胃类癌瘤

　　(一)发病原因

　　Modlin统计胃类癌已由占所有胃肿瘤的0.3％增加至0.54％，占所有类癌的2～6％。高胃泌素血症者诊断率增加更明显，可能与抑酸药物(如H2受体拮抗剂或质子泵抑制剂)的长期应用导致低胃酸、高胃泌素血症有关。同时也可能与现代诊断技术进步使该病的确诊率提高有关。有资料证实，高胃泌素血症超过4个月可引起肠嗜铬样细胞(ECL)增生，进一步可引发胃黏膜的类癌。

　　(二)发病机制

　　1.胃泌素假说人们长久以来一直认为，壁细胞分泌胃酸的调节与胃窦G细胞释放胃泌素有关。起先人们认为胃泌素直接引起壁细胞分泌胃酸，目前发现这一机制至少还包括胃底的ECL细胞。胃窦的胃泌素通过多种机制进入血液循环，随后引起ECL细胞释放组织胺，后者与壁细胞的H2受体结合，激活质子泵，引起胃酸分泌。然而，胃泌素对ECL细胞还具有营养作用，可促进ECL细胞的自身复制，导致ECL细胞增生。因此，胃泌素不仅影响ECL细胞的分泌，还对其有营养作用(图1)。胃窦部酸可通过负反馈抑制降低循环中胃泌素的浓度。胃窦分离术使酸转移，结果诱导高胃泌素血症，手术后8周发现ECL细胞显著增生。相反，胃窦切除术可引起低胃泌素血症，可降低ECL细胞的数量和体积。壁细胞分泌酸减少可反射性地升高循环中胃泌素的水平，因而抑制胃酸分泌的药物可诱导高胃泌素血症，激活ECL细胞，引起ECL细胞增生。一旦停止药物治疗，胃泌素水平降至正常，这一作用可被逆转。胃泌素假说认为胃酸分泌的有效抑制消除了胃腔内酸对胃窦胃泌素细胞的反馈抑制，引起高胃泌素血症，后者激活ECL细胞，首先引起ECL细胞弥散性增生，然后是局灶性增生，微结节形成，最后形成类癌。

　　Hirth and his colleagues continuously administered the H2 receptor antagonist BL-6341 hydrochloride to rats orally for 2 years, finding that the formation of hypergastrinemia is dose-dependent and observed the changes of ECL cells from diffuse hyperplasia, focal adenomatous hyperplasia to carcinoid formation. Moreover, they also proved through toxicological tests that the drug itself has no toxic effects, believing that its tumorigenic effect is mediated by gastrin. Bilch fed rats with feed containing H2 receptor antagonists, finding that the rats first developed hypergastrinemia, and upon autopsy, carcinoids were found in the stomach. These animal experiments indicate that hypergastrinemia is related to the formation of gastric carcinoids.

　　Recent clinical research results have verified the correctness of animal experimental results, further proving that human gastric carcinoids are mainly caused by hypergastrinemia. In 1992, Japanese scholar Toshihisa studied and analyzed 27 cases of multiple gastric carcinoids in Japan, pointing out that type A atrophic gastritis, due to its main lesion in the gastric fundus and corpus, severe destruction of parietal cells, is mostly low acid or few without acid. Prolonged acid deficiency or low acid inevitably leads to hypergastrinemia, ultimately leading to the occurrence of gastric carcinoids. Zollinger-Ellison syndrome is another cause of hypergastrinemia, with a higher risk of gastric carcinoids. 10% to 15% of those with MEN-1 eventually develop carcinoids, while the incidence rate of those without MEN-1 is similar to the general population. It has been reported that microadenomas or carcinoids (ECL cell proliferation) in patients with antrum resection disappear. Borch reported that the plasma gastrin level in patients with malabsorption anemia and argentaffin nodule hyperplasia was higher than that in patients without ECL cell proliferation, and the highest in those with carcinoid formation. To date, there has been no report of gastric carcinoids caused by long-term drug-induced hypergastrinemia in humans.

