| disease | Gastrinoma |
| alias | Gastrinoma, Zollinger-Ellison Syndrome |
Gastrinoma is a tumor with the function of secreting gastrin, clinically manifested as excessive secretion of gastric juice and acid, hypergastrinemia, multiple, atypical refractory peptic ulcers, and/or diarrhea. This syndrome was first reported by Zollinger and Ellison in 1955, hence its name. The syndrome can be caused by gastrin-secreting tumors (gastrinomas) or hyperplasia of antral G cells. The former is referred to as Zollinger-Ellison syndrome type II, while the latter is known as type I. Approximately 20% of gastrinoma patients may exhibit symptoms of multiple endocrine neoplasia type I (MEN-I), also known as type I multiple endocrine adenoma diseases.
bubble_chart Pathological Changes
Gastrinomas occur in 80-90% of cases in various parts of the pancreas, with the head and tail of the pancreas being the most common sites. Approximately 10-20% occur in the duodenal wall, most frequently in the second part of the duodenum, and are usually solitary tumors. They can also occur in the distal small intestine, stomach, liver, spleen, lymph nodes, omentum, mesentery, and other locations, with occurrences in the ovary and parathyroid glands being rare. The diameter of the tumors can range from 0.2 to 20 cm, but most are <1 cm. About 10% of patients exhibit typical clinical manifestations without detectable tumors, showing only diffuse hyperplasia of non-beta islet cells and nest-like or focal microadenomas. Approximately 60% of gastrinomas are malignant and can metastasize to local lymph nodes, liver, spleen, peritoneum, mediastinum, bone, and skin. Microscopically, benign and malignant tumors cannot be distinguished; the only method to determine malignancy is by identifying metastases.
Due to the continuous and strong stimulation of the gastric mucosa by serum gastrin, the gastric folds can hypertrophy, and the total number of parietal cells can increase 3-6 times compared to normal individuals and 3 times compared to patients with duodenal ulcers. This can cause swelling and thickening of the mucosal folds from the duodenum to the proximal jejunum. Microscopically, the intestinal mucosal villi appear flattened, shortened, and shed, with mucosal congestion, edema, superficial erosions, and infiltration of eosinophils and polymorphonuclear cells.
Some patients may concurrently or sequentially develop tumors of the parathyroid or pituitary glands, leading to the multiple endocrine neoplasia type 1 (MEN-1) syndrome associated with hyperfunction of the parathyroid and pituitary glands.bubble_chart Clinical Manifestations
In peptic ulcers, those caused by this disease account for less than 1%. They can occur at any age (7 to 90 years), but are most common between 35 and 65 years. Males are slightly more affected than females.
Although most gastrinomas are malignant, because the tumors are small and develop slowly, the tumors themselves rarely cause significant symptoms. It is not until the advanced stage of the disease that symptoms of malignant tumor infiltration appear. The clinical manifestations are mainly related to the large amount of gastric acid secretion.
(1) Abdominal pain is due to peptic ulcers. 90-95% of patients may develop peptic ulcers during the course of the disease, and there may be a family history of peptic ulcers. This is due to the strong and continuous stimulation of the gastric mucosa by gastrin, leading to a large secretion of gastric acid and pepsin. 75% of ulcers occur in the duodenal bulb and the lesser curvature of the gastric antrum; 25% occur in atypical locations, such as the lower esophagus, postbulbar duodenum, and jejunum. Ulcers are often single but can also be multiple, generally with a diameter of <1cm, and a few may be >2cm. 40-50% of patients may develop complications of peptic ulcers, such as bleeding, perforation, pyloric obstruction, and gastro-jejuno-colic fistula. After partial gastrectomy, ulcers are very prone to rapid recurrence, often occurring at the anastomosis or distal to the anastomosis as recurrent ulcers. Compared to ordinary peptic ulcers, the characteristics of ulcers in this disease are: stubbornness, multiplicity, atypical locations, high incidence of complications, and rapid recurrence of ulcers after partial gastrectomy.
(3) MEN-Ⅰ About 10-40% of patients may have other endocrine tumors. The distribution of affected endocrine glands is in the order of the parathyroid glands, pancreas, pituitary gland, adrenal glands, thyroid gland, etc. The corresponding clinical manifestations related to hyperfunction of the endocrine glands are, in order, hyperparathyroidism, peptic ulcers, hypoglycemia, chromophobe adenoma, acromegaly, diarrhea, steatorrhea, Cushing's syndrome, and hyperthyroidism.
