What are Gastric NENs
Unlike other anatomical types, the word Gastric is used to indicate a tumour (NET) or carcinoma (NEC) in the stomach. The stomach lies at the bottom of your oesophagus and connects to the first part of the small intestine (the duodenum). Clearly a key part of the gastrointestinal system, it processes food on its journey downwards.
The stomach produces strong acid. This kills many microorganisms that might have been swallowed along with the food. It also contains special chemicals called enzymes. These are important for breaking down the food so it can be absorbed by the body. After it leaves the stomach, the partially digested food passed into the intestines where it begins to be absorbed.
The main parts of the stomach are shown below (often this can give clues about the type):
Epidemiology
Gastric neuroendocrine neoplasms (gNENs) are not as common as most other types of NET with multiple observational studies showing that they account for approximately 8% of all digestive NENs and less than 1% of all gastric neoplasms. However, the incidence of gNENs has increased in most countries over recent decades, in part because of greater awareness of the disease among clinicians, improved diagnostic techniques and more widespread use of upper gastrointestinal endoscopy. Percentages by type are given below where known. Mixed Cell tumours, i.e. Mixed Neuroendocrine Non-Neuroendocrine Neoplasms (MINEN) are possible.
General point about gastric polyps. Gastric polyps are often found incidentally on endoscopy. A one-year study conducted in the United States on 120,000 patients showed a 6% prevalence of gastric polyps found on upper endoscopy. About 70% to 90%, are hyperplastic polyps or fundic polyps. Hyperplastic polyps are asymptomatic, found incidentally, rarely carry malignant risk, and occur in the setting of chronic inflammatory conditions or H. pylori infection. In the United States and other western countries, fundic gland polyps are most common due to proton pump inhibitor (PPI) use (see below) and low prevalence of H. pylori infection. These also are unlikely to progress to malignancy. Only a biopsy can confirm if a polyp is a NEN.
Types of Gastric NENs
Like many parts of the anatomy, NENs are categorised due to their heterogenous nature. The types are not always correlated with stage or grade.
Type I
Comprising between 70 and 80% of all Gastric NENs, type I tends to be confined to the stomach and act in an indolent manner. Can present with single or multiple tumours normally less than 1cm in size are polypoid or submucosal growths. They are heavily associated with Chronic atrophic gastritis (CAG), Autoimmune CAG, pernicious anaemia (an autoimmune or genetic condition) and achlorhydria (a condition in which the stomach does not produce hydrochloric acid). Type I gNETs occur in response to hypergastrinemia (elevated fasting serum gastrin levels) in the setting of achlorhydria (gastric pH > 4) typically seen in autoimmune CAG where gastric parietal cells in the gastric body and fundus are destroyed by an autoimmune process. Mainly found in the body and fundus. Risks of metastases very low at between 2 and 5%. Most can be monitored via endoscopy (read here to read why).
Note:
- Source of Gastrin: The gastrin is released by G-cells located in the antrum (the lower part of the stomach).
- The Stimulus: Because atrophic gastritis destroys the stomach’s acid-producing cells, these G-cells overproduce gastrin in a failed attempt to trigger acid production.
- The Tumour Type: The actual tumours are made of ECL cells (enterochromaffin-like cells). These cells normally respond to gastrin by releasing histamine, but under chronic overstimulation, they begin to grow uncontrollably into NETs.
- “Non-functional” Tumours: Because Type 1 gastric NETs typically do not secrete hormones that cause clinical symptoms, they are classified as non-functional.
Type II
Comprising between 5 and 10% of all Gastric NETs and much misunderstood within the NET community. This type also presents in a setting of hypergastrinemia (elevated fasting serum gastrin levels) but unlike Type I, with hyperchlorhydria (gastric pH ≤ 2) and hypertrophic mucosa. Can present often with multiple tumours normally less than 2cm in size.
However, in a Type II gNET, the excessive gastrin is normally released from a secondary source such as from a gastrinoma in the pancreas or duodenum (Zollinger-Ellison syndrome), i.e. an existing NET. They are often associated with MEN1, rarely with sporadic ZES.
Type II gNETs are mainly found in the body, fundus and antrum of the stomach. Risk of metastases is much higher than type I with between 10 and 30% chance, so generally still a good outlook.
Type III
These are heterogenous type of gNEN which can occur sporadically and in large single tumours greater than 2cm. They are normally not related to hypergastrinemia or achlorhydria/hyperchlorhydria with normal levels of Gastrin and pH. Their heterogeneity means they can be any of the 3 NET well differentiated grades or a Neuroendocrine Carcinoma (NEC) which is poorly differentiated by default. Most type III are, however, grade 3 NET. The risk of metastases is high between 50 and 100%.
