibit highly typical symptoms; some may present with chronic hypoglycemic manifestations such as personality changes, memory impairment, unsteady gait, blurred vision, and occasionally agitation, hallucinations, or abnormal behavior, leading to misdiagnosis as psychiatric disorders. Typically, patients with insulin tumor diseases may exhibit four groups of symptoms:

1. Manifestations of sympathetic nervous system excitation

These are compensatory responses induced by hypoglycemia, such as pale complexion, cold extremities, cold sweating, palpitations, and trembling hands with weak legs.

2. Impaired consciousness

This results from glucose deprivation in brain cells due to hypoglycemia, presenting as mental confusion, drowsiness, unconsciousness, or symptoms like mental fog, sluggish reactions, and cognitive decline.

3. Psychiatric abnormalities

These arise from repeated hypoglycemic episodes leading to further inhibition of the cerebral cortex. Symptoms vary widely, and severe cases may exhibit pronounced psychiatric symptoms, sometimes misdiagnosed as mental illness or prompting repeated visits to psychiatric hospitals.

4. Temporal lobe epilepsy

Resembling grand mal seizures, this represents the most severe neuropsychiatric symptom, characterized by loss of consciousness, clenched teeth, limb spasms, and urinary incontinence during episodes.

bubble_chart Auxiliary Examination

1. Laboratory Tests

1. Fasting Blood Glucose Measurement

Fasting for 15 hours with a blood glucose level below 2.78 mmol/L confirms the diagnosis of insulinoma. For mild cases, fasting may be extended to 24–48 hours or longer to induce symptoms. Most patients develop hypoglycemic symptoms within 15–36 hours of fasting. If no symptoms occur after 60–72 hours of fasting, insulinoma can be ruled out.

2. Insulin Measurement

Measuring fasting or symptomatic peripheral venous blood insulin levels is direct evidence for diagnosing insulinoma. Normal fasting peripheral blood insulin levels range from 5–30 μU/ml, averaging below 24 μU/ml. Patients with this condition exhibit significantly elevated insulin levels, which remain high even during hypoglycemia (up to 100–200 μU/ml), making this the most specific test for insulinoma.

In addition to fasting measurements, intraoperative portal vein blood sampling can be performed for insulin measurement. The method involves puncturing the main portal vein with a fine needle before administering glucose infusion during surgery to measure blood glucose and insulin levels. If portal vein insulin levels exceed 100 μU/ml, insulinoma should be suspected; levels above 200 μU/ml confirm the diagnosis. This method is more specific than peripheral venous blood measurements and can also assess whether the insulinoma has been completely resected.

3. Peripheral Venous Blood Insulin-to-Glucose Ratio (IRI/G) Diagnostic Method

After fasting for 15–72 hours, peripheral venous blood insulin and glucose levels are measured, and the insulin (IRI)-to-glucose (G) ratio is calculated. A normal IRI/G ratio is less than 0.3; a ratio above 0.3 supports the diagnosis of insulinoma. This method is more accurate than measuring insulin or glucose alone.

4. Tolbutamide (D860) Stimulation Test

Tolbutamide stimulates insulin release from the pancreas, causing hypoglycemia lasting 3–5 hours.

(1) Intravenous Method: After fasting overnight, blood glucose is measured, and tolbutamide (20–25 mg/kg body weight, dissolved in 20 ml of saline) is injected intravenously. Blood glucose is measured at 5, 15, 30, 45, and 60 minutes post-injection, then every half-hour for 2–3 hours to observe changes. In healthy individuals, blood glucose reaches its lowest level at 30 minutes and returns to normal within 1.5–2 hours. In insulinoma patients, significant hypoglycemia occurs within 5–15 minutes and persists for 2–3 hours.

(2) Oral Method: Tolbutamide and sodium bicarbonate (2 g each) are administered orally, followed by blood glucose measurements every half-hour for 5 hours. Healthy individuals reach the lowest blood glucose level within 1–3 hours, while insulinoma patients exhibit early hypoglycemia lasting 3–5 hours with elevated plasma insulin levels.

Precautions for the tolbutamide test: ① False negatives may occur in individuals insensitive to D860. ② The test should not be performed if fasting blood glucose is below 2.78 mmol/L. ③ Hypoglycemic unconsciousness may occur in patients with cirrhosis.

5. Glucagon Test

After intravenous injection of 1 mg glucagon, blood glucose and plasma insulin levels are measured every 30 minutes. Blood glucose rises rapidly within 30 minutes, while insulin levels drop. Blood glucose normalizes after 1–1.5 hours, followed by hypoglycemia at 2 hours with elevated insulin levels. A blood glucose level below 2.5 mmol/L and insulin >100 μU/ml confirms the diagnosis. Healthy individuals show no hypoglycemia. This test has an 80% positive rate and is safer and more accurate than the tolbutamide method.

