Well differentiated neuroendocrine tumour of the stomach

by Jason Wasserman MD PhD FRCPC
December 11, 2024

This article is designed to help you understand your pathology report for a well differentiated neuroendocrine tumour of the stomach. Each section explains a specific aspect of the diagnosis and what it means for you.

What is a well differentiated neuroendocrine tumour?

A well differentiated neuroendocrine tumour (NET) is a type of stomach cancer that starts in neuroendocrine cells. These cells are found throughout the body, including in the stomach, and help regulate various functions by producing hormones. In the stomach, these tumours originate in specialized neuroendocrine cells that produce hormones like histamine (ECL-cell-like), gastrin (G-cell-like), or serotonin (EC-cell-like).

What are the symptoms of a well differentiated neuroendocrine tumour in the stomach?

Most neuroendocrine tumours in the stomach do not cause noticeable symptoms and are often discovered during tests for other stomach conditions.

• Histamine-producing tumours are sometimes associated with conditions like Zollinger–Ellison syndrome or pernicious anaemia and may cause stomach pain, bloating, or signs of excess acid production.
• Serotonin-producing tumours rarely cause carcinoid syndrome, including flushing, diarrhea, and breathing difficulties.
• Gastrin-producing tumours may lead to increased stomach acid and ulcers in rare cases.
• Advanced tumours can cause weight loss, pain, or bleeding.

What causes a well differentiated neuroendocrine tumour in the stomach?

Well differentiated neuroendocrine tumours in the stomach are divided into several types based on their association with different conditions and their underlying causes. These include tumours that arise from enterochromaffin-like (ECL) cells, enterochromaffin (EC) cells, and gastrin-producing G-cells. Each type has distinct features and causes.

Histamine-producing ECL-cell type 1 neuroendocrine tumours

These tumours are associated with chronic atrophic gastritis, an autoimmune condition that damages the stomach lining. This leads to achlorhydria (reduced stomach acid) and hypergastrinaemia (elevated gastrin levels), which stimulate the growth of ECL cells and increase the risk of tumour development. Autoantibodies against parietal cells or intrinsic factor are often present, and some patients may also develop pernicious anaemia (a vitamin B12 deficiency caused by a lack of intrinsic factor).

Histamine-producing ECL-cell type 2 neuroendocrine tumours

These tumours occur in the context of multiple endocrine neoplasia type 1 (MEN1), a genetic condition that causes hormone-producing tumours in various organs. In MEN1, a gastrinoma (a tumour that produces gastrin) in the duodenum or pancreas leads to hypergastrinaemia, stimulating the growth of ECL cells and tumour formation.

Histamine-producing ECL-cell type 3 neuroendocrine tumours

These tumours arise sporadically in normal stomach tissue (oxyntic or antral mucosa) and are not associated with hypergastrinaemia or chronic gastritis. They tend to behave more aggressively than type 1 and type 2 tumours. Symptoms may include stomach bleeding (melaena), pain, or weight loss. Advanced cases with extensive liver metastases may cause atypical carcinoid syndrome, which includes flushing, facial swelling, and breathing difficulties.

Serotonin-producing EC-cell tumours

This rare type of neuroendocrine tumour typically does not produce symptoms, meaning it is non-functioning. However, in rare cases, it can cause classic carcinoid syndrome, characterized by diarrhea, flushing, asthma-like breathing difficulties, and tricuspid regurgitation, a heart valve problem.

Gastrin-producing G-cell tumours

These tumours are also usually non-functioning, but in a minority of cases, they can cause Zollinger–Ellison syndrome. This syndrome results in excessive stomach acid production, leading to ulcers and other complications. The term gastric gastrinoma is used only for these functioning cases, not for gastrin-expressing tumours that lack clinical symptoms.

Where do these tumours start in the stomach?

Neuroendocrine tumours can start in different parts of the stomach depending on the type of cells involved:

• Enterochromaffin-like (ECL) cell tumours begin in the upper part of the stomach called the corpus or fundus.
• D-cell and G-cell tumours develop in the antrum, the lower part of the stomach.
• Enterochromaffin (EC) cell tumours can arise in both the corpus/fundus and the antrum.

How is this diagnosis made?

Your doctor may suspect a neuroendocrine tumour based on symptoms, imaging tests, or endoscopy. A biopsy is taken from the stomach and examined under a microscope to confirm the diagnosis. Special tests, such as immunohistochemistry, may be used to confirm the diagnosis and identify features of the tumour.

Microscopic features of this tumour

When examined under the microscope, well differentiated neuroendocrine tumours have specific features:

• Histamine-producing tumours: Cells are organized in small clusters or trabeculae with pink cytoplasm and round nuclei.
• Serotonin-producing tumours: Form rounded nests of uniform cells.
• Gastrin-producing tumours: Show ribbon-like patterns of small cells with minimal cytoplasm.

