Gastrinoma

      Etiology of gastrinoma:

　　1. Abnormal gastrin secretion (40%)

　　Due to the trophic effect of gastrin, the gastric mucosa proliferates and thickens, with the capacity of parietal cells reaching 3 to 6 times that of normal people, causing excessive secretion of gastric acid and gastric juice. Gastrinomas are almost seen in any part of the abdominal cavity, not just limited to the pancreas as previously thought. In addition to the pancreas (21% to 65%), the duodenum is also a high-risk area (33% to 38%).

　　2. Genetic factors (10%)

　　Multiple endocrine neoplasia type I (MEN1) is an autosomal dominant genetic abnormality with high penetrance, located on chromosome 11. It is possible that all patients with multiple endocrine neoplasia type I are affected by three organs (parathyroid glands, islets of Langerhans, and pituitary gland), but not all have clinical manifestations of hypersecretion of hormones. Patients with multiple endocrine neoplasia type I and hyperparathyroidism usually develop gastrinomas.

　　About 1/4 of gastrinoma patients have gastrointestinal bleeding, about 1/5 have ulcer disease perforation. 20% to 30% of patients have diarrhea, mostly watery stools, and sometimes fatty diarrhea. It is not uncommon to have other endocrine tumors. Gastrointestinal bleeding is a common and severe clinical symptom, and the gastrointestinal tract refers to the pipeline from the esophagus to the anus, including the stomach, duodenum, jejunum, ileum, cecum, colon, and rectum, as well as the upper gastrointestinal bleeding site.

　　The most common clinical manifestation of gastrinoma patients is peptic ulcer, seen in 90% to 95% of gastrinoma patients. The clinical symptoms are often similar to those of common peptic ulcer disease, but the symptoms are persistent and progressive, and the response to treatment is poor. The distribution of upper gastrointestinal ulcers in gastrinoma patients is similar to that of common peptic ulcers, with about 75% of gastrinoma patients having ulcers located in the first segment of the duodenum, and gastric ulcers are less common. About 1/2 to 2/3 of gastrinoma cases are malignant. The most reliable indicator of the malignancy of gastrinoma is their biological behavior, that is, whether the tumor has metastasized, and there is no significant correlation between histological changes and biological activity. Malignant gastrinoma is usually asymptomatic and grows slowly. However, a small number of gastrinoma patients have rapid tumor growth and early widespread metastasis, which can spread to local lymph nodes, liver, spleen, bone, mediastinum, peritoneal surface, and skin. Gastrinoma of the duodenum usually metastasizes to local lymph nodes and is less likely to metastasize to the liver. Prospective studies have shown that there are differences in the clinical course between gastrinoma patients with lymph node metastasis and those with liver metastasis. Surgery found that patients with only local lymph node metastasis and no liver metastasis are rarely fatal due to tumor invasion, and their survival time often reaches or exceeds 25 years without tumor progression. In fact, the clinical course of gastrinoma patients with lymph node metastasis is similar to that of patients with no tumor found by surgery. Conversely, patients with liver metastasis have a significantly shorter life expectancy, averaging about 8 years, and are often caused by progressive growth of the tumor leading to liver failure.

　　The serum HCG and alpha, beta subunit levels of gastrinoma patients with metastasis are often increased. 20% of malignant gastrinoma patients have increased serum alpha-HCG levels, and gastrinoma patients with extensive metastasis have significantly increased alpha-HCG levels, while there is no increase in serum alpha-HCG levels in benign gastrinoma patients.

　　Gastrinoma patients often have solitary ulcers, but they can also have multiple ulcers. Compared with common peptic ulcers, gastrinoma ulcers can be located in the second, third, or fourth part of the duodenum, and even in the jejunum. A retrospective study showed that 14% of ulcers were located at the distal part of the first part of the duodenum, and 11% were located in the jejunum. Gastrinoma patients often have medium-sized or small ulcers (diameter less than 10mm), but a few ulcers are larger, with a diameter exceeding 20mm, and they are more prone to anastomotic ulcers at the proximal or distal ends after surgery, and they often accompany serious complications such as hemorrhage and/or perforation. Gastrinoma patients can also develop reflux esophagitis, esophageal ulcers, and esophageal stenosis, and digestive reflux diseases caused by gastrinoma patients are more common and severe.

