Medullary carcinoma of the colon

by Jason Wasserman MD PhD FRCPC
February 22, 2023

What is medullary carcinoma of the colon?

Medullary carcinoma is a rare type of colon cancer. It is considered a subtype of adenocarcinoma. Compared to other types of colon cancer, medullary carcinoma is associated with a good prognosis. Despite their similar names, medullary carcinoma of the colon is not related to medullary carcinoma of the thyroid gland.

What are the symptoms of medullary carcinoma of the colon?

The symptoms of medullary carcinoma depend on the location of the tumour within the colon. Tumours in the left colon (descending colon) or rectum can cause changes in bowel habits, bloody stools, abdominal pain, or bloating. Tumours in the right colon (ascending colon) may not cause any symptoms until the tumour is very large or has spread to other parts of the body.

What causes medullary carcinoma of the colon?

At present, we do not fully understand what causes a person to develop medullary carcinoma of the colon. However, this type of cancer is much more common in people with Lynch syndrome and the tumour cells often show a loss of normal DNA mismatch repair proteins. Alterations in the BRAF gene are also common and may contribute to the development of this type of cancer.

How is this diagnosis made?

The diagnosis of medullary carcinoma is usually made after a small tissue sample is removed during an examination called a colonoscopy. The procedure used to remove the tissue may be called a biopsy or polypectomy. The tissue sample is then sent to a pathologist for examination under the microscope. The diagnosis can also be made after the entire tumour is removed along with a portion of the normal colon in a procedure called a colectomy.

What does medullary carcinoma look like under the microscope?

When examined under the microscope, medullary carcinoma of the colon is made up of large tumour cells connected together in groups called sheets. The tumour cells do not form glands (the structures normally found in the colon). The nucleus of the tumour cell (the part of the cell that holds the genetic material) is often large and round and clumps of genetic material called nucleoli are often seen. As the tumour grows it pushes into the surrounding normal colon (pathologists often describe this as a “pushing border”) and immune cells called lymphocytes are often seen throughout the tumour. When a test called immunohistochemistry is performed, the tumour cells typically show a loss of normal colonic markers such as cytokeratin 20 (CK20) and CDX-2.

What does it mean if the tumour is described as poorly differentiated?

In pathology, the term differentiated is used when comparing a tumour with normal, healthy cells. Medullary carcinoma is described as poorly differentiated because, unlike the normal, healthy cells in the colon, it does not form any round structures called glands.

What does invasion mean and why is the level of invasion important?

In pathology, the term invasion is used to describe the spread of cancer cells into organs or tissues surrounding the location where the tumour started. Because medullary carcinoma starts in a thin layer of tissue on the inside surface of the colon called the mucosa, invasion is defined as the spread of cancer cells into the other layers of tissue in the colon (see picture below) or any other organs outside of the colon. Invasion can only be seen after the tumour has been examined under a microscope by a pathologist.

When examining the tumour under the microscope, your pathologist will look to see how far the cancer cells have spread from the mucosa into the surrounding tissue. This is called the level of invasion. The level of invasion is important because tumours that invade deeper into the wall of the colon are more likely to spread to other parts of the body such as lymph nodes, the liver, or the lungs. The level of invasion is also used to determine the pathologic tumour stage (pT).

What does perineural invasion mean and why is it important?​

Perineural invasion is a term pathologists use to describe cancer cells attached to or inside a nerve. A similar term, intraneural invasion, is used to describe cancer cells inside a nerve. 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 important because the cancer cells can use the nerve to spread into surrounding organs and tissues. This increases the risk that the tumour will regrow after surgery.

What does lymphovascular invasion mean and why is it important?​

Lymphovascular invasion means that cancer cells were seen inside a blood vessel or lymphatic vessel. Blood vessels are long thin tubes that carry blood around the body. Lymphatic vessels are similar to small blood vessels except that they carry a fluid called lymph instead of blood. The lymphatic vessels connect with small immune organs called lymph nodes that are found throughout the body. Lymphovascular invasion is important because cancer cells can use blood vessels or lymphatic vessels to spread to other parts of the body such as lymph nodes or the liver. The presence of cancer cells inside a large vein past beyond the wall of the colon (outside of the thick bundle of muscle) is associated with a high risk that the cancer cells will eventually be found in the liver.

​What is a margin?

In pathology, a margin is the edge of a tissue that is cut when removing a tumour from the body. The margins described in a pathology report are very important because they tell you if the entire tumour was removed or if some of the tumour was left behind. The margin status will determine what (if any) additional treatment you may require.

Most pathology reports only describe margins after a surgical procedure called an excision or resection has been performed for the purpose of removing the entire tumour. For this reason, margins are not usually described after a procedure called a biopsy is performed for the purpose of removing only part of the tumour. The number of margins described in a pathology report depends on the types of tissues removed and the location of the tumour. The size of the margin (the amount of normal tissue between the tumour and the cut edge) depends on the type of tumour being removed and the location of the tumour.

Pathologists carefully examine the margins to look for tumour cells at the cut edge of the tissue. If tumour cells are seen at the cut edge of the tissue, the margin will be described as positive. If no tumour cells are seen at the cut edge of the tissue, a margin will be described as negative. Even if all of the margins are negative, some pathology reports will also provide a measurement of the closest tumour cells to the cut edge of the tissue.

A positive (or very close) margin is important because it means that tumour cells may have been left behind in your body when the tumour was surgically removed. For this reason, patients who have a positive margin may be offered another surgery to remove the rest of the tumour or radiation therapy to the area of the body with the positive margin. The decision to offer additional treatment and the type of treatment options offered will depend on a variety of factors including the type of tumour removed and the area of the body involved. For example, additional treatment may not be necessary for a benign (non-cancerous) type of tumour but may be strongly advised for a malignant (cancerous) type of tumour.