Type IV (2026 addition)
ATP4A mutation–associated ECL‑cell NET. Caused by inactivating germline or somatic mutations in ATP4A which encodes the α‑subunit of the gastric H⁺/K⁺ ATPase Mutation → chlorhydria → severe hypergastrinaemia. Hypergastrinaemia → ECL‑cell hyperplasia → NET. The difference is that the severe hypergastrinaemia, was not atrophic or autoimmune gastritis you can see in Type 1. Background mucosa shows parietal cell dysfunction, not autoimmunity. Often multiple NETs. Behaviour resembles Type 1 but can be more variable.
It is not yet clear whether the mutation is germline (hereditary), or somatic (sporadic)
WHO created this category because ATP4A‑driven NETs are:
– Distinct genetically
– Distinct pathophysiologically
– Increasingly recognised
– Not autoimmune (Type 1)
– Not MEN1/ZES (Type 2)
Type V (2026 addition)
Proton pump inhibitor (PPI)–related ECL‑cell NET Definition. Occurs in patients with long‑term PPI exposure
PPI → chronic acid suppression → compensatory hypergastrinaemia Hypergastrinaemia → ECL‑cell hyperplasia → NET
Key features
– ECL‑cell phenotype
– Hypergastrinaemia, but drug‑induced
– Background mucosa is non‑atrophic
– Usually indolent, similar to Type 1
– Often discovered incidentally
From other refences (e.g. Poynter et al., Gastroenterology, 2017, Waldum et al., Therapeutic Advances in Gastroenterology, 2019, Calvete et al., Modern Pathology, 2021
…..Risk increases with:
-10 years of PPI use
-High‑dose or continuous therapy
-Genetic susceptibility (still being studied)
Why WHO created this category because PPI‑associated NETs are now:
-Common
-Distinct from autoimmune gastritis
-Distinct from MEN1/ZES
-Distinct from sporadic Type 3 NETs
-Increasingly clinically relevant
This type is a major and overdue recognition. It is the opinion of the author that many patients with some type I and III diagnoses, may now appear in Types IV and V if reviewed.
Gastric Neuroendocrine Carcinoma (i.e. poorly differentiated)
These are rarely found but are very aggressive and treated similar to other Neuroendocrine Carcinomas. They can be small or large cell. It’s possible they have been included in Type III category and may be a loose end for clarification by WHO.
Supporting Information for Gastric NENs
What is Gastrin?
Gastrin is a hormone secreted by G cells in the stomach lining. At physiological concentrations, gastrin controls gastric acid production, and repairs and maintains the stomach lining.
When we eat food, G cells release gastrin into the bloodstream. Gastrin stimulates gastrin receptors (also called CCK2 receptors, CCK2 R) on enterochromaffin-like (ECL) cells in the stomach lining to release histamine, which in turn stimulates histamine H2-receptors (H2R) on adjacent parietal cells (acid-producing cells) to secrete acid into the stomach via the proton pump in the parietal cells. As acid rises, and food passes out of the stomach, it switches on D cells in the stomach lining to release another hormone, somatostatin, which enters the bloodstream and switches off gastrin production by the G cells.
What is Hypergastrinemia?
Anything that reduces gastric acid production (hypoacidity) results in persistently increased blood levels of gastrin (hypergastrinemia), which leads to: irregular gene expression in cells of the stomach lining; increased growth of those cells and their potential to metastasise (spread); and reduced apoptosis (natural cell death). All of those effects increase the risk of malignancy.
The main causes of hypoacidity and hypergastrinemia are:
- Autoimmune chronic atrophic gastritis (CAG), a condition in which patients make antibodies against their parietal cells. Hypergastrinaemia causes growth of ECL cells and, in some patients, formation of multiple gastric neuroendocrine tumours (gNETs).
- Inflammation of the stomach lining by infection with H. pylori bacteria. A study in an animal model has shown that hypergastrinaemia is the cause of the inflammation. H. pylori is also the main cause of stomach ulcers and gastric cancer.
- Medicines that suppress acid production, such as a proton pump inhibitor (PPI) or potassium-competitive acid inhibitor and are mainly used to treat heartburn and indigestion caused by backflow of acid (reflux) from the stomach into the oesophagus (gullet).
What is Pernicious anemia?
Pernicious anemia occurs when your body can’t absorb enough vitamin B12 to function properly. This type of anemia is called “pernicious” because it was once considered a deadly disease. Today, though, it’s relatively easy to treat. While vitamin B12 deficiency anemia may be caused by a lack of vitamin B12 in the diet, pernicious anemia is caused by an inability to absorb vitamin B12. Pernicious anemia can be autoimmune or genetic related. Associated with Type I.
