A well-differentiated neuroendocrine tumor of the stomach is a type of cancer that starts in hormone-producing cells in the stomach lining. These cells are called neuroendocrine cells. Most of these tumors grow very slowly, and many are small and found by chance during an endoscopy. An older name for this tumor is carcinoid tumor, and your report may use either name.
Doctors divide neuroendocrine tumors of the stomach into three types, and the type has a large effect on how the tumor behaves and how it is treated. This article explains the three types of neuroendocrine tumor of the stomach, how the tumor is graded and staged, and what the other findings in your pathology report mean.
Most neuroendocrine tumors of the stomach are caused by long-term exposure to high levels of gastrin. Gastrin is a hormone that tells the stomach to make acid. It also signals certain neuroendocrine cells in the stomach, called enterochromaffin-like (ECL) cells, to grow. When gastrin levels stay high for many years, these cells multiply and can eventually form a tumor.
The most common cause of high gastrin levels is atrophic gastritis, especially the autoimmune type. In atrophic gastritis, the glands that make stomach acid are damaged and lost. The body responds to the low acid by making more and more gastrin. A much less common cause is a gastrin-producing tumor called a gastrinoma, which is usually found in the pancreas or small intestine.
Some neuroendocrine tumors of the stomach develop without high gastrin levels. The cause of these tumors is not known.
Many neuroendocrine tumors of the stomach cause no symptoms. They are often found during an endoscopy to evaluate anemia or as part of follow-up for atrophic gastritis. When symptoms occur, they may include:
The diagnosis of a neuroendocrine tumor of the stomach is usually made after a biopsy taken during an upper endoscopy. Small tumors are often removed completely during the endoscopy using a procedure called endoscopic mucosal resection or endoscopic submucosal dissection. A pathologist then examines the tissue under a microscope.
Under the microscope, a well-differentiated neuroendocrine tumor consists of small, uniform cells arranged in nests, cords, or small glands. The cells have round nuclei with finely speckled chromatin, which pathologists often describe as a “salt and pepper” pattern. The term well differentiated means the tumor cells still look a lot like normal neuroendocrine cells.
Your doctor will often also take biopsies from the normal-looking lining in different parts of the stomach. These biopsies show whether atrophic gastritis is present, which helps determine the type of tumor. They may also show ECL cell hyperplasia, an increase in ECL cells caused by high gastrin levels. A blood test for gastrin and imaging such as an endoscopic ultrasound or CT scan may also be used, especially for tumors larger than 1 cm.
Immunohistochemistry is a test that uses antibodies to show which proteins are present in cells. For a neuroendocrine tumor of the stomach, it confirms that the tumor cells are neuroendocrine cells and helps separate the tumor from adenocarcinoma, the most common type of stomach cancer. Your report may describe some of the following results.
Not every laboratory performs every one of these tests, so your report may include only some of them.
The World Health Organization (WHO) classification (5th edition, 2019) divides well differentiated neuroendocrine tumors of the stomach into three types. Your pathology report may not state the type directly, because it depends on information from your doctor, blood tests, and the biopsies of the surrounding stomach lining.
The grade of a neuroendocrine tumor of the stomach describes how quickly the tumor cells are dividing. Pathologists use two measurements to decide the grade. One is the number of dividing cells, called mitotic figures, counted in an area of 2 square millimeters. The other is the Ki-67 index, the percentage of tumor cells that stain with Ki-67. When the two measurements disagree, assign the higher grade.
The size of a neuroendocrine tumor of the stomach is one of the most important findings in your report. Tumors 1 cm or smaller rarely spread, while larger tumors carry a higher risk. If more than one tumor is present, which is common in type 1 tumors, your report will usually give the number of tumors and the size of the largest one.
Depth of invasion describes how far a neuroendocrine tumor of the stomach has grown into the stomach wall. Most small tumors are found in the lamina propria or the submucosa, the layers just below the surface. Tumors that reach the thick muscle layer, called the muscularis propria, or go beyond it are more likely to spread. Depth of invasion helps determine the tumor stage.
Lymphovascular invasion means that cells from the neuroendocrine tumor were seen inside a blood vessel or lymphatic channel. Tumor cells can use these vessels to spread to lymph nodes and other organs. Finding lymphovascular invasion increases the risk of spread, and it may lead your doctors to recommend further treatment after an endoscopic removal.
Perineural invasion means that cells from the neuroendocrine tumor were seen along or around a nerve. It is uncommon in small stomach tumors. When present, it is usually seen in larger tumors that have grown deeper into the stomach wall.
A margin is the edge of the tissue that was cut to remove the neuroendocrine tumor of the stomach. For an endoscopic removal, the pathologist checks the deep margin at the bottom of the tissue and the mucosal margins around the sides. For a surgical removal of part of the stomach, the pathologist checks the proximal, distal, and omental margins.
Lymph nodes are only removed when part of the stomach is removed by surgery, which is more common for type 3 tumors. The pathologist examines each lymph node under a microscope to look for tumor cells. Your report will give the number of lymph nodes examined and the number that contain tumor. Finding tumor cells in a lymph node is called a metastasis and increases the stage.
The pathologic stage of a neuroendocrine tumor of the stomach is based on the AJCC staging system (Version 9, in use since January 2024). The stage is assigned only after the tumor has been removed, and it is often not given for small tumors removed during endoscopy. The stage combines the tumor stage (pT), the nodal stage (pN), and, when known, distant spread (pM).
If more than one tumor is present, the letter “m” may be added to the tumor stage, for example pT1(m).
Distant spread is only included in the pathology report when a tumor sample from another organ has been examined. The category pM1a means spread to the liver only, pM1b means spread to sites outside the liver, and pM1c means spread to both.
The prognosis for a person with a well differentiated neuroendocrine tumor of the stomach depends mostly on the type, size, grade, and stage of the tumor. For type 1 tumors, the outlook is excellent, and more than 95% of people are alive 5 years after the diagnosis. Type 1 tumors may come back in the stomach because the atrophic gastritis that caused them is still present, but these new tumors are usually small and easy to remove.
Type 2 tumors also have a good outlook, although about 10% to 30% spread to lymph nodes or other organs. Type 3 tumors behave more like other stomach cancers, and more than half have spread by the time they are found. For all types, small grade 1 tumors confined to the lamina propria or submucosa have the best outlook.
Treatment for a neuroendocrine tumor of the stomach depends mostly on the type and size of the tumor. The European Neuroendocrine Tumor Society (ENETS) published guidance on managing these tumors in 2023.
People with type 1 tumors also need follow-up for atrophic gastritis itself, which can cause low vitamin B12 levels and slightly increase the risk of stomach adenocarcinoma.