6. Proinsulin-to-Insulin Ratio Measurement

In normal individuals, the ratio of proinsulin to insulin does not exceed 25%; in patients with insulinoma, this ratio is increased; it becomes even more pronounced when malignant transformation occurs.

7. Other Tests

L-leucine test, calcium stimulation test, and serum C-peptide measurement are all helpful in the diagnosis of insulinoma and can aid in ruling out other causes of hypoglycemia.

II. Localization Studies

1. Non-invasive Examinations

（1）Ultrasound: Due to its simplicity, non-invasiveness, and low cost, ultrasound has certain clinical value. The Mayo Clinic reported a preoperative localization rate of 59% for insulinoma cases using ultrasound, while the University of Michigan reported a positive rate of only 25%. Therefore, ultrasound alone cannot be relied upon for preoperative localization of insulinoma.

（2）Computed Tomography (CT): CT is the most widely used non-invasive method for localizing insulinomas. Enhanced CT scans are more sensitive than non-contrast scans and provide better visualization of the tumor's relationship with the pancreas and common bile duct. However, reported positive rates vary significantly: Broughan and Dunnick reported a localization rate of over 60%, while the Mayo Clinic reported 35%, and Vinik et al. reported only 15%.

（3）Magnetic Resonance Imaging (MRI): With the gradual adoption of MRI, it has also been applied to the localization of pancreatic islet cell tumors. Due to its relatively recent introduction and the rarity of insulinomas, there are currently no large-scale studies on its use. Generally, its sensitivity is considered comparable to that of CT.

2. Invasive Examinations

（1）Selective Abdominal Angiography: Insulinomas are highly vascularized, and high-selective abdominal angiography (splenic artery or gastroduodenal artery) can clearly reveal the tumor's location. When combined with newer techniques like Digital Subtraction Angiography (DSA), the accuracy of localization improves further. Most authors report a localization rate of 80% for insulinomas using abdominal angiography (Fraker and Norton: 84%; Fulton et al.: 88%), though some report slightly lower rates, such as 52%.

（2）Percutaneous Transhepatic Portal Catheterization Sampling (PTPC) for Insulin Measurement: Also known as Selective Portal Venous Sampling (SPVS), this method involves percutaneous transhepatic puncture of a portal vein branch, inserting a catheter into the splenic vein, and sequentially drawing blood from pancreatic drainage vessels to measure insulin levels. A curve is plotted from the measurements, and the segment with the highest hormone peak indicates the tumor's location. PTPC has a high concordance rate for tumor localization: Vinik and Roche reported rates of 81% and 95%, respectively, while Fraker and Norton achieved 100%. In China, Zeng Xianjiu et al. successfully localized insulinomas using this method in all six patients tested since 1981.

(3) Intraoperative ultrasound: This method is particularly suitable for the diagnosis of tumors located in the head of the pancreas, which are deep-seated and small in size. Islet cell tumors can be easily distinguished from the surrounding pancreatic parenchyma; it also helps to identify the relationship between the tumor and surrounding large blood vessels, pancreatic ducts, and common bile ducts. Grant et al. performed intraoperative ultrasound examinations on 36 cases of insulin tumor diseases, with a localization diagnosis rate of 90%.

(4) Selective stirred pulse injection of methylene blue (selective arterial methylene blue injection): Since insulinomas can selectively bind to biological dyes such as methylene blue, injecting methylene blue via stirred pulse or intravenous injection helps locate the insulinoma. Fedorak et al. described performing superselective celiac stirred pulse catheterization on the morning of the surgery, leaving a 5.0F stirred pulse angiography catheter in the gastroduodenal stirred pulse or splenic stirred pulse. During the procedure, 2 ml of sterilized methylene blue is rapidly injected into the catheter, staining all tissues within the stirred pulse blood supply area blue within 15 seconds. After 2 minutes, the normal pancreatic tissues outside the tumor fade, while the tumor area retains its stain for more than 15 minutes. Cordon reported administering methylene blue (5 ml/kg body weight) via peripheral intravenous drip, dissolved in 1000 ml of glucose saline, completed within half an hour. Observations made after 1 hour showed normal pancreatic tissues stained light blue, while the tumor appeared dark red-blue. However, a few domestic institutions conducting similar tests failed to achieve comparable results.

bubble_chart Diagnosis

The diagnosis of insulinoma is usually straightforward based on the classic Whipple's triad, which includes: ① spontaneous periodic episodes of hypoglycemic symptoms, {|###|}unconsciousness{|###|}, and neuropsychiatric symptoms, occurring during fasting or after physical exertion; ② blood glucose levels below 2.78 mmol/L during episodes; ③ immediate relief of symptoms after oral or intravenous glucose administration. However, some patients present with atypical symptoms. In such cases, diagnostic tests such as blood glucose measurement, insulin assay, tolbutamide (_D860) stimulation test, glucagon test, L-leucine test, calcium stimulation test, and serum C-peptide measurement can aid in the diagnosis of insulinoma and help exclude other causes of hypoglycemia.