　　More than 1/3 of gastrinoma patients have diarrhea, and it can occur up to 8 years before the symptoms of peptic ulcer disease. Approximately 7% of gastrinoma patients have diarrhea without peptic ulcer disease. Diarrhea is mainly caused by a large amount of hydrochloric acid in the upper gastrointestinal tract. By aspirating the gastric juice, diarrhea can be reduced or eliminated. The gastrin in the circulation may directly affect the secretion and absorption of the small intestinal mucosa, especially an excessively high level of gastrin in the blood can increase intestinal secretion of K and reduce the absorption of water and sodium in the jejunum, all of which can lead to diarrhea. The serum gastrin and gastric acid secretion rate in patients with common duodenal ulcer are normal, and they usually do not have diarrhea, which is also the supporting evidence for this theory.

　　A small number of gastrinoma patients have steatorrhea, and the mechanism of steatorrhea is related to the following factors:

　　1. Lipase is easily acidified by a large amount of hydrochloric acid in the upper small intestine, causing irreversible denaturation and inactivation. After inactivation, lipase cannot hydrolyze triglycerides into diglycerides, monoglycerides, and fatty acids, causing obstruction in fat absorption.

　　2. The low pH in the small intestine makes some primary bile acids unable to dissolve, reducing the formation of lipid micelles, which are necessary for the absorption of fatty acids and monoglycerides.

　　Patients with gastrinoma may have poor absorption of vitamin B12, which is not related to intrinsic factor. Although the function of secreting intrinsic factor is normal, the low pH in the small intestine affects the function of intrinsic factor in promoting the absorption of vitamin B12 in the distal jejunum. When the intestinal pH is adjusted to 7, this function is restored.

　　Stomach disease is a common disease, including various types of gastritis such as superficial gastritis, atrophic gastritis, ulcer disease, as well as benign and malignant tumors in the stomach. Clinical experience proves that stomach disease is preventable, which is to pay attention to the 'Ten Abstentions' in life.

　　1Abstain from long-term mental stress

　　Long-term mental stress can affect the autonomic nervous system through the cerebral cortex, causing the vessels of the gastric mucosa to contract, gastric function to be disordered, and excessive secretion of gastric acid and pepsin, leading to gastritis and ulcers. Clinically, patients with long-term stress and anxiety or depression have a significantly higher incidence of gastric and duodenal ulcers.

　　2. Abstain from overexertion

　　Whether engaged in physical labor or intellectual labor, one cannot overwork, otherwise it will cause insufficient blood supply to the digestive organs, disordered secretion of the gastric mucosa, and lead to various stomach diseases.

　　3. Abstain from unbalanced diet

　　Unbalanced diet can cause great harm to the stomach. When hungry, the stomach is empty, and the gastric acid and pepsin secreted by the gastric mucosa are easily harmful to the gastric wall, leading to acute or chronic gastritis or ulcers. Overeating can cause the gastric wall to overexpand, and food to stay in the stomach for too long, which also easily leads to acute or chronic gastritis or ulcers, or even acute gastric dilation or perforation.

　　4. Abstain from excessive alcohol consumption

　　Alcohol can cause congestion and edema of the gastric mucosa, even erosion and hemorrhage, leading to ulcers. Long-term alcohol consumption also damages the liver, causing alcoholic cirrhosis, and the occurrence of pancreatitis is also related to excessive alcohol consumption. These damages can further exacerbate the damage to the stomach.

　　5. Abstain from the habit of smoking

　　Smoking can cause vasoconstriction of the gastric mucosal blood vessels, reducing the synthesis of prostaglandins in the gastric mucosa, which is a protective factor for the gastric mucosa. The reduction of prostaglandins can harm the gastric mucosa. Smoking also stimulates the secretion of gastric acid and pepsin, so the habit of smoking is an important cause of various gastric diseases.

　　6. Abstain from strong tea and coffee

　　Both strong tea and coffee are central nervous system stimulants that can cause the gastric mucosa to become congested, disrupt secretion function, and damage the mucosal barrier through neural reflexes and direct effects, leading to the occurrence of ulcer disease. In addition, attention should be paid to the moderate consumption of foods that are strongly irritating to the stomach.

　　7. Abstain from eating food in a hurry

　　Chewing food slowly and thoroughly is conducive to digestion, while eating in a hurry increases the burden on the stomach. Studies have also found that when eating slowly, the secretion of saliva increases, which plays a role in protecting the gastric mucosa and can prevent harmful substances from damaging the gastric mucosa.

　　8. Abstain from eating before going to bed

　　Eating before going to bed not only affects sleep but also stimulates gastric acid secretion, making it easy to trigger ulcers.

　　9. Abstain from unhygienic behavior

　　It has now been found that Helicobacter pylori infection is the primary cause of the onset of gastritis, ulcers, and gastric cancer. It can be transmitted through tableware, toothbrushes, kissing, and other means. Therefore, paying attention to hygiene, not using others' tableware or toothbrushes, can prevent Helicobacter pylori infection and thus prevent various gastric diseases.

