Well-differentiated neuroendocrine tumour of the stomach

by Jason Wasserman MD PhD FRCPC
November 9, 2022


What is a well-differentiated neuroendocrine tumour in the stomach?

A well-differentiated neuroendocrine tumour (NET) in the stomach is a type of cancer made up of specialized neuroendocrine cells. Pathologists divide well-differentiated NETs of the stomach into three grades (see WHO grade below) with higher-grade tumours being associated with more aggressive behaviour and worse overall prognosis.

Is a well-differentiated neuroendocrine tumour malignant?

Yes. All well-differentiated neuroendocrine tumours are malignant (cancerous) tumours that can metastasize (spread) to other parts of the body.

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

Most well-differentiated NETs in the stomach do not cause any symptoms and the tumour is only found when the patient undergoes an examination of the stomach called an endoscopy. Some patients with these tumours may have previously been diagnosed with chronic atrophic gastritis, an autoimmune condition that damages the cells on the inside of the stomach. Rare serotonin-producing tumours may cause symptoms such as flushing, diarrhoea, and shortness of breath.

What causes a well-differentiated neuroendocrine tumour in the stomach?

People who have been diagnosed with an autoimmune stomach disease called chronic atrophic gastritis or who have the genetic syndrome multiple endocrine neoplasia type 1 (MEN1) are at higher risk for developing well-differentiated NETs in the stomach. However, for many people who develop a well-differentiated NET, no specific cause is identified.

How do pathologists make the diagnosis of a well-differentiated neuroendocrine tumour in the stomach?

The diagnosis of well-differentiated NET is usually made after a small piece of the tumour is removed in a procedure called a biopsy. The tissue is sent to a pathologist for examination under a microscope. The diagnosis can also be made after the entire tumour is removed in a larger surgical procedure called a resection.

What does a well-differentiated neuroendocrine tumour look like under the microscope?

When examined under the microscope, the tumour is made up of specialized neuroendocrine cells that can show a variety of growth patterns including nested, trabecular, pseudo-glandular, pseudo-acinar, and solid. The cells throughout the tumour tend to be very similar looking which pathologists describe as monomorphic or monotonous. The genetic material or chromatin inside the nucleus of the cell often appears as small dots which pathologists describe as “salt and pepper”.

Well differentiated neuroendocrine tumour of the stomach
Well-differentiated neuroendocrine tumour of the stomach.

What other tests are performed to confirm the diagnosis of the well-differentiated neuroendocrine tumour?

A special test called immunohistochemistry may be performed to confirm the diagnosis. This test allows pathologists to better understand cells based on the specific proteins they produce. This test allows pathologists to better understand both the function and origin of the cell.

The cells in a well-differentiated NET commonly produce two proteins: synaptophysin and chromogranin. Both of these proteins are considered markers of neuroendocrine differentiation because they are made by neuroendocrine cells. Pathologists describe tumour cells that produce a protein as positive or reactive. Those that do not produce the protein are called negative or non-reactive.

What is the WHO grade and why is it important?

Well-differentiated NETs in the stomach are divided into three grades (1 through 3). The grade is important because higher grade (grades 2 and 3) tumours are more likely to spread to other parts of the body. The grade can only be determined after the tumour is examined under the microscope by your pathologist.

Pathologists determine the grade by measuring the number of tumour cells that are in the process of dividing to create new tumour cells. These cells are called mitotic figures and they are undergoing a process called mitosis. The mitotic rate is the number of dividing cells seen when the tumour is examined at high magnification through the microscope (pathologists call this a ‘high powered field’ or ‘HPF’).

Your pathologist may also do a test called immunohistochemistry for Ki-67 to highlight cells that are able to divide. The Ki-67 index (or proliferative index) is the percentage of tumour cells that produce Ki-67. The proliferative index for well-differentiated neuroendocrine tumours can range from 1% to over 20%.

