Well differentiated neuroendocrine tumour of the appendix

What is a well-differentiated neuroendocrine tumour?

A well-differentiated neuroendocrine tumour (NET) is a type of cancer made up of specialized neuroendocrine cells and the most common type of cancer in the appendix. Many patients present with symptoms of acute appendicitis. Pathologists divide well-differentiated NETs of the appendix into three grades (see WHO grade below) although most are associated with a good prognosis.

The appendix

The appendix is a small, hollow, finger-shaped organ that connects with the first part of the colon by a thin opening. The open space on the inside of the appendix is called the lumen. The lumen is surrounded by a wall that is made up of six layers of tissue.

  1. Mucosa – The mucosa is the tissue that lines the inside surface of the appendix. The mucosa includes epithelial cells that form structures called glands. The glands are surrounded and supported by a tissue called lamina propria.
  2. Muscularis mucosa – This is a thin layer of muscle that sits directly below the mucosa.
  3. Submucosa – The submucosa sits directly below the mucosa. It contains many thick blood vessels and lymphatic channels.
  4. Muscularis propria – The muscularis propria is a thick bundle of muscle. The muscles in the muscularis propria help move digested food and waste out of the appendix.
  5. Subserosal adipose tissue – This is a layer of fat that sits directly below the muscularis propria. The subserosal adipose tissue is near the outside surface of the appendix.
  6. Serosa – The serosa is a thin layer of tissue that covers the subserosal adipose tissue and the outside of the appendix.

The mesoappendix is a layer of fatty tissue on the outside of the appendix that surrounds and supports the appendix. The mesoappendix is part of the abdominal peritoneum.

Neuroendocrine cells in the appendix

Within the glands and hidden in between the epithelial cells, there is a small population of specialized cells, called neuroendocrine cells. These cells can receive signals from the nervous system and in turn release substances called proteins. There are many kinds of proteins and each has a specific function.

Functional and non-functional neuroendocrine tumours

Well-differentiated neuroendocrine tumours (NETs) can be divided into functional and non-functional tumours based on the types of symptoms they produce.  Functional tumours produce proteins that can result in specific symptoms. These symptoms or the detection of specific proteins in the blood or urine can help doctors make the correct diagnosis. Non-functional tumours do not produce proteins, and as a result, may go undetected for many years.

Some patients with a functional well-differentiated NET present with a very specific set of symptoms that doctors call “carcinoid syndrome”. The presence of this syndrome suggests that the tumour has spread to the liver.

How do pathologists make this diagnosis?

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.

When examined under the microscope, the tumour is made up of medium-sized 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 appendix

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 three proteins: CD56, synaptophysin and chromogranin. By performing immunohistochemistry, your pathologist can ‘see’ these proteins inside the cell. Most cancers produce all three proteins, but some may produce two or even just one of the three. Cells that produce a protein will be called positive or reactive. Those that do not produce the protein are called negative or non-reactive.

WHO grade

Well-differentiated NETs of the appendix are divided into three grades. While higher grade tumours (grade 2 and 3) are more likely to spread to other parts of the body, the risk is still very small. The grade can only be determined after the tumour is examined under the microscope by your pathologist.

The grade is based on the percentage 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 histologic 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 to look for in your report after the tumour is removed

Tumour size

These tumours are measured in three dimensions but only the largest dimension is typically included in the report. For example, if the tumour measures 5.0 cm by 3.2 cm by 1.1 cm, the report may describe the tumour size as 5.0 cm in the greatest dimension.

The tumour size is important because it is used to determine the tumour stage (see Pathologic stage below). Tumours larger than 2 centimetres are associated with a higher risk of cancer cells spreading to a lymph node or other part of the body.

Tumour extension

Pathologists use the term tumour extension to describe how far the tumour cells have travelled from the mucosa and into the wall of the appendix or surrounding tissues. Tumour cells that cross the serosa on the outer surface of the appendix can spread into nearby organs and tissues such as the colon, small intestine, or abdominal wall.

Tumour extension is used to determine the tumour stage (see Pathologic stage below). Tumour cells that spread further from the mucosa are more likely to come back (recur) in the area of the original tumour or to spread to another part of the body such as a lymph node or the liver. The movement of tumour cells to another part of the body is called metastasis.

Perineural invasion

Nerves are like long wires made up of groups of cells called neurons. Nerves send information (such as temperature, pressure, and pain) between your brain and your body. Perineural invasion means that cancer cells were seen attached to a nerve.

Cancer cells that have attached to a nerve can use the nerve to travel into tissue outside of the original tumour. This increases the risk that the tumour will come back in the same area of the body (recurrence) after treatment.

perineural invasion

Lymphovascular invasion

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.

Cancer cells can use blood vessels and lymphatics to travel away from the tumour to other parts of the body. The movement of cancer cells from the tumour to another part of the body is called metastasis.

Before cancer cells can metastasize, they need to enter a blood vessel or lymphatic. This is called lymphovascular invasion. Lymphovascular invasion increases the risk that cancer cells will be found in a lymph node or a distant part of the body such as the lungs.

lymphovascular invasion

Margins

A margin is any tissue that was cut by the surgeon in order to remove the tumour from your body. For most appendiceal tumours, the margin is the area of the appendix that was previously attached to the colon. In some cases, the margin may include a part of the right colon such as the cecum. Margins will only be described in your report after the entire 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

Lymph nodes

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

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

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

Lymph node

Pathologic stage (pTNM)

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.

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 travelled into the wall of the appendix or the surrounding tissues.​

  • T1 – The tumour is 2 cm or less in size.
  • T2 – The tumour is greater than 2 cm in size but less than or equal to 4 cm in size.
  • T3 – The tumour is greater than 4 cm in size or it has invaded the subserosa or the mesoappendix.
  • T4 – The tumour has spread beyond the serosa of the appendix or it has spread into surrounding organs.
Nodal stage (pN) for well-differentiated neuroendocrine tumour

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

  • N0 – No cancer cells are seen in any of the lymph nodes examined.
  • N1 – Cancer 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.

by Ipshita Kak MD FRCPC and Jason Wasserman MD PhD FRCPC (updated August 25, 2021)
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