NETs in the stomach are known as Gastric NETs.
Clinically, gastric NETs are categorized into types I, II, III and some texts list a type IV. Gastrin is produced by G cells in the stomach after ingestion of food. Gastrin binds to cholecystokinin-2 receptors on ECL cells, which subsequently release histamine to activate parietal cells to produce hydrochloric acid. Acid production is regulated by negative feedback so that D cells in the antrum produce somatostatin that inhibits G cell production of gastrin. Therefore, in states where acid production is lacking (achlorhydria), there is compensatory G cell hyperplasia and hypergastrinemia that leads to ECL cell hyperplasia in an effort to boost acid production. Hypersecretory states with unchecked gastrin production, such as Zollinger–Ellison syndrome (ZES), are also predisposed to ECL cell hyperplasia and NET growth. Type I and II gastric NETs develop due to hypergastrinemia and ECL cell hyperplasia, while type III gastric NETs arise sporadically.
Type I tumors are most common and represent 70–80% of all gastric NETs. They tend to be multiple, smaller than 1 cm in size, and are often discovered incidentally or during endoscopic evaluation for anemia. Their behaviour is typically indolent, and metastases are infrequent (occurring in <10% of patients for lesions <2 cm in size). Achlorhydric conditions associated with type I gastric NETs include chronic atrophic gastritis (e.g. from type A autoimmune gastritis or vagotomy). Although long-term use of proton pump inhibitor (PPI) leads to chronic hypergastrinemia, there have only been case reports of gastric NETs associated with PPI use.
Type II gastric NETs represent 5–10% of gastric NETs. Like type I disease, they are also typically multiple, small, asymptomatic, and well-differentiated tumors. The risk of metastasis is slightly higher in type II gastric NETs compared to type I lesions but is still low. Overall, tumor invasion beyond the submucosa into the muscularis propria or lymph node and liver involvement occurs in 5–12% of cases. Type II gastric NETs are also associated with hypergastrinemia, but the feature that distinguishes them from type I tumors is their association with ZES and multiple endocrine neoplasia type 1 (MEN1) syndrome, which are hypersecretory states. Up to 30–50% of patients with MEN1 syndrome will develop gastric NETs, especially if ZES is present. Type II gastric NETs unsurprisingly have a high rate of loss of heterogyzosity at the MEN1 gene locus of 75–100%. Interestingly, 17–73% of type I gastric NETs and 25–50% of type III gastric NETs carry the same mutation, suggesting that MEN1 mutations cannot be used to distinguish among the 3 types of gastric NETs. Type II gastric NETs are typically non-functioning tumors, and symptoms upon presentation are usually secondary to peptic ulcer disease and ZES. While other genetic syndromes such as type 1 neurofibromatosis, von Hippel–Landau disease, and tuberous sclerosis complex are associated with NETs, gastric involvement is rare.
Type III. Approximately 10–15% of gastric NETs are categorized as type III tumors. These lesions typically exist as solitary larger tumors, often >2 cm in size. Histopathologically, they vary from well- to poorly differentiated tumours (where they would be called NEC), and their overall prognosis is relatively poor. Upon initial presentation, the incidence of concurrent metastasis is >50%, typically with hepatic involvement. Unlike type I and II gastric NETs, type III lesions do not have any associated predisposing conditions. Fasting gastrin levels are normal without any G cell or ECL cell hyperplasia. While type I and II gastric NETs tend to be non-functional tumours, type III NETs with hepatic metastases may be associated with carcinoid syndrome, although this occurrence is rare.
Type IV. Tends to be used for the much less common scenario of a poorly differentiated Gastric Neuroendocrine Carcinoma (NEC)
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For diagnosis and management, this succinct diagram from UKINETs is very good. Always check with your NET specialist as this may differ between countries and between healthcare systems.