Your pathologist may also observe changes in the surrounding stomach lining, such as inflammation or hyperplasia (increased cell growth).

Immunohistochemistry

Immunohistochemistry is a special test that pathologists use to detect specific proteins in tumour cells. This test is commonly performed to confirm the diagnosis of a well differentiated neuroendocrine tumour by identifying general markers found in neuroendocrine cells, such as synaptophysin and chromogranin A.

Although neuroendocrine tumours in the stomach can produce hormones like histamine, serotonin, or gastrin, pathologists rarely test for these specific hormone markers. Hormone-specific tests are not usually necessary for diagnosis or treatment decisions. When performed, these tests may provide additional information about the tumour type but are not typically included in most pathology reports.

WHO grade

Well differentiated neuroendocrine tumours in the stomach are divided into three grades based on how quickly the tumour cells divide. This information is important because higher-grade tumours (grades 2 and 3) are more likely to spread to other body parts. The grade can only be determined after examining the tumour under a microscope.

Pathologists measure the number of dividing tumour cells, called mitotic figures, to determine the grade. The number of mitotic figures is typically counted in an area measuring 2 mm2. To highlight cells capable of dividing, a special test called immunohistochemistry for Ki-67 may also be performed. The results are used to calculate the proliferative index (the percentage of tumour cells producing Ki-67).

• Grade 1 (G1): Mitotic rate of less than 2 per 2 mm2 or Ki-67 index of less than 3%.
• Grade 2 (G2): Mitotic rate between 2 and 20 per 2 mm2 or Ki-67 index between 3% and 20%.
• Grade 3 (G3): Mitotic rate greater than 20 per 2 mm2 or Ki-67 index greater than 20%.

Tumour extension

Well differentiated neuroendocrine tumours begin in the mucosa on the inside surface of the stomach. As the tumour grows, it can invade deeper into the wall of the organ.

The stomach has several layers:

1. Mucosa: The innermost layer where most tumours begin. The mucosa includes the epithelium, lamina propria, and muscularis mucosae.
2. Submucosa: A supportive layer beneath the mucosa.
3. Muscularis propria: A thick muscle layer that helps the stomach contract.
4. Subserosa and serosa: Outer layers that protect the stomach and separate it from nearby organs.

The depth of invasion is important because tumours that extend deeper into the stomach wall are more likely to spread to other organs or lymph nodes. Tumour extension is also used to determine the pathologic tumour stage (pT).

Margins

In pathology, a margin is the edge of tissue removed during tumour surgery. The margin status in a pathology report is important as it indicates whether the entire tumour was removed or if some was left behind. This information helps determine the need for further treatment.

Pathologists typically assess margins following a surgical procedure, such as an excision or resection, that removes the entire tumour. They aren’t usually evaluated after a biopsy, which removes only part of the tumour. The number of margins reported and their size—how much normal tissue is between the tumour and the cut edge—vary based on the tissue type and tumour location.

Pathologists examine margins to check if tumour cells are at the tissue’s cut edge. A positive margin, where tumour cells are found, suggests that some cancer may remain in the body. In contrast, a negative margin, with no tumour cells at the edge, suggests the tumour was fully removed. Some reports also measure the distance between the nearest tumour cells and the margin, even if all margins are negative.

Pathologic stage

The TNM staging system describes how far the tumour has spread and helps guide treatment decisions:

• Tumour stage (T):
  • T0: No tumour found.
  • T1: Tumour is small and confined to the mucosa or submucosa.
  • T2: Tumour invades the muscularis propria or is larger than 1 cm.
  • T3: Tumour grows into the subserosa.
  • T4: Tumour spreads to the serosa or nearby organs.
• Nodal stage (N):
  • N0: No cancer in nearby lymph nodes.
  • N1: Cancer found in nearby lymph nodes.

What is the prognosis for a person diagnosed with a well differentiated neuroendocrine tumour of the stomach?

The prognosis for a well differentiated neuroendocrine tumour of the stomach depends on two key factors: grade and stage.

• Grade refers to how quickly the tumour cells are dividing and growing. Tumours with a higher grade (grades 2 and 3) tend to grow and spread more quickly than low-grade (grade 1) tumours.
• Stage describes how far the tumour has spread. Tumours that are confined to the stomach wall (low stage) have a better prognosis than those that have spread to nearby lymph nodes or distant organs (high stage).

In general, well differentiated neuroendocrine tumours that are low grade and low stage have an excellent prognosis, with a very low risk of spreading or recurring after treatment. Higher-grade and higher-stage tumours are more likely to require additional treatments, such as surgery or medical therapy, to manage the disease effectively.