Your pathologist will use the mitotic rate and/or the Ki-67 index to determine the grade as follows:

  • Grade 1 (G1) – These tumours have a mitotic rate of less than 2 or a Ki-67 index of less than 3%.
  • Grade 2 (G2) – These tumours have a mitotic rate between 2 and 20 or a Ki-67 index of between 3% and 20%.
  • Grade 3 (G3) – These tumours have a mitotic rate of greater than 20 or a Ki-67 index of greater than 20%.
What does invasion mean?

Pathologists use the word invasion to describe the spread of tumour cells from the inside of the stomach into surrounding tissues. All well-differentiated NETs are believed to start from neuroendocrine cells normally found within the glands on the inside surface of the stomach. The glands are part of a thin layer of tissue called the mucosa. The layers of tissue below the mucosa include the submucosa, muscularis propria, subserosal adipose tissue, and serosa. As the tumour grows the cells can spread into these layers. Eventually, the tumour cells can break through the outside surface of the stomach and spread directly into nearby organs and tissues.

The level of invasion is the deepest point of invasion and it can only be measured after the tumour is examined under the microscope by a pathologist. The level of invasion is important because tumours that invade deeper into the wall of the stomach are more likely to spread to other parts of the body. The level of invasion is also used to determine the pathologic tumour stage (pT).

What is perineural invasion and why is it important?

Perineural invasion is a term pathologists use to describe cancer cells attached to or inside a nerve. A similar term, intraneural invasion, is used to describe cancer cells inside a nerve. Nerves are like long wires made up of groups of cells called neurons. Nerves are found all over the body and they are responsible for sending information (such as temperature, pressure, and pain) between your body and your brain. Perineural invasion is important because the cancer cells can use the nerve to spread into surrounding organs and tissues. This increases the risk that the tumour will regrow after surgery. If perineural invasion is seen, it will be included in your report.

Perineural invasion

What is lymphovascular invasion and why is it important?

Lymphovascular invasion means that cancer cells were seen inside a blood vessel or lymphatic vessel. Blood vessels are long thin tubes that carry blood around the body. Lymphatic vessels are similar to small blood vessels except that they carry a fluid called lymph instead of blood. The lymphatic vessels connect with small immune organs called lymph nodes that are found throughout the body. Lymphovascular invasion is important because cancer cells can use blood vessels or lymphatic vessels to spread to other parts of the body such as lymph nodes or the lungs. If lymphovascular invasion is seen, it will be included in your report.

Lymphovascular invasion

What is a margin?

In pathology, a margin is the edge of a tissue that is cut when removing a tumour from the body. The margins described in a pathology report are very important because they tell you if the entire tumour was removed or if some of the tumour was left behind. The margin status will determine what (if any) additional treatment you may require.

Most pathology reports only describe margins after a surgical procedure called an excision or resection has been performed for the purpose of removing the entire tumour. For this reason, margins are not usually described after a procedure called a biopsy is performed for the purpose of removing only part of the tumour. The number of margins described in a pathology report depends on the types of tissues removed and the location of the tumour. The size of the margin (the amount of normal tissue between the tumour and the cut edge) also depends on the type of tumour being removed and the location of the tumour.

Pathologists carefully examine the margins to look for tumour cells at the cut edge of the tissue. If tumour cells are seen at the cut edge of the tissue, the margin will be described as positive. If no tumour cells are seen at the cut edge of the tissue, a margin will be described as negative. Even if all of the margins are negative, some pathology reports will also provide a measurement of the closest tumour cells to the cut edge of the tissue.

A positive (or very close) margin is important because it means that tumour cells may have been left behind in your body when the tumour was surgically removed. For this reason, patients who have a positive margin may be offered another surgery to remove the rest of the tumour or radiation therapy to the area of the body with the positive margin. The decision to offer additional treatment and the type of treatment options offered will depend on a variety of factors including the type of tumour removed and the area of the body involved. For example, additional treatment may not be necessary for a benign (non-cancerous) type of tumour but may be strongly advised for a malignant (cancerous) type of tumour.