　　10. Abstain from monitoring drugs

　　Long-term use of many drugs can damage the gastric mucosa, leading to erosive gastritis and hemorrhagic gastritis, as well as the occurrence of gastric ulcers. Among them, the commonly used drugs that can damage the gastric mucosa are divided into three categories: one is antipyretic and analgesic drugs such as aspirin, indomethacin, and phenylbutazone; another is hormone drugs such as prednisone and dexamethasone; and the third is antibacterial drugs such as erythromycin. When using these drugs, it is necessary to strictly follow the doctor's advice and use them cautiously to avoid causing damage to the stomach.

　　First, laboratory examination for gastrinoma

　　1. Gastric acid secretion measurement:The majority (79%) of gastrinoma patients have a baseline gastric acid secretion rate greater than 15mmol/h, which can reach up to 150mmol/h. Some people believe that comparing the baseline gastric acid secretion with the maximum stimulated gastric acid secretion is useful for diagnosing gastrinoma, but even some normal people may have high acid secretion rates. Moreover, the baseline acid secretion of 1/2 to 2/3 of gastrinoma patients is also less than 60% of the maximum acid secretion, so its value is still questionable. Currently, many medical institutions no longer use this technique, and some other diagnostic methods have basically replaced this test.

　　2. Gastrin Measurement:The most sensitive and specific method for diagnosing gastrinoma is to measure the serum gastrin concentration. In patients with ordinary ulcers and normal individuals, the average fasting serum gastrin level is 50～60pg/ml (or less), with the upper limit at 100～150pg/ml. The fasting serum gastrin level in patients with gastrinoma is usually >150pg/ml, with an average level of about 1000pg/ml, and sometimes it can be as high as 450,000pg/ml. In clinical cases with symptoms of peptic ulcer and high gastric acid secretion, if the fasting serum gastrin concentration is significantly increased (>1000pg/ml), the diagnosis of gastrinoma can be established. There are reports that when the fasting serum gastrin level in patients with gastrinoma is >1500pg/ml, there is a high suspicion of metastatic gastrinoma.

　　If there is a history of hypergastrinemia or urinary tract stones, unexplained diarrhea, multiple ulcers, or ulcers occurring at the distal duodenum or jejunum in patients suspected of having gastrinoma, the serum gastrin level should be tested; for patients with a family history of endocrine diseases, especially multiple endocrine neoplasia type 1, recurrent ulcers after surgery, and those whose ulcer symptoms cannot be improved with medication, this test should also be performed.

　　It should be noted that some diseases that cause a decrease in gastric acid secretion can also lead to increased serum gastrin levels, such as pernicious anemia. Patients with pernicious anemia have serum gastrin levels comparable to those with gastrinoma, but the pH value of the gastric contents in patients with pernicious anemia will not be less than 6 even under maximum stimulation, and the infusion of 0.1mmol/L hydrochloric acid can reduce their serum gastrin levels to approximately normal, which helps differentiate from gastrinoma.

　　Secondly, Imaging Examinations for Gastrinoma:

　　1. X-ray Barium Meal Examination:Abnormal radiographic findings have certain value in the diagnosis of gastrinoma, with the gastric folds often significantly prominent and the stomach containing a large amount of fluid. However, similar large gastric folds are also seen in patients with giant hypertrophic gastritis, gastric lymphoma, or other infiltrative diseases. Other X-ray signs of gastrinoma include: thickening and widening of the mucosal folds of the entire duodenum and part of the jejunum, duodenal dilation, separation of small intestinal loops, and a large amount of fluid in the small intestinal lumen, causing irregular flocculent precipitation of barium. Upper gastrointestinal barium meal examination generally cannot show pancreatic gastrinoma, but it often can reveal a tumor protruding from the duodenal wall.

　　2. Stimulation Test:Several gastrin stimulation tests have been used for the diagnosis of gastrinoma, and these tests are of great value for patients with不明显 increased serum gastrin levels. If the patient's clinical manifestations are highly suggestive of gastrinoma and the serum gastrin concentration is at the critical or slightly increased level (150～1000pg/L), the stimulation test is essential for establishing or excluding the diagnosis. The main stimulation tests include: secretin stimulation test; calcium stimulation test; standard meal stimulation test. Each test requires multiple measurements of serum gastrin concentration.