　　2. Other hypotheses exist despite the abundant evidence supporting the significant role of gastrin in promoting the formation of ECL cells in the development of carcinoids. Axelson, in his research on rats, found that porto-caval shunt can cause ECL cell proliferation even in the absence of hypergastrinemia. Treatment with omeprazole in rats undergoing porto-caval shunt induced hypergastrinemia, and the ECL cell proliferation was significantly higher compared to those treated with omeprazole alone. This suggests that, in addition to gastrin, there are also nutritional factors for ECL cells. Berendt reported three cases of multicentric gastric carcinoids with argentaffin positivity, secreting serotonin and P substance. Since this staining characteristic is a typical manifestation of EC cells in the small intestine and small intestinal carcinoids, the authors believe that the tumor originates from endocrine cells of the intestinal metaplasia type, rather than from proliferating ECL cells. Some scholars also believe that carcinoids themselves can produce gastrin-releasing factors or gastrin, rather than depending on hypergastrinemia caused by acid deficiency or Zollinger-Ellison syndrome. Solcia reviewed 44 cases of gastric cardia carcinoids and found no association between carcinoid formation and Helicobacter pylori infection.

　　Although gastric carcinoids often secrete serotonin precursors 5-hydroxytryptophan (5-HTP), histamine, and various peptide hormones, due to the lack of dopamine decarboxylase in gastric tissue, it affects the synthesis of vasoactive substances such as serotonin, so there are fewer cases of carcinoid syndrome in gastric carcinoids. If there is a carcinoid syndrome, it is often variable and mostly occurs in patients with liver metastasis, presenting with symptoms such as diarrhea and erythema of the face.

　　The clinical manifestations of gastric carcinoid are similar to those of gastric cancer, generally without characteristic symptoms. Upper abdominal pain is the most common symptom, followed by hematemesis, melena, weight loss, anemia, nausea and vomiting. The clinical manifestations of gastric carcinoid are variable and often accompanied by other gastrointestinal diseases, endocrine diseases, and autoimmune diseases, etc. It can coexist with diseases such as chronic atrophic gastritis, peptic ulcer, gastric cancer, hypothyroidism, diabetes, esophageal cancer, prostate cancer, Crohn's disease, and cerebral arteriovenous malformations. Gough et al. conducted a retrospective analysis of the clinical symptoms of 36 cases of gastric carcinoid, of which 72% had anemia (58% pernicious anemia), 69% had abdominal pain, 11% had carcinoid syndrome. Among the accompanying diseases, chronic atrophic gastritis accounted for 67%, hypothyroidism accounted for 39%, diabetes accounted for 19%, Addison's disease accounted for 6%, hyperparathyroidism accounted for 6%, and a few patients had no clinical symptoms at all, but were accidentally found during surgery or endoscopic examination.

　　Hakan et al. divided gastric carcinoid into 4 types:

　　1. Type I: Accompanied by A-type chronic gastritis, it is a common type, accounting for about 65%, with tumors mainly occurring in the fundus and body mucosa of the stomach. There is A-type chronic atrophic gastritis or pernicious anemia accompanied by G-cell hyperplasia in the gastric antrum, leading to hypergastrinemia. The lesions are mostly multiple polypoid lesions with a diameter less than 1.0 cm. The tumor grows slowly and rarely occurs lymphatic or hematogenous metastasis. The malignancy is low, and the 5-year survival rate after treatment is more than 95%.

　　2. Type II: Also known as disseminated type, it is the most common type reported in clinical practice, accounting for about 21%, with tumors occurring in the mucosa of the lesser curvature of the gastric antrum. It is rarely complicated by chronic atrophic gastritis and hypergastrinemia. The lesions are mostly solitary, isolated nodules with a diameter greater than 2.0 cm. There is an increase in histamine excretion in urine, with obvious endocrine symptoms. In advanced stages, there is often metastasis, with lymphatic metastasis accounting for 55% to 80%, hematogenous metastasis for 20% to 30%, and a higher degree of malignancy.