Margin

Were lymph nodes examined and did any contain cancer cells?

Lymph nodes are small immune organs found throughout the body. Cancer cells can spread from a tumour to lymph nodes through small vessels called lymphatics. The cancer cells in acinic cell carcinoma typically do not spread to lymph nodes and for this reason, lymph nodes are not always removed at the same time as the tumour. However, when lymph nodes are removed, they will be examined under a microscope and the results will be described in your report.

Lymph node

Cancer cells typically spread first to lymph nodes close to the tumour although lymph nodes far away from the tumour can also be involved. For this reason, the first lymph nodes removed are usually close to the tumour. Lymph nodes further away from the tumour are only typically removed if they are enlarged and there is a high clinical suspicion that there may be cancer cells in the lymph node. Most reports will include the total number of lymph nodes examined, where in the body the lymph nodes were found, and the number (if any) that contain cancer cells. If cancer cells were seen in a lymph node, the size of the largest group of cancer cells (often described as “focus” or “deposit”) will also be included.

The examination of lymph nodes is important for two reasons. First, this information is used to determine the pathologic nodal stage (pN). Second, finding cancer cells in a lymph node increases the risk that cancer cells will be found in other parts of the body in the future. As a result, your doctor will use this information when deciding if additional treatment such as chemotherapy, radiation therapy, or immunotherapy is required.

What does it mean if a lymph node is described as positive?

Pathologists often use the term “positive” to describe a lymph node that contains cancer cells. For example, a lymph node that contains cancer cells may be called “positive for malignancy” or “positive for metastatic carcinoma”.

What does it mean if a lymph node is described as negative?

Pathologists often use the term “negative” to describe a lymph node that does not contain any cancer cells. For example, a lymph node that does not contain cancer cells may be called “negative for malignancy” or “negative for metastatic carcinoma”.

What is the pathologic stage for a well-differentiated neuroendocrine tumour in the stomach?

The pathologic stage for well-differentiated neuroendocrine tumours (NETs) is based on the TNM staging system, an internationally recognized system originally created by the American Joint Committee on Cancer (AJCC). This system uses information about the primary tumour (T), lymph nodes (N), and distant metastatic disease (M)  to determine the complete pathologic stage (pTNM). Your pathologist will examine the tissue submitted and give each part a number. In general, a higher number means a more advanced disease and a worse prognosis. The pathologic stage will only be described in your report after most or all of the tumour has been removed.

Tumour stage (pT) for well-differentiated neuroendocrine tumour

These tumours are given a tumour stage between 1 and 4 based on the size of the tumour and how far the tumour cells have spread into the wall of the stomach or the surrounding tissues.​

  • T1 – The tumour invades the lamina propria or submucosa and is less than or equal to 1.0 cm in size.
  • T2 – The tumour invades muscularis propria or greater than 1 cm in size
  • T3 – The tumour invades through the muscularis propria into subserosal tissue without going through the overlying serosa.
  • T4 – The tumour invades the serosa or other organs or adjacent structures.​
Nodal stage (pN) for well-differentiated neuroendocrine tumour

These tumours are given a nodal stage of 0 or 1 based on the presence or absence of tumour cells in a lymph node.

  • N0 – No tumour cells are seen in any of the lymph nodes examined.
  • N1 – Tumour cells are seen in at least one lymph node.
  • NX – No lymph nodes were sent for pathologic examination.
Metastatic stage (pM) for well-differentiated neuroendocrine tumour

A well-differentiated neuroendocrine tumour is given a metastatic stage of 0 or 1 based on the presence of tumour cells at a distant site in the body (for example the liver). The metastatic stage can only be assigned if tissue from a distant site is submitted for pathological examination. Because this tissue is rarely present, the metastatic stage cannot be determined and is listed as MX.

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