Well differentiated neuroendocrine tumour (NET) of the stomach is a rare type of cancer that starts from neuroendocrine cells in the lining of the stomach. Neuroendocrine cells are specialized cells that receive signals from the nervous system and release hormones into the bloodstream. NETs grow more slowly than other types of stomach cancer and often behave in a less aggressive way. However, some NETs can spread to other parts of the body and require treatment.
What causes a neuroendocrine tumour in the stomach?
Most well differentiated NETs in the stomach are caused by hormonal changes that lead to abnormal stimulation of neuroendocrine cells. One common cause is a condition called chronic atrophic gastritis, often due to autoimmunity or long-standing Helicobacter pylori infection, which results in low stomach acid and increased levels of a hormone called gastrin. The extra gastrin causes certain neuroendocrine cells (called ECL cells) in the stomach to grow and divide more than normal, which can eventually lead to the development of a NET.
There are three main types of ECL-cell NETs:
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Type 1 – The most common type, associated with autoimmune chronic atrophic gastritis.
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Type 2 – Less common, associated with a rare condition called Zollinger–Ellison syndrome, often seen in patients with multiple endocrine neoplasia type 1 (MEN1).
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Type 3 – Not associated with high gastrin levels. These tumours usually arise sporadically in otherwise normal stomach lining and tend to be larger and more aggressive.
What are the symptoms of a gastric neuroendocrine tumour?
Many NETs of the stomach do not cause symptoms and are found by chance during an endoscopy performed for another reason. When symptoms are present, they may include:
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Stomach pain or discomfort.
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Nausea or vomiting.
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A feeling of fullness after eating a small amount.
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Gastrointestinal bleeding (which may cause dark stools or anemia).
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Rarely, hormonal symptoms like flushing, diarrhea, or wheezing (called carcinoid syndrome).
How is this diagnosis made?
Gastric NETs are typically diagnosed during an upper endoscopy. During this procedure, your doctor uses a thin tube with a camera to examine the inside of your stomach. If abnormal tissue is seen, your doctor may take a biopsy (a small tissue sample) or remove the entire tumour using a technique called endoscopic mucosal resection (EMR) or endoscopic submucosal dissection (ESD).
The tissue sample is sent to a pathologist who examines it under the microscope to confirm the diagnosis and determine the tumour type, grade, and other important features.
What does a well differentiated neuroendocrine tumour look like under the microscope?
When examined under the microscope, well differentiated NETs are made up of uniform, round cells arranged in nests, cords, or small gland-like structures. The cells usually have round nuclei and a characteristic pattern of chromatin called “salt and pepper” that helps identify them as neuroendocrine.
Other tests performed to confirm the diagnosis
Pathologists use a test called immunohistochemistry to confirm the diagnosis. This test uses special antibodies to detect proteins commonly produced by neuroendocrine cells. In well differentiated NET, the tumor cells are typically positive for:
These tests help distinguish NET from other types of stomach cancer, such as adenocarcinoma.
Some NETs may also produce specific hormones depending on their cell type, such as gastrin (G-cell), serotonin (EC-cell), or somatostatin (D-cell).
WHO grade
Well differentiated neuroendocrine tumours (NETs) of the stomach are divided into three grades based on how quickly the tumour cells are dividing. The grade is important because higher-grade tumours (grades 2 and 3) are more likely to grow quickly and spread to other parts of the body. The tumour grade is determined by a pathologist after examining the tissue under a microscope.
To determine the grade, pathologists count the number of tumour cells that are dividing. These dividing cells are called mitotic figures, and the number is counted in a specific area measuring 2 mm². Immunohistochemistry for Ki-67 may also be performed. This test highlights cells that are actively growing and produces a percentage called the proliferative index (the percentage of tumour cells making Ki-67).
The three tumour grades are:
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Grade 1 (G1): Less than 2 mitotic figures per 2 mm², or a Ki-67 index of less than 3%. These tumours grow slowly and are the least likely to spread.
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Grade 2 (G2): Between 2 and 20 mitotic figures per 2 mm², or a Ki-67 index between 3% and 20%. These tumours grow more quickly than grade 1 and have a higher risk of spreading.
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Grade 3 (G3): More than 20 mitotic figures per 2 mm², or a Ki-67 index greater than 20%. These tumours grow rapidly and have the highest risk of spreading. Some grade 3 NETs may be difficult to distinguish from poorly differentiated neuroendocrine carcinomas and require additional testing.