　　3. Type Ⅲ: This type is accompanied by type Ⅰ Zollinger-Ellison syndrome. This type may have a deletion at chromosome 11q13 site, and it often occurs in the mucosa of the gastric fundus. Chronic atrophic gastritis is usually mild, with marked hypergastrinemia. The malignancy and prognosis of this type are between types Ⅰ and Ⅱ.

　　4. Type Ⅳ: This type is accompanied by other rare endocrine tumors within the stomach, such as G-cell tumors, neuroendocrine cancers, and mixed endocrine-exocrine tumors, etc. Carcinoma tissue containing only a small number of endocrine cells is not included in this type. These tumors have low malignancy and slow development, but the symptoms caused by various hormones secreted by the tumor tissue are obvious. Foreign scholars generally hold the same opinions on types Ⅰ and Ⅱ in the above classification, but there is not enough unity of understanding for other types. Some Chinese scholars also divide gastric carcinoid into three types, and classify gastric carcinoids with Zollinger-Ellison syndrome or multiple endocrine adenoma type Ⅰ syndrome as type Ⅲ. However, regardless of the typing view, it is generally believed that gastric carcinoid induced by gastrinemia is a benign or low-grade malignant tumor, often manifested as multiple small tumors. Other types of gastric carcinoid have a higher malignancy and often accompanied by metastasis. Lymph nodes, liver, and bones are common sites of metastasis.

　　Food diversity

　　Pay attention to food diversity, with plant-based foods as the main component, which should account for more than 2/3 of each meal. Plant-based diets should contain fresh vegetables, fruits, legumes, and coarse grains.

　　Control weight

　　Avoid being overweight or underweight. After adulthood, the weight increase should not exceed 5kg. Overweight or obesity can easily increase the risk of endometrial cancer, renal cancer, and colorectal cancer.

　　Do not eat charred food

　　Avoid burning the meat juice when grilling fish or meat. Fish, meat, and smoked meat grilled directly over the fire should only be consumed occasionally. It is best to cook, steam, or stir-fry food.

　　Eat more starchy foods

　　Consume 600-800g of various cereals, legumes, and plant tubers every day, and the less processed, the better. Intake of refined sugars should be limited. Starch in food has a preventive effect on colon cancer and rectal cancer, and a high-fiber diet may prevent the occurrence of colon cancer, rectal cancer, breast cancer, and pancreatic cancer.

　　The serum carcinoembryonic antigen (CEA) in patients with carcinoid tumors rarely increases, therefore, a gastric cancer patient with normal CEA should consider the possibility of a carcinoid. 65% of patients have elevated serum gastrin levels, and about 66% of tumors in patients with normal serum gastrin levels are greater than 2.0 cm, indicating that the malignancy of this type of carcinoid is high. Large amounts of 5-HTP can be found in urine tests, and a small amount of 5-hydroxyindoleacetic acid (5-HIAA) can also be detected, meaning that the ratio of 5-HTP to 5-HIAA in urine increases, which is a characteristic urinary examination finding of gastric carcinoid.

　　1. X-ray examination

　　X-ray examination has little diagnostic value for submucosal carcinoid, is effective in detecting polypoid carcinoid, and for polyps larger than 2cm, gastrointestinal barium meal can show circular or oval filling defects. Sometimes there is a depression in the center of the shadow. When ring-shaped filling defects are found, the edges are整齐 and sharp, the surrounding boundaries are clear like a knife cut, the central depression is relatively regular, and it should be considered as a possible carcinoid. Balthazar et al. summarized its X-ray manifestations into four types: solitary intramural filling defect type, multiple gastric polyp type, large ulcer type, and polypoid intraluminal tumor type.

　　2. Endoscopic examination

　　Nakamura described the characteristics of the endoscopic findings in 8 cases of gastric adenocarcinoma as follows:呈息肉状改变，多见于胃底，胃体，突起多数无蒂，个别有蒂，单发者多，呈灰白色至粉红色，外表为正常黏膜覆盖，光滑圆形黏膜下肿块伴有不规则的凹陷性红斑或溃疡是胃类癌的特征性表现，于此处取活检阳性率高，胃恶性类癌的胃镜下表现很难与胃癌相鉴别，胃镜结合活检是诊断类癌的最佳工具，for patients who cannot be diagnosed by routine biopsy, endoscopic mucosal resection biopsy can be adopted. Giovannini reported that ultrasound endoscopy can provide the location and surrounding infiltration of submucosal carcinoid before surgery.

