Neuroendocrine carcinoma of the colon

What is neuroendocrine carcinoma?

Neuroendocrine carcinoma is a type of colon cancer. It starts from the neuroendocrine cells normally found in the colon. Neuroendocrine carcinoma can develop anywhere along the length of the colon from the cecum to the rectum. It is an aggressive type of cancer that often present at a late stage (the tumour is often large, or the cancer cells have already spread to a distant body site). Pathologists divide neuroendocrine carcinoma of the colon into two types: small cell carcinoma and large cell carcinoma.

The colon

The colon is a part of the gastrointestinal tract which also includes the mouth, esophagus, stomach, small bowel, and anus. The colon is a long hollow tube that starts at the small bowel and ends at the anal canal. The colon is divided into sections which include the cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum. The functions of the colon are to absorb water from the food that we eat and to move waste out of the body.

The colon is made up of six layers of tissue:

  1. Mucosa – The mucosa is the tissue that covers the inside surface of the colon. The mucosa is lined by specialized cells that connect together to form structures called glands. When examined under the microscope, the normal, healthy glands look like long, straight test tubes with the opening at the mucosal surface and the base normally sitting on the submucosa (see below). In the colon, these long, straight glands are called crypts.
  2. Muscularis mucosae – The muscularis mucosae is a thin layer of tissue made up of muscle cells. The muscularis mucosae separates the mucosa from the submucosa.
  3. Submucosa – The submucosa sits directly below the mucosa. It contains many thick blood vessels that bring nutrients and lymphatic channels that remove waste.
  4. Muscularis propria – The muscularis propria is a thick bundle of muscle. The contraction of the muscle that forms the muscularis propria helps to propel food through the colon.
  5. Subserosal adipose tissue – This is a layer of fat that surrounds 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 on the outside of the colon. It covers the subserosal adipose tissue.

Neuroendocrine cells

Within the glands and hidden in between the epithelial cells, there is a small population of specialized 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.

How do pathologists make this diagnosis?

The diagnosis of neuroendocrine carcinoma is usually made after a small sample of the tumour is removed in a procedure called a biopsy. The diagnosis can also be made after the entire tumour is removed in a procedure called a resection.

A 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 neuroendocrine carcinoma commonly express 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 cancer cells that produce Ki-67 is called the proliferative index and this number may be included in your report. The normal proliferative index for poorly differentiated neuroendocrine carcinoma is usually between 20% and 90%.

Small cell and large cell carcinoma

Neuroendocrine carcinoma is divided into two groups depending on how the cells look under the microscope.  These two groups are called small cell carcinoma and large cell carcinoma. As the names suggest, small cell carcinoma is made up of small tumour cells with very little cytoplasm. Large cell carcinoma is made up of much larger tumour cells with more cytoplasm and round pieces of genetic material called nucleoli. Some tumours have features of both small cell and large cell carcinoma. In this situation, your pathologist may simply call the tumour a poorly differentiated neuroendocrine carcinoma.

What to look for in your report after the tumour is removed

Tumour size

This is the size of the tumour measured in centimetres. Your report may only describe the greatest dimension. 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.

Tumour extension

All neuroendocrine carcinomas start in glands found on the inner surface of the colon. Tumour extension describes how far the tumour cells have travelled from the glands into the layers of tissue below the mucosa.

The movement of tumour cells from the glands into the tissue below is called invasion. Once the cancer 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 cells that travel deeper in the wall are more likely to come back (recur) in the area of the original tumour or to travel to a distant site such as the liver. The movement of tumour cells to a different 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 is a term pathologists use to describe cancer cells attached to a nerve.

perineural invasion

Perineural invasion is important because cancer cells that have attached to a nerve can use the nerve to travel into tissue outside of the original tumour. This increases the chance that the tumour will grow back after treatment.

Lymphovascular invasion

Lymphatics and blood vessels are channels that normal cells use to travel around the body. The presence of cancer cells within a lymphatic or blood vessel is called lymphovascular invasion and is associated with a higher risk that tumour cells will travel to either a lymph node or a distant site such as the lungs.

lymphovascular invasion


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 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.


Tumour deposits

A tumour deposit is a group of tumour cells that are separate from the main tumour but not in a lymph node. The presence of tumour deposits is associated with a higher risk that tumour cells will spread to a distant body site such as the liver. The spread of cancer cells to another part of the body is called metastasis.

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.

Lymph node

Most reports include the total number of lymph nodes examined and the number, if any, that contain cancer cells. Your pathologist will carefully examine all lymph nodes 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.

Finding cancer cells in a lymph node is important because it is associated with a higher risk that the cancer cells will be found in other lymph nodes or in a distant organ such as the lungs. The examination of lymph nodes is also used to determine the nodal stage (see Pathologic stage below).

Pathologic stage (pTNM)

The pathologic stage for neuroendocrine carcinoma is based on the TNM staging system, an internationally recognized system originally created by the American Joint Committee on Cancer (AJCC). The AJCC system incorporates information about the primary tumour (T), lymph nodes (N), and distant metastatic disease (M) with each variable being given a number (usually from 1 to 4). As a general rule, a higher stage number indicates a more advanced disease.

Pathologic stage is not reported on a biopsy specimen. It is only reported when the entire tumour has been removed in an excision or resection specimen.

Tumour stage (pT) for neuroendocrine carcinoma

This cancer is given a tumour stage between 1 and 4 based on how far the cancer cells have travelled into the wall of the colon or surrounding tissues.

  • T1 – The cancer cells have entered the submucosa.
  • T2 – The cancer cells have entered the muscularis propria of the colon.
  • T3 – The cancer cells have gone through the entire muscular wall and are near the serosa on the outer surface of the colon.
  • T4 – The cancer cells have passed the serosa and are on the outer surface of the colon or they have gone into surrounding organs such as the bladder or abdominal wall.
Nodal stage (pN) for neuroendocrine carcinoma

This cancer is given a nodal stage between 0 and 2 is based on the presence or absence of cancer cells in a lymph node, the number of lymph nodes that contain cancer cells, or the presence of tumour deposits. If no lymph nodes are involved the nodal stage is N0. If no lymph nodes are submitted for pathological examination, the nodal stage cannot be determined and the nodal stage is listed as NX.

Metastatic stage (pM) for neuroendocrine carcinoma

Neuroendocrine carcinoma is given a metastatic stage between 0 and 1 based on the presence of cancer cells at a distant site in the body (for example the liver). The metastatic stage can only be given if tissue from a distant site is sent 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 (updated July 23, 2021)
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