Syndromes and Gastric NENs
So called ‘carcinoid syndrome‘ is very rare in gNENs and any clinical manifestation may be considered atypical consisting exclusively of redness due to certain peptides. Diarrhea can be a symptom of hypergastrinemia rather than carcinoid syndrome. Hypoacidity and hypergastrinemia are not carcinoid syndrome, the causes of those symptoms are listed above.
Type II gNET are a secondary effect of excessive gastrin is being released from a secondary source such as a gastrinoma in the pancreas or duodenum i.e. an existing NET outside the stomach. This existing NET is related to a syndrome known as Zollinger-Ellison syndrome (ZES). Gastrinomas are frequently associated with MEN1, a hereditary NET syndrome. ZES is not carcinoid syndrome.
What are Proton Pump Inhibitors?
Proton pump inhibitors (PPIs) are among the most commonly used medications in the world. They reduce the production of acid by blocking the enzyme in the wall of the stomach that produces acid. Acid is necessary for the formation of most ulcers in the oesophagus, stomach, and duodenum, and the reduction of acid with PPIs prevents ulcers and allows any ulcers that exist in the oesophagus, stomach, and duodenum to heal. PPIs are prescribed to treat acid-related conditions such as:
- Esophageal, duodenal and stomach ulcers
- NSAID-associated ulcer
- Ulcers
- Gastroesophageal reflux disease (GERD)
- Zollinger-Ellison Syndrome – ZES (note this is a syndrome associated with a functioning duodenal or pancreatic NET known as a Gastrinoma)
- They also are used in combination with antibiotics for eradicating Helicobacter pylori, a bacterium that together with acid causes ulcers of the stomach and duodenum for eradicating H. pylori, a bacterium that together with acid causes ulcers of the stomach and duodenum.
The PPI connection
This continues to be a controversial area. It is already well known that PPI use causes elevation of the gold standard NEN tumour marker to the point that many doctors no longer use the Chromogranin A test There are several other potential causes of elevation but PPI is the most common given its wide use in the general population.
More controversial is the suggestion that hypergastrinemia exerts a proliferative effect on ECL-cells in the stomach, leading to linear and micronodular ECL-cell hyperplasia and subsequently dysplasia and NET development. In the hypo-acidic stomach of patients with autoimmune chronic atrophic gastritis (CAG) or mutations of genes controlling acid production, somatostatin production by D cells is not switched on and gastrin production by G cells continues. Hypergastrinemia ensues and causes ECL-cell growth and, in some patients, gNETs, which can be seen at gastroscopy. Although PPIs also reduce acid production and cause hypergastrinemia, there are only a few case reports of gNETs in patients on long-term PPI therapy.
Two add-on points on PPI.
One NET clinic has suggested that those taking PPI could be just as well served by migration to Histamine H2 Receptor Antagonists (H2RA) that reduce the amount of acid produced by the cells in the lining of the stomach. They are also commonly called H2 blockers. This includes a tapering off timeline given the adverse effect of suddenly stopping PPI use. You can read about a suggested migration strategy by clicking here. You should NEVER stop taking PPIs without speaking to the doctor who prescribed them.
According to UKINETs, Type I Gastric NETs should preferably stop PPIs as continued use will further increase gastrin and little rationale for ongoing treatment. You should NEVER stop taking PPIs without speaking to the doctor who prescribed them.
Hereditary connections
Nothing observed other than the relationship with some Type II and MEN1 already covered under Type II.
Treatment and Surveillance
The treatment of gNETs depends on the clinical type, disease extent, the differentiation of the lesion and the presence or absence of poor prognostic factors. For the purposes of this summary, Types 1, 2 and 3 are well differentiated NETs.
This differs from regional/national guidelines but in general:
Type I gNETs will normally be managed via gastroscopy surveillance with polyp removal when necessary. B12 supplementation and treatment for iron deficiency anaemia and pernicious anaemia may be necessary. The majority of Gastric NETs are type 1.
Type II gNETs may already have a management system in place for the Gastrinoma and where applicable for MEN1. If the Gastrinoma is considered a causal factor in the gNET, surgery may be considered to remove the Gastrinoma. Endoscopic resection of gastric polyps with gastroscopy surveillance is normally sufficient if no other prognostic factors are present.
Type III gNETs may need more aggressive treatment including surgery and chemotherapy where applicable.
Type IV and 5 gNETs (added 2026). to follow once guidelines are updated.
The use of somatostatin analogues (SSA) for localised gNENs is generally not required although some Type II gNETs may already be established on SSAs via the Gastrinoma. Guidelines say they should be considered in metastatic cases and for Type II gNET if not already established. Guidelines indicate a possibility for metastatic Type III.