The tumour grade helps your doctor decide which treatment options are most appropriate and how often you should be monitored after treatment.
Depth of invasion and pathologic tumor stage (pT)
Well differentiated neuroendocrine tumours start from specialized cells located in the innermost layer of the stomach called the mucosa. As the tumour grows, it can spread into deeper layers of the stomach wall.
Pathologists determine the tumour stage (pT) by examining how far the tumour has grown into the stomach:
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T1 – Tumour is limited to the mucosa or submucosa and is 1 cm or smaller.
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T2 – Tumour is larger than 1 cm and may grow into the muscularis propria.
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T3 – Tumour grows into the subserosal tissue near the outer surface of the stomach.
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T4 – Tumour grows through the outer surface (serosa) or into nearby organs.
Tumours with deeper invasion have a higher risk of spreading and may require more extensive treatment.
Perineural invasion
Perineural invasion (PNI) means that tumour cells are seen growing along or around a nerve. This is considered an aggressive feature because it suggests the tumour may spread more easily into nearby tissues. Pathologists look for this under the microscope, and if seen, it will be described as “present” in your report. If no tumour cells are found near nerves, the report will say “absent.” Perineural invasion may influence decisions about further treatment or follow-up.
Lymphovascular invasion
Lymphovascular invasion (LVI) means that tumour cells were seen inside small blood vessels or lymphatic vessels. This is important because it shows that the cancer has the potential to spread to other parts of the body, especially to lymph nodes or the liver. If no tumour cells are found in these vessels, your pathology report will say “absent” or “negative.”
Margins
A margin is the edge or border of tissue that is cut during surgery to remove a tumour. After the surgery, a pathologist examines the margins under a microscope to see if any tumour cells are present at the edge.
For stomach tumours, the following margins may be described:
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Proximal margin – The edge of the stomach closer to the esophagus.
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Distal margin – The edge closer to the small intestine (duodenum).
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Radial (serosal) margin – The outer surface of the stomach that faces the abdominal cavity.
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Deep margin – The margin at the base of the tumour, especially in endoscopic resections.
The goal of surgery is to completely remove the tumour with a clear (negative) margin. A negative margin means no tumour cells were found at the cut edge, suggesting the tumour was fully removed. A positive margin means tumour cells are present at the edge, which raises concern that some tumour may have been left behind. In some cases, the report may include the distance between the tumour and the closest margin.
Margins are important because they help doctors decide if additional treatment is needed or if the surgery was likely curative.
Lymph nodes
Lymph nodes are small immune organs found throughout the body. Cancer cells can travel from the stomach to nearby lymph nodes through small channels called lymphatic vessels. This process is called metastasis.
During surgery for a gastric neuroendocrine tumour, nearby lymph nodes are often removed and sent to the pathologist for examination. These lymph nodes may be located along:
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The lesser and greater curvature of the stomach.
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The perigastric fat (fat around the stomach).
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The celiac axis or peripancreatic region, if the tumour is large or deeply invasive.
The pathologist examines each lymph node under a microscope to look for tumour cells. If tumour cells are found, the node is called positive. If no tumour is seen, the node is negative.
The number of positive lymph nodes is used to determine the pathologic nodal stage (pN), which helps doctors assess how far the tumour has spread:
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pN0 – No cancer in any lymph nodes.
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pN1 – Cancer in 1 or 2 lymph nodes.
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pN2 – Cancer in 3 to 6 lymph nodes.
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pN3a – Cancer in 7 to 15 lymph nodes.
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pN3b – Cancer in 16 or more lymph nodes.
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pNX – No lymph nodes were available or examined.
Lymph node involvement is important because it increases the risk of the cancer spreading to other organs. It also helps guide decisions about additional treatment, such as chemotherapy or more frequent monitoring.
Prognosis
The prognosis for well differentiated NET of the stomach is generally very good, especially when the tumour is small, well differentiated (grade 1), and has not spread beyond the mucosa or submucosa. Most type 1 tumours behave in a non-aggressive way and can often be managed with endoscopic resection and regular follow-up. Larger or more advanced tumours, especially type 3 NETs, may require more extensive treatment and have a higher risk of spread or recurrence.
Questions to ask your doctor
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What grade is the tumour?
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Has the tumour been completely removed?
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What is the pathologic stage (pT and pN)?
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Was lymphovascular or perineural invasion found?
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Will I need additional treatment, such as surgery or medication?
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How often should I have follow-up endoscopies or imaging?
