Well differentiated neuroendocrine tumour - Colon -

This article will help you read and understand your pathology report for well differentiated neuroendocrine tumour of the colon.

by Ipshita Kak MD FRCPC, updated on September 1, 2020

Quick facts:
  • A well differentiated neuroendocrine tumour is a type of cancer that develops from specialized neuroendocrine cells in the colon.
  • This tumour can develop anywhere along the length of the colon.
The anatomy of the colon

The colon is part of a system called the gastrointestinal tract. It has six sections: cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum.

The colon is made up of six layers of tissue:

  1. Mucosa – The mucosa is the tissue that lines the inside surface of the colon. 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 along the colon.
  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 colon.
  6. Serosa – The serosa is a thin layer of tissue that covers the subserosal adipose tissue and the outside of the colon.
normal colon layers
Neuroendocrine cells

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.

What is a neuroendocrine tumour?

Neuroendocrine tumour is a type of cancer that starts from these neuroendocrine cells. It can develop anywhere along the length of the colon (from the cecum to the rectum).

Neuroendocrine tumours 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 neuroendocrine tumour 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. The tumours can also be detected by imaging and endoscopy.

How do pathologists make this diagnosis?

The diagnosis 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. A special test called immunohistochemistry may be performed to confirm the diagnosis.

Most patients are then offered surgery to removed the tumour entirely. Once removed, the entire tumour will be sent to a pathologist who will examine parts of it under the microscope. This report will confirm or revise the original diagnosis and provide additional important information such tumour size, extension, margins, and spread of tumour cells to lymph nodes. This information is used to determine the cancer stage and to decide if additional treatment is required.

What to look for in your pathology report after a biopsy

Histologic grade

Well differentiated neuroendocrine tumours (NETs) are divided into three grades. The grade depends 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 a 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.

  • Grade 1 – These tumours have a mitotic rate of less than 2 or a Ki-67 index of less than 3%.
  • Grade 2 – These tumours have a mitotic rate between 2 and 20 or a Ki-67 index of between 3% and 20%.
  • Grade 3 – These tumours have a mitotic rate of greater than 20 or a Ki-67 index of greater than 20%.

Higher grade (grade 2 and 3) tumours are more likely to spread to other parts of the body. The movement of cancer cells to another part of the body is called metastasis.

Immunohistochemistry

Immunohistochemistry (IHC) is a commonly used test that 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 neuroendocrine tumour 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’.

Your pathologist may also perform immunohistochemistry to look for a protein called Ki-67. This protein is produced by cells that can divide and create new cancer cells. The percentage of tumour cells that produce Ki-67 is called the ‘proliferative index’ and this number may be included in your report. The normal proliferative index for well differentiated neuroendocrine tumour can range from 1% to over 20%.

The proliferative index will be used to determine the tumour grade (see Histologic grade above).

What to look for in your pathology 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 greatest dimension.

The tumour size is important because it is used to determine the tumour grade (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 location

Neuroendocrine tumours in the rectum make up approximately 25% of all the neuroendocrine tumours that develop in the gastrointestinal tract. They are usually small (less than 1-2 cm), solitary (there is only one tumour), and are unlikely to spread to other parts of the body.

In contrast, neuroendocrine tumours in other parts of the colon are less common but when they occur, they tend to be large and aggressive tumours that quickly spread to nearby organs and distant parts of the body. The spread of tumour cells to another part of the body is called a metastasis.

Tumours that start in the rectum are associated with a higher risk of metastasis and worse prognosis.

Tumour extension

All neuroendocrine tumours start in the mucosa on the inner surface of the colon. Tumour extension describes how far the cancer cells have spread from the mucosa into the wall of the colon or tissue outside of the colon.

The spread of tumour cells from mucosa into the tissue below is called invasion. Once the tumour cells cross the serosa, they are on the outer surface of the colon and may invade nearby organs and tissues such as the bladder 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

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.

Lymphovascular 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.

Margins

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 the entire tumour has been removed.

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. A negative margin means that no tumour cells were seen at any of the cut edges of tissue.

Lymph nodes

Lymph node

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 a 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 worse prognosis.

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 worse prognosis.

The pathologic stage will only be included in your report after the entire tumour has been removed. It will not be included in your report after a biopsy.

Tumour stage (pT) for well differentiated neuroendocrine tumours

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 traveled into the wall of the colon or the surrounding tissues.​

  • T1 – The tumour is located entirely within the mucosa and it is 2 cm or less in size.
  • T2 – The tumour is greater than 2 cm in size or it has invaded the muscularis propria.
  • T3 – The tumour has gone through the entire muscular wall of the colon and is into the subserosal tissue (just under the outer surface of the colon).
  • T4 – The tumour is on the outer surface of the colon or has gone into surrounding organs.​
Nodal stage (pN) for well differentiated neuroendocrine tumours

These tumours are given a nodal stage between of 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 tumours

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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