(1) Clinical Diagnosis: The following manifestations should raise suspicion of this disease: ① Persistent, multiple, atypical peptic ulcers, especially those that rapidly recur after subtotal gastrectomy. ② Peptic ulcers accompanied by diarrhea. ③ Abnormal thickening of gastric mucosal folds, thickened duodenal and jejunal folds. ④ Peptic ulcers accompanied by clinical manifestations of other endocrine tumors.
(2) Qualitative Diagnosis
1. Gastric juice analysis is of some value. The total volume of gastric juice over 12 hours at night is >1000ml (normal <100ml). Basal acid output (BAO) >15mEq/h, and BAO >5mEg/h after subtotal gastrectomy. In patients with this disease, almost all parietal cells in the stomach are in a state of maximum stimulation, so they no longer respond strongly to pentagastrin stimulation, and the maximum acid output (MAO) does not increase significantly, making BAO/MAO >60%.
2. Serum gastrin measurement (radioimmunoassay) is a special diagnostic tool. In normal individuals and patients with peptic ulcers, fasting serum gastrin is 50-150pg/ml, while in this disease, it is often >500pg/ml, and can even reach 1000pg/ml. When fasting serum gastrin >1000pg/ml, accompanied by corresponding clinical symptoms, the diagnosis of this disease can be established. Patients with pernicious anemia have significantly elevated fasting serum gastrin, with an average of 1000pg/ml, and can even reach 10000pg/ml. Other conditions such as gastric antrum G cell hyperplasia, renal failure, hyperparathyroidism, atrophic gastritis, residual gastric antrum, and treatment with H2 receptor blockers and proton pump inhibitors can also increase serum gastrin, and should be differentiated.
Through gastric juice analysis and serum gastrin measurement, the diagnosis can be established in more than 95% of patients.
3. Provocation tests are suitable for patients suspected of this disease with grade I elevation of fasting serum gastrin. There are three methods.
(1) Secretin test: This is the most valuable provocation test, as it is time-saving and has few adverse reactions. After intravenous injection of secretin 2u/kg, serum gastrin concentration is measured every 5 minutes. In patients, serum gastrin levels can rise to 500pg/ml 5-10 minutes after injection. Secretin can inhibit gastric acid secretion, so in patients with gastric antrum G cell hyperplasia and duodenal ulcers, both gastrin and gastric acid can decrease during the secretin test, or remain unchanged or only show grade I elevation.
(2) Calcium infusion test: Calcium ions can stimulate tumors to release gastrin. Commonly, 12-15mg/kg of calcium gluconate is intravenously infused over 3 hours, and serum gastrin concentration is measured every 30 minutes. In patients, serum gastrin levels often peak 3 hours after infusion, with a large increase often >400pg/ml. This test is contraindicated in patients with hypercalcemia. Patients with duodenal ulcers may show a slight increase, while those with gastric antrum G cell hyperplasia show no consistent pattern.
(3) Standard meal test: A standard meal consisting of a slice of bread, 200ml of milk, one boiled egg, and 50g of cheese (containing 20g of fat, 30g of protein, and 25g of carbohydrates) is used as a stimulant. Serum gastrin concentration is measured every 15 minutes after the meal. In patients, serum gastrin does not increase or increases very little after the test meal, with an increase of <50% of fasting serum gastrin, while in those with gastric antrum G cell hyperplasia, serum gastrin can increase more than 2-fold. Patients with duodenal ulcers show grade II increase.
(3) Localization Diagnosis
1. B-mode ultrasound, CT, MRI, and 111In-pentetreotide scanning are non-invasive tests and should be used first, aiding in the localization and size diagnosis of gastrinomas.
2. Fiberoptic endoscopy and endoscopic ultrasonography can detect changes in the upper gastrointestinal tract ulcers and mucosal folds, and can also identify gastrinomas present in the stomach, duodenum, and pancreas.
3. Selective angiography is an effective auxiliary examination method when the above tests are negative. It is often performed by inserting a catheter through the celiac artery to perform angiography of the superior mesenteric artery and pancreatic vessels. Approximately 50% of cases may show positive results.
4. Percutaneous transhepatic portal venous sampling (PTPVS) can separately collect venous blood from the pancreas, duodenum, and jejunum to measure gastrin levels, aiding in localization diagnosis.