　　(1) Secretin stimulation test: It is the most valuable stimulation test for diagnosing gastrinoma patients. In normal people or patients with common duodenal ulcers, the serum gastrin level may slightly decrease, remain unchanged, or slightly increase after intravenous injection of secretin. In contrast, gastrinoma patients often show a marked increase in serum gastrin concentration after intravenous injection of secretin. Currently, pure porcine secretin 2U/kg is injected intravenously within 30 minutes, and the serum samples are measured by radioimmunoassay. Gastrinoma patients show a significant increase in serum gastrin concentration at least rapidly (within 2-10 minutes) after intravenous injection of secretin, and then gradually return to the level before injection. After intravenous injection of secretin, over 95% of gastrinoma patients show a positive response, and the false-positive rate of this test is rare.

　　(2) Calcium stimulation test: In the calcium stimulation test, blood samples are taken to measure the radioimmunomarked gastrin in the blood sample 30 minutes before the injection of calcium, and then the radioimmunomarked gastrin in the blood sample is measured every 30 minutes after the start of the experiment, a total of 9 times. 80% of gastrinoma patients show an increase in gastrin release after calcium infusion, and most gastrinoma patients show a significant increase in concentration (increase > 400pg/L), while normal people or common ulcer patients only show a slight increase, and the highest gastrin concentration is usually reached at the initial injection. The sensitivity and specificity of the calcium stimulation test are lower than those of the secretin stimulation test. If gastrinoma patients do not have a positive response to the secretin stimulation test, they generally will not have a response to the calcium stimulation test either.

　　(3) Standard meal stimulation test: The standard meal includes 1 slice of bread, 200ml of milk, 1 boiled egg, and 50g of cheese (including 20g of fat, 30g of protein, and 25g of carbohydrates). Blood is drawn to measure gastrin levels at 15 minutes before, 0 minutes, and every 1 minute after eating until 90 minutes after eating.

　　The characteristics of serum gastrin in gastrinoma patients include fasting hypergastrinemia (over 150pg/L), a rapid and significant increase in serum gastrin after intravenous injection of secretin (increase over 200pg/L), a significant increase in serum gastrin after calcium infusion (increase over 400pg/L), and the most common error in interpreting fasting serum gastrin levels is to make a diagnosis of gastrinoma as soon as hypergastrinemia is found. It should be noted that hypochlorhydria or insufficient hydrochloric acid is more commonly associated with hypergastrinemia than gastrinoma. Once fasting hypergastrinemia is present, it should be determined whether it is caused by excessive hydrochloric acid secretion, insufficient hydrochloric acid, or hypochlorhydria. The above tests should be completed before starting any provocative test (such as secretin stimulation test). If hypergastrinemia is caused by hypochlorhydria or insufficient hydrochloric acid, there is no need for further examination of gastrinoma. The following are 3 diseases with gastrin stimulation tests.

　　3. Gastrinoma tumor localization:After the diagnosis of gastrinoma is confirmed, it is necessary to localize the gastrinoma. However, determining the location of the gastrinoma is often very difficult, even impossible to localize. About 40% to 45% of patients have definite clinical and laboratory evidence, but the tumor is not found during surgery. Somatostatin receptor scintigraphy has a higher sensitivity than other imaging methods and is usually the first choice, although CT has a lower sensitivity for primary tumors, it is widely used due to its ease of implementation and can also be used to detect abdominal metastases.

　　If there are obvious liver metastasis foci, surgical resection or percutaneous biopsy can be performed. Bone metastasis foci only occur in patients with liver metastasis foci, and accurate detection can be obtained through somatostatin receptor scintigraphy. If no tumor or metastasis is found, but the clinical suspicion is still high, endoscopic ultrasound or dual-source CT scanning can be used.

　　If these methods still cannot localize the tumor, the patient can undergo angiography. Recent research suggests that selective angiography can detect about 1/3 of gastrinomas with clinical and biochemical evidence (about 60% can be found by surgery). However, angiography cannot distinguish between pancreatic tumors and their adjacent duodenal wall tumors, and selective portal and hepatic artery angiography is the best means to identify and judge the liver metastasis of gastrinomas. CT scanning can show about 30% of gastrinomas. Ultrasound examination has a lower sensitivity, with a positive rate of only 15%. It is reported that the combined use of selective angiography and CT can detect 44% of gastrinoma patients' gastrinomas and 80% of gastrinomas localized later during surgery. However, both visceral angiography and CT cannot diagnose tumors with a diameter less than 1.5 cm, and the positive rate of MRI for gastrinomas is not high either, with its value approximately equivalent to that of abdominal ultrasound. The positive rate of MRI for diagnosing liver metastatic gastrinomas is not as high as that of selective angiography and CT, and it cannot detect tumors with a diameter less than 1 cm, and the detection rate of tumors larger than 3 cm is only 30%. Recent research believes that new magnetic resonance imaging technology has great value in gastrinoma localization. Upper gastrointestinal endoscopy can detect gastrinomas located in the proximal duodenal wall, and the combination of the above-mentioned examination techniques is more effective than using a single method.

