Well differentiated neuroendocrine tumour of the stomach

by Jason Wasserman MD PhD FRCPC
May 2, 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.

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”.

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.

How are well differentiated neuroendocrine tumours in the stomach graded?

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 does perineural invasion mean?

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 a term pathologists use to describe tumour cells attached to a nerve. Perineural invasion is important because tumour cells that have become attached to a nerve can grow along the nerve and into surrounding tissues. This increases the risk that the tumour will re-grow after treatment.

perineural invasion

What does lymphovascular invasion mean?

Blood moves around the body through long thin tubes called blood vessels. Another type of fluid called lymph which contains waste and immune cells moves around the body through lymphatic channels. The term lymphovascular invasion is used to describe tumour cells that are found inside a blood vessel or lymphatic channel. Lymphovascular invasion is important because once the tumour cells are inside a blood vessel or lymphatic channel they are able to metastasize (spread) to other parts of the body such as lymph nodes or the lungs.

lymphovascular invasion

​What is a margin?

A margin is any tissue that was cut by the surgeon in order to remove the tumour from your body. The types of margins described in your report will depend on the organ involved and the type of surgery performed. Margins will only be described in your report after most or all of the tumour has been removed.

A negative margin means that no tumour cells were seen at any of the cut edges of tissue. A margin is called positive when there are tumour cells at the very edge of the cut tissue. A positive margin is associated with a higher risk that the tumour will recur in the same site after treatment.

Margin

What are lymph nodes?

Lymph nodes are small immune organs located throughout the body. Tumour cells can spread from the tumour to a lymph node through lymphatic vessels located in and around the tumour (see Lymphovascular invasion above). The movement of tumour cells from the tumour to a lymph node is called lymph node metastasis.

Your pathologist will carefully examine each lymph node for tumour cells. Lymph nodes that contain tumour cells are often called positive while those that do not contain any tumour cells are called negative. Most reports include the total number of lymph nodes examined and the number, if any, that contain tumour cells.

The examination of lymph nodes is used to determine the nodal stage (see Pathologic stage below). Finding tumour cells in a lymph node increases the nodal stage and is associated with a worse prognosis.

Lymph node

How do pathologists determine the pathologic stage (pTNM) 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 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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