5. Surgical exploration should carefully examine the pancreas, duodenum, splenic hilum, liver, and nearby lymph nodes for the presence of tumors. Medical facilities with the capability can perform intraoperative ultrasound and collect venous blood from the pancreas and duodenum via portal vein catheterization to measure serum gastrin levels, which has certain value for localization. If no tumor is found, a pancreatic biopsy can be taken for frozen section pathological examination to determine the presence of islet cell hyperplasia and microadenoma diseases.
bubble_chart Treatment Measures
The fundamental treatment for this disease is the removal of the gastrin-producing tumor. For those in whom the tumor cannot be found or completely removed, drug therapy can be used.
(I) Surgical Treatment
1. Tumor resection: If the gastrinoma is single and without metastasis, surgical resection is often advocated. However, less than 10% of tumors located within the pancreas can be completely removed and cured, hence some advocate for total pancreatectomy. Gastrinomas located outside the pancreas, outside the intestines, or within the duodenal folds are often single and more likely to be surgically removed. If the pre-located tumor is not found during surgery, a thorough exploration for tumors in rare or unusual locations should be conducted. If the gastrinoma is completely removed, gastric acid secretion and serum gastrin levels will quickly return to normal.
2. Total gastrectomy: In the past, for patients whose tumors could not be removed or whose gastric acid and serum gastrin levels did not decrease after tumor removal, total gastrectomy was performed to effectively cure peptic ulcers by removing the target organ of gastrin action. There have been rare reports of regression of primary and metastatic tumors. Given the high mortality rate of 5-27% and numerous postoperative complications, this method is now less commonly used.
3. Highly selective vagotomy: This can significantly reduce gastric acid secretion, enhance the acid-suppressing effect of histamine H2 receptor blockers, and reduce their dosage.
4. Removal of other endocrine tumors: For patients with parathyroid tumors, it is generally recommended to perform parathyroid tumor resection before abdominal surgery. Postoperative diarrhea and peptic ulcer symptoms often improve, with reductions in gastric acid and serum gastrin levels.
(II) Drug Therapy
1. Acid-suppressing drugs: The advent of histamine H2 receptor blockers has made medical treatment of this disease possible. Patients require larger doses of histamine H2 receptor blockers than those with ordinary peptic ulcers. Cimetidine 0.6, Q4h (some patients may require 5-10g/d); Ranitidine 0.3, Q8h; Famotidine 20mg, Q4h. To reduce the dosage of histamine H2 receptor blockers, anticholinergic drugs can be used in combination for a synergistic effect. Omeprazole and Lansoprazole, which are proton pump inhibitors, can strongly inhibit gastric acid secretion caused by various stimuli and are the most effective drugs for treating this disease. The former is dosed at 60mg, B.i.d; the latter at 60mg, Qid. Long-term treatment is well tolerated. The dosage of acid-suppressing drugs should be individualized, generally aiming for BAO <10mEq/h, and post-gastrectomy BAO <5mEq/h as the standard for adequate drug dosage. For patients whose tumors cannot be removed, acid-suppressing drug therapy will be long-term and uninterrupted, otherwise, complications of peptic ulcers are likely to occur.
2. Chemotherapy drugs: Suitable for patients whose tumors cannot be removed and those with metastases. Streptozotocin has a therapeutic effect on tumors. When necessary, combined use with 5-Fluorouracil (5-Fu) yields better results. Currently, it is often recommended to administer streptozotocin via intraperitoneal stirred pulse catheter for interventional therapy, which can reduce adverse reactions and increase efficacy.
Once the gastrinoma is removed, the disease is cured. Malignant gastrinomas have a low degree of malignancy and grow relatively slowly. Even if the tumor is large or has metastasized elsewhere, patients can still live normally for many years. It is reported that the 5 to 10-year survival rate is 30 to 40%. The main cause of death is the metastasis of the malignant tumor, followed by complications of peptic ulcers and severe diarrhea causing water and electrolyte disturbances.
After total gastrectomy, to avoid malnutrition such as osteoporosis and osteomalacia, oral calcium and vitamin D supplements should be taken. Due to the lack of intrinsic factor after total gastrectomy, the absorption of vitamin B12 is impaired. Generally, it takes 2 to 4 years after surgery for the liver's stored vitamin B12 to be depleted. To prevent megaloblastic anemia, a monthly intramuscular injection of 100μg of vitamin B12 is required.