　　The concentration gradient of gastrin in the portal vein and its tributaries has been used for gastrinoma localization, but the technical difficulty is great. Some scholars believe that the positive rate of this examination is approximately equivalent to that of CT, while others report that when all imaging examinations are negative, it can detect about 63% of the lesions. Recently, there have been reports of using selective injection of secretin into the superior mesenteric artery, splenic artery, and gastroduodenal artery to localize gastrinomas, thus obtaining gastrinoma localization based on the different distribution of gastrin in the arterial blood vessels of the organs after injection. Selective secretin arterial injection test can be used for the localization of gastrinomas that cannot be detected by CT, ultrasound, and selective arteriography.

　　Gastrinoma食疗方法: 15 grams of hawthorn (with kernel), 3 grams of notoginseng, 50 grams of glutinous rice, boil the above medicine with water to make a porridge, and then add a suitable amount of honey for consumption. Gastric cancer or colorectal cancer patients should drink this porridge on an empty stomach every morning, and 15 days is a course. This recipe has the effects of invigorating the spleen and intestines, softening hard masses, and dissipating accumulations.

Dietary注意事项 for gastrinoma patients

　　1. Eat Less Fried Foods:Because these foods are not easy to digest, they will increase the burden on the digestive tract, and eating too much will cause indigestion, and will also increase blood lipids, which is not good for health.

　　2. Eat Less Canned Foods:These foods contain a lot of salt and certain carcinogens, and should not be eaten in large quantities.

　　3. Eat Less Cold and Spicy Foods:Cold and刺激性强的食物对消化道黏膜具有较强的刺激作用，容易引起腹泻或消化道炎症。

　　4. Regular Diet:Studies have shown that regular meals and quantitative intake can form conditioned reflexes, which are conducive to the secretion of digestive glands and more beneficial for digestion.

　　5. Regular and Quantitative Intake:It is necessary to have moderate food intake at each meal, have three meals a day at regular times, and actively eat regardless of whether one is hungry or not at the designated time, avoiding overeating or under-eating.

　　The greatest threat to the life of gastrinoma patients is not the complications of ulcers but the invasion of malignant tumors. The treatment goal for gastrinoma patients is to control ulcers, prevent complications, and control tumor progression.

　　1. Treatment of gastrinoma

　　Before effective acid-suppressing treatment appears, the main cause of death in gastrinoma patients is peptic ulcers and their complications. Total gastrectomy is the only effective solution. The introduction of H2 receptor blockers and proton pump inhibitors has greatly reduced the incidence and mortality rates of the syndrome with peptic ulcers, effectively avoiding total gastrectomy. Now, the greatest threat to the life of gastrinoma patients is not the complications of ulcers but the invasion of malignant tumors. Data show that more than 50% of gastrinoma patients who have not undergone surgical resection die of direct invasion by the tumor. The treatment goal for gastrinoma patients is to control ulcers, prevent complications, and control tumor progression.

　　1. Medical treatment:The main objective of medical treatment for gastrinoma patients is to alleviate clinical symptoms, inhibit gastric acid secretion, and prevent peptic ulcers, with the basis of treatment being the use of acid-suppressing drugs. All gastrinoma patients should periodically titrate gastric acid concentration to determine the dosage of acid-suppressing drugs, aiming to reduce gastric acid secretion to less than 10 mmol/h before the next dose.

　　It has been reported that two special subgroups of gastrinoma patients (patients with partial gastrectomy and those with gastrinoma complicated with moderate or severe gastroesophageal acid reflux) need to be more actively treated to reduce gastric acid secretion than other gastrinoma patients, and maintain it at

　　(1) Proton pump inhibitors: Proton pump inhibitors such as omeprazole, lansoprazole, pantoprazole, rabeprazole, and esomeprazole effectively inhibit gastric acid secretion by irreversibly binding to the H-KATPase of parietal cells, with an effect that can last for more than 24 hours, and many patients can be administered once daily.

　　Gastrinoma patients can start treatment with omeprazole 60mg once daily, lansoprazole 45mg once daily, or rabeprazole 60mg once daily. Some patients may require higher doses at the beginning of treatment, but once the gastric acid secretion is controlled, the dosage of the drug can usually be gradually reduced. For example, a study included 37 gastrinoma patients using high-dose omeprazole, and the research found that nearly 50% of the patients could reduce the maintenance dose to 20mg once daily over the past two years. In summary, 95% of patients with MEN-I syndrome, severe gastroesophageal reflux disease, or a history of partial gastrectomy can safely reduce the dosage of the drug. Before reducing the dosage of the drug, the gastric acid secretion should be measured for 2 weeks for each patient. If symptoms recur or the gastric acid secretion is greater than 10mmol/h before the next dose, the original dose must be restored.