　　3. Radionuclide scanning

　　Radionuclide scanning has been used in clinical localization diagnosis of carcinoid tumors in recent years, and can detect small lesions that cannot be displayed by B-ultrasound and CT, with a positive rate of 80% to 90%. Radio-labeled somatostatin analogs help determine the location and invasion depth of the tumor.

　　4. Other examinations

　　Ultrasound, CT, and magnetic resonance imaging are of guiding significance for the diagnosis of primary or metastatic liver cancer. CT rarely detects primary gastric adenocarcinoma and is only helpful in determining whether there are lymph node and liver metastases. Under ultrasound guidance, liver puncture or abdominal mass puncture biopsy can help clarify the diagnosis, while endoscopic ultrasound or endoscopic ultrasound examination can simultaneously make a diagnosis of tumor size, tissue invasion depth, and whether there is lymph node metastasis.

　　Since gastric adenocarcinoma occurs in the stomach, the occurrence of the disease is definitely related to our daily diet and lifestyle. Therefore, to prevent stomach cancer effectively, we should pay attention to our diet in life, control our mouths, and eat more foods that are beneficial to prevent diseases. For example, eating the following five foods can effectively prevent stomach cancer.

　　Garlic:This is the first choice of food for preventing stomach cancer, and it is recognized by the public as a preventive food for stomach cancer, with obvious anticancer effects. Epidemiological studies show that the incidence of stomach cancer is very low among people who eat raw garlic, because garlic can significantly reduce the content of nitrite in the stomach, reduce the possibility of nitrosamine synthesis, and thus has a preventive effect against cancer.

　　Onion:Eating onions frequently in our diet can effectively reduce the content of nitrite in the stomach, and the most important point is that onions contain a substance called quercetin, which is a natural anticancer substance. Studies show that people who eat onions regularly have a 25% lower incidence of stomach cancer than those who eat little or no onions, and the mortality rate of stomach cancer is also 30% lower.

　　Mushroom foods:主要包括有冬菇、香菇、金针菇等以及木耳等。If long-term consumption of these foods in the diet has a good anticancer effect and can prevent cancer. For example, the polysaccharides in mushrooms have a very high anticancer rate. The polysaccharides contained in black fungus and white fungus are also effective anticancer substances. The coarse fibers and calcium in mushroom foods have anticancer effects and can also enhance the body's immunity.

　　Tomato:The most abundant substances in tomatoes are lycopene and beta-carotene, both of which are antioxidants, especially lycopene, which can neutralize free radicals in the body and is beneficial for preventing gastric cancer and digestive system cancers.

　　Broccoli:The most important anticancer substance in broccoli is the trace element molybdenum, and its content is quite rich, which can block the synthesis of carcinogenic substances nitrosamines and play an anticancer and anticarcinogenic role. Some research reports indicate that broccoli also contains an enzyme called sulfoxide that can stimulate cell activity, which can prevent the formation of cancer cells. Eating broccoli has a certain effect on preventing esophageal cancer, gastric cancer, and other cancers.

　　(一) Treatment

　　Gastric carcinoids belong to the category of交界性肿瘤, the treatment principles should be the same as those for gastric cancer, and early surgical treatment should be performed once diagnosed. The choice of surgical method should be determined by the degree of tissue differentiation, solitary or multiple, tumor size, infiltration range, and biological behavior. Common methods include:

　　Endoscopic electrocoagulation resection, the biological behavior of type I gastric carcinoid is mostly benign, rarely progresses, and can even disappear spontaneously. Therefore, for multicentric microcarcinoids (only a few millimeters) accompanied by chronic atrophic gastritis, repeated endoscopic examinations are sufficient. Type I gastric carcinoids with a diameter of 1.0 to 1.5 cm can be resected by endoscopic electrocoagulation. Those with a diameter of 1 to 2 cm are low-grade malignant, and electrocoagulation resection can also be performed if there is no deep infiltration of the gastric wall according to histological examination. Endoscopic resection should be limited to less than 1 cm for other types of solitary gastric carcinoids, regardless of whether they are associated with MEN-Ⅰ or ZES. Emphasis is placed on regular endoscopic monitoring and follow-up after surgery to prevent recurrence.