Guidelines
There are numerous clinical practice guidelines on management of gNETs where management of these tumours is stratified according to risk of locoregional and distant metastasis. NCCN and ENETS cited below.
NCCN
Most small gNETs can be removed with curative intent with only endoscopic surveillance going forward (Reference 6). If “invasive”, surveillance using conventional imaging (e.g. CT/MRI) can be used with more frequent checks in the short and long term (Reference 6 – page NET-8). Treatments are factored in if either functional or non-functional. (Reference 6 – Page NET-5). Metastatic cases may require additional treatment (e.g. somatostatin analogues and targeted therapies; and wider surveillance (Reference 6 – page NET-9).
ENETS
Guidance for gNETs has recently been reinforced by the publication of revised guidelines in 2023. Read more here
NEC/MiNEN
Guidelines for gNEC and MiNEN involving stomach will be similar to other NEC and MiNEN. To follow.
Resources
- Exarchou, K., Stephens, N.A., Moore, A.R. et al. New Developments in Gastric Neuroendocrine Neoplasms. Curr Oncol Rep 24, 77–88 (2022). https://doi.org/10.1007/s11912-021-01175-y
- McCarthy DM. Proton Pump Inhibitor Use, Hypergastrinemia, and Gastric Carcinoids-What Is the Relationship? Int J Mol Sci. 2020 Jan 19;21(2):662. doi: 10.3390/ijms21020662. PMID: 31963924; PMCID: PMC7014182.
- NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Neuroendocrine and Adrenal Tumors Version 2.2022 — December 21, 2022
- UKINETS Clinical Practice Management of patients with Gastric Neuroendocrine Neoplasm
- European Neuroendocrine Tumor Society (ENETS) 2023 guidance paper for gastric neuroendocrine tumours (NETs) G1–G3 (ronnyallan.net)
- 2024 thinking on Type III gNETs
- Gastric neuroendocrine tumors arising from chronic proton pump inhibitor use: characteristics and outcomes of a fourth subtype, Journal of Gastrointestinal Surgery,
Volume 29, Issue 11, 2025, 102207, ISSN 1091-255X, https://doi.org/10.1016/j.gassur.2025.102207.
(https://www.sciencedirect.com/science/article/pii/S1091255X25002665) - The indolent nature of type 1 gastric neuroendocrine tumors under 1 cm, Elisabetta Dell’Unto, Dalvinder Mandair, George Riding, Alessandro Rimondi, Maria Rinzivillo, Gianluca Esposito, Tu Vinh Luong, Edith Lahner, Jennifer Watkins, Bruno Annibale, Alberto Murino, Edward John Despott, Martyn Caplin, Marco Marini, Francesco Panzuto, Christos Toumpanakis, Digestive and Liver Disease, 2025, ISSN 1590-8658, https://doi.org/10.1016/j.dld.2025.09.011.
Clinical Trial Drug
Phase 2 clinical trials took place in several countries including UK and Norway. The manufacture never launched a Phase 3 clinical trial. Read more here or by clicking on the graphic. But this trial should not be used as a reference – it has probably been discontinued.
ENETS guidelines for Gastric NET
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Hi Ronny, thanks for this article, much appreciated – would it be ok to print a copy to give to my GP?
I have gastric NETs type 1, but I also have atypical carcinoid syndrome, proven recently by a prolonged episode of carcinoid syndrome on cessation off my prophylactic IV meds 12 hours after surgery; this meant I required 4 sub cut sandostation injections over 24 hours before it abated. Prior to this my specialist suspected it but now it is proven of course and I carry a I.C.E letter with me at all times. My specialist, as you’ve said in the article, has told me it is rare, and that he doesn’t know why I have it. I’ve read a few articles about it but they are thin on the ground.
Thank you for highlighting this rare possibility as most GP’s know very little about GNETs (or any other NETs for that matter) or carcinoid syndrome, but this article would help my GP to know a little more about my situation, especially from the atypical carcinoid syndrome standpoint.
Interestingly I was put on high strength PPI’s by my GP (14 years ago) for at least 3 – 4 years, my husband and I eventually worked out that they were making me very ill indeed – I couldn’t eat, couldn’t excrete food or even drink much by the end when I was hospitalised.
I diagnosed GNet’s myself through reading articles and insisting on a second gastroscopy because of the histology report findings on the first gastroscopy – I was finally diagnosed 5 years ago and my specialist congratulated me on my research and for catching them (GNETs) early.
I can’t thank you enough for this article.
Yes, but once printed, it will become out if date. I’m always tweaking my blogs.
(But you won’t find a better summary 🙂)