　　(2) H2 receptor antagonists: The advent of H2 receptor antagonists has made it possible for the medical treatment of gastrinoma patients. H2 receptor antagonists can alleviate symptoms, reduce acid secretion, and cure ulcers. Cimetidine is the first H2 receptor antagonist proven to be effective, which can cure 80% to 85% of the ulcers in gastrinoma patients, and ranitidine and famotidine are also effective. The dosage of H2 receptor antagonists used in the treatment of this disease is much higher than that of common duodenal ulcers. To reduce the patient's gastric acid secretion to a satisfactory level (less than 10mmol/h), the average daily dosage of H2 receptor antagonists is: cimetidine 7.8g (1.2-13.2g), ranitidine 2.1g (0.6-3.6g), and famotidine 0.24g (0.08-0.48g). H2 receptor antagonists have no effect on serum gastrin levels and the biological behavior of gastrinomas. It is not uncommon for gastrinoma patients to be sensitive to H2 receptor antagonist treatment at the beginning and then develop resistance. After long-term treatment observation, it was found that 50% of the patients failed to respond to H2 receptor antagonist treatment, and there was no significant correlation between symptom control and ulcer cure or recurrence after H2 receptor antagonist treatment. Therefore, some scholars suggest that the dosage of H2 receptor antagonists or other acid-suppressing agents should be adjusted to ensure that the gastric acid secretion is less than 10mmol/h before the next acid-suppressing agent is taken. The combination of H2 receptor antagonists with anticholinergic drugs can enhance the efficacy of H2 receptor antagonists in reducing gastric acid secretion.

　　(3) Octreotide: By directly inhibiting the release of parietal cells and gastrin, octreotide reduces gastric acid secretion. Natural octreotide is limited in its application due to its short half-life. The synthetic octreotide analog has a half-life of 2 hours and can be administered subcutaneously. It can reduce serum gastrin concentration for 16 hours and reduce gastric acid secretion for 18 hours. Its long-term application is not superior to omeprazole, but it can be used for acid-suppressing treatment in gastrinoma patients who need parenteral administration for a short period of time.

　　2. Surgical Treatment:Surgical resection of gastrinoma is the best treatment for gastrinoma patients, with the goal of completely resecting the tumor to eliminate high gastrin secretion, high gastric acid secretion, and peptic ulcers, and protecting patients from the invasion of malignant tumors. A careful localization and assessment of the gastrinoma should be made before surgery, and except for patients with contraindications to surgery, those who refuse surgery, and those with multiple liver metastases who are unable to undergo surgery, all other patients should undergo surgical treatment.

　　If no metastatic focus is found during surgical exploration or if metastasis is limited to lymph nodes, the possibility that the patient will die from tumor metastasis is not high. Liver metastasis is a sign of poor prognosis, with nearly 20% to 30% of patients having liver metastasis at the time of diagnosis, and 15% of these patients have metastasis limited to one lobe. Some believe that aggressive resection of intraperitoneal metastatic foci is beneficial clinically, and if the metastatic gastrinoma is limited to one lobe of the liver, complete resection is considered safe and feasible. Patients with liver-limited metastases can also undergo liver transplantation, but whether it improves survival rates is still uncertain. There are also reports of solitary primary gastrinomas originating in the liver, which are cured by complete resection of the liver tumor. There has been controversy about the surgical treatment of gastrinoma patients with MEN-Ⅰ, with some believing that patients with MEN-Ⅰ should not undergo surgery because these tumors are polymorphic and multicentric. After resection of the gastrinoma, neither a cure nor the normalization of serum gastrin levels can be achieved.

　　3. Other Surgery:The general view is that patients with hyperparathyroidism in MEN-Ⅰ should first undergo parathyroidectomy. For patients with gastrinoma, partial gastrectomy is not considered, and patients who have undergone total gastrectomy for gastrinoma should be injected intramuscularly with vitamin B12 and early oral calcium and vitamin D every month to prevent osteoporosis and osteomalacia. Performing a vagotomy of the proximal stomach at the same time as tumor resection can allow patients to avoid postoperative medication, which is particularly valuable for those who have completely removed the tumor but still cannot solve the problem of high gastric acid secretion. Most scholars believe that in exploratory surgery, vagotomy of the proximal stomach should be performed in all patients. Observations of 124 patients who had no tumor metastasis found in imaging examinations and underwent surgical treatment showed a decrease in mortality rate. Among the 98 patients followed up for 6.3 years after tumor resection, only 3% showed liver metastasis, whereas, among the 26 patients treated medically over an 8.7-year follow-up period, 23% had tumor metastasis. Two patients in the medical treatment group died of metastatic gastrinoma, while no patient in the surgical group died directly from the tumor.