　　Gastric antrum resection can cause hypergastrinemia to induce ECL cell hyperplasia and carcinoid formation. Gastric antrum resection can reduce the elevated gastrin level to normal, thereby reducing the risk of tumor progression. Hirschowitz reported 3 cases of pernicious anemia, hypergastrinemia, and multicentric gastric carcinoids, and the serum pepsinogen levels were all reduced to normal after gastric antrum resection. Endoscopic biopsy follow-up for 12 to 18 months showed microcarcinoid foci, and biopsy at 21 to 30 months found complete disappearance of carcinoids and ECL cell hyperplasia. Despite the plasma gastrin level being reduced to normal, multiple gastric carcinoids at the fundus could still further develop 23 months after surgery. Therefore, gastric antrum resection is suitable for early lesions, and patients with larger primary lesions accompanied by nodular hyperplasia should undergo total or subtotal gastrectomy. Regular endoscopic follow-up after surgery is required.

　　3. Local Resection for Gastric Carcinoid Tumors This surgical procedure is suitable for lesions with a diameter less than 2cm, without invasion of the serosa, and without lymph node metastasis. Local resection can be performed 2 to 3cm from the tumor margin.

　　4. Palliative Gastrectomy When gastric malignant carcinoid tumors develop multiple liver metastases, the primary lesion can still be resected.

　　5. Radical Gastrectomy and Total Gastrectomy are indicated for poorly differentiated or undifferentiated cases with tumor diameter >2cm, invasion of the serosa, or regional lymph node metastasis, or lesions presenting as diffuse or multiple. Total gastrectomy can also be performed in cases of gastrinoma with致命性溃疡, where the primary lesion is not found during exploration.

　　Christopher proposed a diagnostic and treatment model for gastric carcinoid tumors. For type I and II gastric carcinoid tumors with lesions less than 1cm and fewer than 3 to 5 in number, endoscopic polypectomy can be performed, and gastroscopy should be reviewed every 6 months after surgery. If recurrence occurs, subtotal gastrectomy or local resection should be performed. For type I and II gastric carcinoid tumors with lesions greater than 1cm and more than 5 in number, subtotal gastrectomy or local resection should be performed, and gastroscopy should be reviewed every 6 months after surgery. If recurrence occurs, total gastrectomy should be performed. Type III gastric carcinoid tumors often have local lymph node or liver metastases, and radical gastrectomy for gastric cancer should be performed.

　　The liver must be explored during surgery, and attention must be paid to the presence of metastatic foci. For patients with localized liver metastases, resection of the metastatic foci, lobectomy, or hemihepatectomy should be performed according to the situation. For patients with multiple lesions or large lesions that cannot be resected, liver artery catheter chemotherapy, subcutaneous implantation of chemotherapy pumps, ligation of the normal hepatic artery, or hepatic artery embolization, and cryotherapy can be tried to alleviate the pain of patients and prolong their survival time. The use of somatostatin analogs before surgery can prevent the occurrence of carcinoid crisis.

　　(II) Prognosis

　　Gastric carcinoid tumors generally grow slowly, and patients have a relatively long survival time after diagnosis. The overall 5-year survival rate of gastric carcinoid tumors is about 52%. The prognosis of patients depends on the histological characteristics of the lesion, the pathological type, whether there is distant metastasis, the extent of surgical resection, the severity of clinical symptoms, and the general condition of the patient. The presence of metastasis, atypical histological findings, invasion of the serosa, and tumor size greater than 2cm are poor prognostic indicators. The 5-year survival rate of localized lesions can reach about 90%, and the 5-year survival rate of localized metastases is about 23%. Poor prognosis is associated with distant metastasis, large tumor size, and carcinoid syndrome, with most patients dying within two years. Race, gender, and age have no significant impact on survival rates.