Well differentiated neuroendocrine tumour of the pancreas

by Stephanie Reid MD FRCPC
January 20, 2023

What is a well differentiated neuroendocrine tumour of the pancreas?

A well differentiated neuroendocrine tumour is a type of pancreatic cancer which starts from the neuroendocrine cells in the endocrine (hormone-producing) part of the pancreas.  These tumours are common in patients with the genetic syndrome multiple endocrine neoplasia type 1 (MEN1). However, most patients with these tumours do not have any known genetic syndrome.

Where in the pancreas do these tumours start?

Well differentiated neuroendocrine tumours start in the endocrine part of the pancreas. The endocrine part of the pancreas is made up of small round structures called acini. The acini are made up of specialized neuroendocrine cells which are like nerve cells (neurons), but they also make hormones like cells of the endocrine system (endocrine cells). They receive messages (signals) from the nervous system and the blood and respond by making and releasing hormones. These hormones control many body functions including the way your body uses sugar. Hormones made by the endocrine part of the pancreas include insulin, glucagon, gastrin, somatostatin, and vasoactive intestinal peptide (VIP).

What is a functioning well differentiated neuroendocrine tumour of the pancreas?

Up to half of all well differentiated neuroendocrine tumours of the pancreas will produce one or more of the hormones normally found in the pancreas. These tumours are described as functioning and they can produce a variety of symptoms depending on the type of hormone produced.

Types of functioning well differentiated neuroendocrine tumours include:

• Insulinoma – Produces insulin.
• Glucagonoma – Produces glucagon.
• Gastrinoma – Produces gastrin.
• Somatostatinoma – Produces somatostatin.
• VIPoma – Produces vasoactive intestinal peptide (VIP).
• ACTH-secreting tumour – Produces adrenocorticotropic hormone (ACTH).

What is a non-functioning tumour?

A well differentiated neuroendocrine tumour is described as non-functioning if the tumour cells are not making any hormones. Overall, half of all well differentiated neuroendocrine tumours of the pancreas are found to be non-functioning. Because these tumours do not produce any hormones or cause any significant symptoms, they can grow quite large before they are found.

How is this diagnosis made?

The diagnosis is usually made after a procedure that removes a small sample of tissue. This procedure may be called a fine needle aspiration biopsy (FNAB) or a needle core biopsy. Some tumours are located in a part of the pancreas that cannot be reached by a biopsy needle. In this case, the diagnosis may be made after a test called an Octreotide scan is performed.

After the diagnosis, surgery is usually performed to remove the entire tumour. There are two main types of surgeries for removing neuroendocrine tumours from the pancreas. The surgery which removes a tumour from the end of the pancreas is called a distal pancreatectomy. The surgery which removes the tumour along with part of the pancreas, small bowel, and stomach is called a Whipple procedure.

What does grade mean and why is it important?

Grade is a word pathologists use to describe the difference between cancer cells and the normal, healthy cells they have replaced. For neuroendocrine tumours, the grade is determined by the number of tumour cells dividing to create new tumour cells. These dividing cells are called mitotic figures and the process is called mitosis. Some pathology reports will describe the number of mitotic figures in a defined area of tissue (for example 2 millimetre square).

Your pathologist may also perform a special test called immunohistochemistry to look for a marker called Ki-67. This marker identifies cells that are in the process of dividing. The percentage of Ki-67 positive cells is called the proliferative index or labelling index. If both mitotic figure count and Ki-67 labelling index are performed the one with the highest number is used to determine the grade. The grade is important because high grade (grade 3) tumours tend to grow more quickly and are more likely to metastasize (spread) to other parts of the body.

Mitotic count:

1. Grade 1: < 2 mitoses/2mm2
2. Grade 2: 2 to 20 mitoses/2mm2
3. Grade 3: > 20 mitoses per 2mm2

Ki-67 labelling index:

1. Grade 1: <3%
2. Grade 2: 3% to 20%
3. Grade 3: >20%

Why is the size of the tumour important?