　　Gastric acid secretion may not necessarily return to normal after resection of the gastrinoma, which may be due to the nutritional effects of the long-term elevated gastrin before surgery and the excessive gastrin remaining after surgery on the gastric mucosal cells. nearly 40% of patients still need to extend the acid-suppressing drug treatment to control the increased gastric acid secretion after surgery, and these patients also need to monitor the gastric acid secretion.

　　Gastrinoma patients who have undergone complete tumor resection usually have their serum gastrin levels immediately drop to normal, gastric acid secretion decreases, ulcers heal, diarrhea disappears, and survival rates are close to those of normal people. Nearly 40% of gastrinoma patients can have their tumors completely resected. Long-term omeprazole treatment for patients who cannot be resected can also reduce gastric acid secretion, alleviate symptoms of ulcers and diarrhea, and promote ulcer healing. One should not discontinue or reduce the dose of omeprazole when long-term treatment has begun, as this may have the potential to cause tumor infiltration and lead to recurrence after discontinuation.

　　Patients who cannot be surgically resected for gastrinoma and have undergone proximal gastric vagotomy may be able to reduce the dose of omeprazole. Gastrinoma patients who have undergone total gastrectomy may have improved symptoms, disappearance of ulcers, but the serum gastrin concentration of most patients does not change, only about 1/3 may have a moderate decrease in serum gastrin levels, which may be due to the resection of the gastrinoma located in the first part of the duodenum during total gastrectomy.

　　The treatment of gastrinoma patients is a lifelong process. Although the course and monitoring of each patient have individual differences, some programmed monitoring methods are introduced below: After clear resection of gastrinoma, routine evaluation should be carried out annually, including medical history and physical examination, fasting serum gastrin and gastric acid secretion determination, and secretin stimulation test. If there is progressive increase in fasting gastrin levels, one should be vigilant for tumor recurrence. If the fasting serum gastrin level is normal in the first year after surgical resection of the tumor, then 95% of the patients will have normal fasting serum gastrin levels after 3 years. In the cases of gastrinoma patients who seem to have been successfully resected, the secretin stimulation test is considered the best detection method, and regular imaging examinations are not necessary unless the fasting serum gastrin level increases or the secretin stimulation test is positive. For patients who have not found or resected or only partially resected gastrinoma, the monitoring methods are the same as before, and these patients should also measure the gastric acid secretion rate before the next dose to determine the dosage. In addition, regular evaluations should be carried out for gastrinoma patients who have not localized the tumor, including imaging examinations every 2 to 3 years to find the tumor and perform surgical resection.

　　4. Reoperation:Although surgery reduces the incidence and mortality rate of tumor metastasis, less than 30% of patients can achieve long-term biological cure. For those patients with recurrent gastrinoma that can be detected by imaging, reoperation may be beneficial. For example, in 17 patients with gastrinoma confirmed by imaging, 5 patients were able to survive without disease for a median follow-up period of 28 months, and there were no deaths in the reoperation cure group.

　　5. Treatment for patients with tumor metastasis:The liver is the most common site of gastrinoma metastasis. A study group used various imaging methods to detect it, and found that 7% of all patients had bone metastasis, 31% had liver metastasis, but all patients with bone metastasis had liver metastasis. Bone metastasis mainly affects the axial skeleton (such as the spine and sacrum), but can also affect other parts of the skeleton. Octreotide (Sandostatin) receptor scanning and MRI are the best methods to detect these lesions, the former is better in detecting bone metastases outside the axial skeleton. Gastrinoma metastasis occurs frequently in gastrinoma patients and is the most common cause of death, and there is still no effective treatment method to date.