What is a tumour deposit?​

A tumour deposit is a group of cancer cells that are separate from the main tumour but not in a lymph node. Tumour deposits are associated with a higher risk that the tumour cells will spread to another part of the body such as the liver or lungs after treatment. Tumour deposits are also used to determine the pathologic tumour stage (pT).

Were lymph nodes examined and did any contain cancer cells?​

Lymph nodes are small immune organs found throughout the body. Cancer cells can spread from a tumour to lymph nodes through small vessels called lymphatics. For this reason, lymph nodes are commonly removed and examined under a microscope to look for cancer cells. The movement of cancer cells from the tumour to another part of the body such as a lymph node is called metastasis.

Cancer cells typically spread first to lymph nodes close to the tumour although lymph nodes far away from the tumour can also be involved. For this reason, the first lymph nodes removed are usually close to the tumour. Lymph nodes further away from the tumour are only typically removed if they are enlarged and there is a high clinical suspicion that there may be cancer cells in the lymph node.

If any lymph nodes were removed from your body, they will be examined under the microscope by a pathologist and the results of this examination will be described in your report. Most reports will include the total number of lymph nodes examined, where in the body the lymph nodes were found, and the number (if any) that contain cancer cells. If cancer cells were seen in a lymph node, the size of the largest group of cancer cells will also be included.

The examination of lymph nodes is important for two reasons. First, this information is used to determine the pathologic nodal stage (pN). Second, finding cancer cells in a lymph node increases the risk that cancer cells will be found in other parts of the body in the future. As a result, your doctor will use this information when deciding if additional treatment such as chemotherapy, radiation therapy, or immunotherapy is required.

What does it mean if a lymph node is described as positive?

Pathologists often use the term “positive” to describe a lymph node that contains cancer cells. For example, a lymph node that contains cancer cells may be called “positive for malignancy” or “positive for metastatic carcinoma”.

What does it mean if a lymph node is described as negative?

Pathologists often use the term “negative” to describe a lymph node that does not contain any cancer cells. For example, a lymph node that does not contain cancer cells may be called “negative for malignancy” or “negative for metastatic carcinoma”.

What does extranodal extension mean?

All lymph nodes are surrounded by a thin layer of tissue called a capsule. Extranodal extension means that cancer cells within the lymph node have broken through the capsule and have spread into the tissue outside of the lymph node. Extranodal extension is important because it increases the risk that the tumour will regrow in the same location after surgery. For some types of cancer, extranodal extension is also a reason to consider additional treatment such as chemotherapy or radiation therapy.

Mismatch repair proteins (MMR)

What are mismatch repair proteins?

Mismatch repair (MMR) is a system inside all normal, healthy cells for fixing mistakes in our genetic material (DNA). The system is made up of different proteins and the four most common are called MSH2, MSH6, MLH1, and PMS2.

The four mismatch repair proteins MSH2, MSH6, MLH1, and PMS2 work in pairs to fix damaged DNA. Specifically, MSH2 works with MSH6 and MLH1 works with PMS2. If one protein is lost, the pair cannot function normally. A loss of one of these proteins increases the risk of developing cancer.

Pathologists order mismatch repair testing to see if any of these proteins are lost in a tumour. If mismatch repair testing has been ordered on your tissue sample, the results will be described in your pathology report.

Why is testing for mismatch repair proteins important?

Mismatch repair (MMR) testing is performed on colon cancers to identify patients who may have Lynch syndrome, also known as hereditary nonpolyposis colorectal cancer (HNPCC). Lynch syndrome is a genetic disorder that increases the risk of developing various types of cancer, including colon cancer, endometrial cancer, ovarian cancer, gastric cancer, and others.

How do pathologists test for mismatch repair proteins?

The most common way to test for mismatch repair proteins is to perform a test called immunohistochemistry. This test allows pathologists to see if the tumour cells are producing all four mismatch repair proteins. Most reports will list all four proteins and say whether each is “retained” (normal production) or “deficient” (lost or not produced).

How do pathologists determine the pathologic stage (pTNM) for medullary carcinoma of the colon?

​The pathologic stage for medullary carcinoma of the colon 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 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 a more advanced disease and a worse prognosis.

The 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 medullary carcinoma

Medullary carcinoma of the colon is given a tumour stage between 1 and 4 based on the distance the cancer cells have spread from the mucosa into the wall of the colon or surrounding tissues (depth of invasion).

• T1 – The cancer cells have spread into the submucosa just below the mucosa on the inner surface of the colon.
• T2 – The cancer cells have spread into the muscularis propria of the colon.
• T3 – The cancer cells have spread into fat near the outer surface of the colon.
• T4 – The cancer cells have spread into a layer of tissue called the serosa on the outer surface of the colon or the cancer cells have spread into surrounding organs such as the bladder or abdominal wall.​

Nodal stage (pN) for medullary carcinoma

Medullary carcinoma of the colon is given a nodal stage between 0 and 2 based on whether any cancer cells were found in any of the lymph nodes examined or the finding of tumour deposits. If no cancer cells were found in any of the lymph nodes examined, the nodal stage is N0. If no lymph nodes were sent for pathologic examination, the nodal stage cannot be determined and is listed as NX.

Metastatic stage (pM) for medullary carcinoma

Medullary carcinoma of the colon is given a metastatic stage of 0 or 1 based on the presence of cancer cells at a distant site in the body (for example the liver). The M stage can only be assigned if tissue from a distant site is submitted for pathological examination. Because this tissue is rarely present, the M stage cannot be determined and is listed as X.