Due to the small size and variable location of insulinomas, imaging techniques such as ultrasound, computed tomography (CT), magnetic resonance imaging (MRI), abdominal stirred pulse angiography, selective portal venous sampling (SPVS), and selective stirred pulse injection of methylene blue can be employed for precise tumor localization.

bubble_chart Treatment Measures

Once the diagnosis of insulinoma is confirmed, surgical treatment should be performed as early as possible to remove the tumor. Prolonged coexistence with recurrent episodes of hypoglycemic unconsciousness can cause irreversible damage to brain tissue, especially the cerebrum.

1. Surgical Treatment

General anesthesia or continuous epidural block anesthesia is used. The incision is made in the left upper abdomen as a paramedian incision or an upper abdominal arc incision. The Qingdao Municipal Hospital uses the Mason incision, which is reported to provide excellent exposure. Regardless of whether the tumor location has been identified during preoperative examinations, a thorough and comprehensive exploration of the entire pancreas should be performed during surgery to determine the tumor's location, size, number, depth, and the presence of liver metastases. For this purpose, a Kocher incision should be made to mobilize the duodenum and pancreatic head; the peritoneum at the upper and lower edges of the pancreatic body and tail should be incised to mobilize the pancreatic body and tail; and the retroperitoneal tissue along the superior mesenteric vessels should be incised and dissected to explore the uncinate process of the pancreas. If necessary, ectopic pancreatic tissue should also be explored. Intraoperative ultrasound combined with surgical exploration can improve the accuracy of the examination. The surgical approach should be determined based on the tumor's location and number:

(1) Simple tumor resection: For superficial, small, solitary benign insulinomas, simple tumor resection is sufficient.

(2) Distal pancreatectomy: For tumors located in the body or tail of the pancreas that are large, deep, multiple, or difficult to distinguish between benign and malignant, distal pancreatectomy may be performed.

(3) For benign insulinomas in the pancreatic head, wedge resection can be used, but the resection margin should be 0.5–1 cm from the tumor. The pancreatic duct should be avoided during surgery. If the pancreatic duct is injured, a pancreaticojejunostomy (Roux-en-Y) should be performed; if both the pancreatic duct and common bile duct are injured, a pancreaticoduodenectomy should be performed.

(4) For cases where the tumor cannot be located despite thorough and careful exploration, blind distal pancreatectomy may be performed, as more than two-thirds of insulinomas are located in the body and tail. In recent years, many have adopted a stepwise distal pancreatectomy approach, which involves segmental resection starting from the pancreatic tail. Each resected segment is sent for frozen section examination, blood glucose, and insulin level testing. If the frozen section confirms insulinoma but blood glucose remains low and insulin levels do not drop, it may indicate multiple tumors, and further pancreatic tissue resection should be performed until blood glucose levels rise and insulin levels decrease before stopping the surgery. For such occult insulinomas, total pancreatectomy is generally not recommended.

(5) If pathological examination confirms islet cell hyperplasia, resection of more than 80% of the pancreatic tissue is often required.

(6) Intraoperative considerations: ① Intraoperative glucose-free fluid infusion and continuous blood glucose monitoring are emphasized. ② After complete tumor resection, blood glucose levels may double compared to pre-resection levels. If no increase is observed, a 90-minute wait is necessary before concluding incomplete tumor removal. ③ Seasonal disease pathological sections are also difficult to distinguish between benign and malignant insulinomas. In such cases, careful examination for liver or peripancreatic lymph node metastases is required; if metastases are present, the tumor is malignant.

(7) Postoperative management: ① Blood glucose and urine glucose should be measured daily for the first 5 days postoperatively. Some patients may develop postoperative hyperglycemia and glycosuria, which can be managed by adjusting the rate and volume of glucose infusion. A few patients may require insulin. Levels typically normalize within 15–20 days. ② In some patients, symptoms may reappear after tumor resection, possibly due to missed multiple tumors, intraoperative fistula disease, or postoperative tumor recurrence. ③ Common postoperative complications include pancreatic fistula, pseudocyst, postoperative pancreatitis, and subphrenic infection.

2. Non-Surgical Treatment

(1) For a minority of patients who cannot undergo surgery, long-term use of diazoxide can inhibit insulin secretion. Increasing meal frequency and consuming more carbohydrates can also alleviate hypoglycemic symptoms.

(2) For malignant tumors or those with liver metastasis, nitrogen dioxide (Nitrogen Dioxide) or streptozotocin (Streptozotocin) can be used. This Yaodui selectively damages pancreatic B cells and also has a certain therapeutic effect on metastatic islet cell carcinoma. L-asparaginase (L-asparaginase) and streptonigrin (Streptonigrin) also have effects on malignant insulinomas.