　　6. Chemotherapy:There are different chemotherapy regimens for malignant gastrinoma, including streptozocin (streptozotocin), streptozocin plus 5-fluorouracil, or both combined with doxorubicin. In an experiment involving patients with insulinoma, the combination of streptozocin and doxorubicin was effective in 69% of patients and significantly improved survival rates. However, in the retrospective analysis of different patient groups later, there is no evidence to show that it has such a good effect. There are few studies evaluating the efficacy of systemic chemotherapy in gastrinoma patients. In a single-center study report, 10 gastrinoma patients received combined treatment with 5-fluorouracil, doxorubicin, and streptozocin, and 4 patients achieved the expected goal (tumor shrinkage of 25%), but the median effective period did not exceed 10 months. Considering these uncertain results and the side effects of chemotherapy such as bone marrow suppression and gastrointestinal symptoms, the benefits and risks should be carefully weighed before chemotherapy. There are reports suggesting that interferon alpha is effective for gastrointestinal neuroendocrine tumors including gastrinoma, and can keep 20% to 40% of patients in a stable state, but its widespread application is limited by its side effects such as influenza-like symptoms, fatigue, and depression.

　　Some scholars advocate early chemotherapy, while more scholars believe that chemotherapy should only be recommended when symptoms caused by tumor masses or organ erosion occur (the liver is always involved almost). No chemotherapy for those who are only involved by lymph nodes. Chemotherapy cannot reduce gastric acid secretion, but it has certain effects on reducing tumor volume and alleviating symptoms caused by tumor masses or infiltration. Chemotherapy cannot improve survival rates, and it is currently believed that interferon can cause tumor growth to stop in 25% of patients with metastatic gastrinoma, but it cannot reduce tumor volume or improve survival rates.

　　There are also reports suggesting that long-acting somatostatin analogs can alleviate symptoms caused by tumor activity function and slow down tumor growth in patients with malignant gastrointestinal neuroendocrine tumors, but imaging examination did not find tumor shrinkage after treatment.

　　7. Hepatic artery embolization method:Hepatic artery embolization can be used as a palliative therapy for liver metastasis of insulinoma, which has more than half of the effective rate in reducing hormone secretion or tumor shrinkage under imaging. However, its efficacy is short-lived, and its possible side effects, including pain, gastrointestinal reactions, and liver function abnormalities, limit its use.

　　8. Treatment of gastrinoma patients:General guidelines for the selection of proton pump inhibitors, which can effectively inhibit gastric acid secretion, facilitate the healing of ulcers in patients with gastrinoma, can be used during the stage of disease evaluation and before surgery; they should also be used for patients who are unable to undergo surgery or whose tumor lesions cannot be found. Stable patients require intravenous acid-suppressing drugs during disease evaluation and preoperative preparation. After careful evaluation and localization, surgery aimed at tumor resection should be performed for each patient with gastrinoma, unless the patient has clearly stated that surgery is not possible (such as when liver metastasis exceeds one lobe) or the patient refuses surgery or has contraindications to surgery. During surgery, the tumor should be identified and completely removed, and all lymph nodes involved by the tumor should also be removed. If it is safe and possible to completely remove the metastatic lesions, the liver metastatic lesions should also be removed; there is no need for a total gastrectomy. As for whether there is a need for surgery in patients with gastrinoma complicated with MEN-Ⅰ syndrome, there is still controversy. However, the improved success rate of surgery now suggests the value of tumor resection. For all first-degree relatives of patients with MEN-Ⅰ syndrome, the possibility of tumor should be considered, and it is advisable to detect fasting gastrin and perform secretin stimulation tests in this group to exclude potential tumor possibilities. For patients with a clear diagnosis of gastrinoma but who, despite maximum efforts, cannot locate and remove the tumor, both patients and doctors face several treatment options. The most cautious method is lifelong acid-suppressing drug therapy (such as omeprazole). For patients who cannot or do not want to accept lifelong drug treatment and it is impossible to completely remove the gastrinoma, consider total gastrectomy or proximal vagotomy, but it may still be necessary to take a small amount of acid-suppressing drugs for a long time after surgery.

　　Second,GastrinomaPrognosis

　　The application of general acid-suppressing and anticholinergic drugs in this disease can only achieve temporary efficacy, and it is difficult to be completely cured. According to literature reports, about half of the death causes of patients treated without surgery are complications of peptic ulcer disease rather than death from malignant tumors.

　　The mortality rate of total gastrectomy as an elective surgery is about 5%, and as an emergency surgery, it can reach as high as 50%, generally around 20%. The one-year survival rate of patients after total gastrectomy is 75%, the five-year survival rate is 55%, and the ten-year survival rate is 42%. About half of the deceased patients die of tumors. Some people believe that total gastrectomy may inhibit tumor growth and extend the life of patients. Among a group of 243 cases with proven metastatic tumors, 66% had long-term survival after total gastrectomy, while those who did not undergo total gastrectomy were only 32%. Some people also believe that total gastrectomy has no significant inhibitory effect on tumor growth, and treatment with drugs such as streptozocin or 5-FU is still needed after the operation.