After the tumour is removed entirely from your body, it will be measured to determine its size in millimetres or centimetres. Tumour size is not reported in a biopsy report. For well differentiated neuroendocrine tumours of the pancreas, the tumour size is important because it is used to determine the pathologic tumour stage (pT) and because larger tumours are more likely to metastasize (spread) to other parts of the body.

What is a margin?

A margin is any tissue that was cut by a surgeon in order to remove a tumour from the body. The number of margins described in your report will depend on the type of surgery that was performed and how many cuts were made through tissues or organs to remove the tumour. Most reports will describe margins in the pancreas and in any surrounding organs that were removed at the same time as the tumour. Margins are only described in your report after the entire tumour has been removed. Margins are not described after a biopsy.

Commonly described margins in pancreatic resection specimens include:

• Pancreatic margin – This is the part of the pancreas that was cut in order to remove the tumour. The amount of pancreas removed depends on the location of the tumour within the pancreas.
• Common bile duct. The common bile duct is a channel that connects the liver to the pancreas and transports bile. Sometimes tumours within the pancreas can grow through the outside of the pancreas and involve the nearby common bile duct.
• Uncinate process – This is a part of the pancreas that rests against the back of the abdomen. The tissue at the end of the uncinate process needs to be cut in order for the surgeon to remove the tumour.
• Gastric (stomach) margin – In certain types of pancreas surgeries, a part of the stomach is removed at the same time as the tumour in the pancreas. The gastric margin is the place where a surgeon cuts the stomach to remove the tumour.
• Small bowel or duodenal margin – In the same surgery involving removal of portion of stomach (Whipple procedure), a segment of small bowel, called the duodenum, will have to be removed as well. The small bowel margin is the place where the surgeon cuts across the small bowel to remove the tumour.

All of the margins are examined under a microscope by your pathologist to determine the margin status. A margin is considered positive when there are tumour cells within 1 millimetre of the edge of the cut tissue. A margin is negative when cancer cells are more than 1 mm from the cut tissue edge. A positive margin is associated with a higher risk of the tumour re-growing in the same site after surgery or treatment.

What is the pathologic stage (pTNM) for well differentiated neuroendocrine tumour of the pancreas?

The pathologic stage for well differentiated neuroendocrine tumours of the pancreas is based on the TNM staging system, an internationally recognized system originally created by the American Joint Committee on Cancer. This system uses information about 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 of the three parts a number. In general, a higher number means a more advanced disease and a worse prognosis.

Tumour stage (pT) for well differentiated neuroendocrine tumour

Well differentiated neuroendocrine tumours are given a tumour stage of either 1, 2, 3, or 4. The tumour stage is based on the size of the tumour, and which organs or tissues it involves.

• T1 – Tumour limited to the pancreas and is less than 2 cm.
• T2 – Tumour limited to the pancreas and is 2 – 4 cm.
• T3 – Tumour limited to the pancreas and is greater than 4 cm OR tumour invades the duodenum or common bile duct.
• T4 – Tumour invading adjacent organs (stomach, spleen, colon, adrenal gland) or the wall of large vessels.

Nodal stage (pN) for well differentiated neuroendocrine tumour

Well differentiated neuroendocrine tumour is given a nodal stage of 0 or 1. If no cancer cells are seen in any of the lymph nodes examined, the stage is pN0. If cancer cells are found in any lymph nodes, the stage is pN1. If no lymph nodes are sent for pathologic examination, the nodal stage cannot be determined and is listed as pNX.

Metastatic stage (pM) for well differentiated neuroendocrine tumour

Well differentiated neuroendocrine tumour is given a metastatic stage of 1 if there are cancer cells at a distant site in the body. The metastatic stage can only be determined if tissue from a distant site is submitted for pathological examination. If no tissue from a distant site has been sent for pathologic examination, the metastatic stage cannot be determined and is listed as pMX.

The metastatic stage can be further classified as follows:

• M1a –  Metastasis is confined to liver.
• M1b –  Metastatic in at least one extrahepatic site (an area of the body outside of the liver).
• M1c – Both hepatic (liver) and extrahepatic metastases.