Your pathology report for medullary carcinoma of the colon and rectum

by Jason Wasserman MD PhD FRCPC
July 21, 2025

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Medullary carcinoma is a rare and distinct subtype of colorectal cancer. Like other types of colon and rectal cancer, it starts from the inner lining of the bowel. However, medullary carcinoma has unique features when examined under the microscope. It tends to grow in large sheets of tumor cells and is usually associated with an intense immune response. Medullary carcinoma is most often found in the right side of the colon and occurs more frequently in older adults.

Although it is a type of adenocarcinoma, medullary carcinoma behaves differently than more common colorectal cancers. It is often linked to a condition called microsatellite instability, which affects how cells repair their DNA. This condition may help explain why medullary carcinoma can have a better prognosis than some other colorectal cancers.

What are the symptoms of medullary carcinoma?

The symptoms of medullary carcinoma are similar to those of other types of colorectal cancer. Common symptoms include:

• A change in bowel habits, such as diarrhea or constipation.

• Abdominal pain or discomfort.

• Unexplained weight loss.

• Rectal bleeding or blood in the stool.

• Anemia (low red blood cell count), which can cause fatigue.

In some cases, people may have no symptoms, and the cancer is found during routine screening such as a colonoscopy.

What causes medullary carcinoma?

Medullary carcinoma is often associated with a condition called microsatellite instability (MSI), which happens when the body’s normal system for repairing DNA damage does not work properly. This can occur for two main reasons:

• Sporadic cases: Most often, MSI in medullary carcinoma is caused by changes in a gene called MLH1. These changes are not inherited but occur during a person’s lifetime. A common cause is something called MLH1 promoter hypermethylation, which turns off the gene and prevents it from functioning normally.

• Lynch syndrome: In some cases, MSI is due to an inherited condition called Lynch syndrome. People with Lynch syndrome have mutations in DNA repair genes that they inherit from a parent. These people are at higher risk for medullary carcinoma and other cancers, including uterine, stomach, and ovarian cancer.

Medullary carcinoma often shows a mutation in a gene called BRAF (specifically a change called V600E), which is seen in many sporadic cases with MSI. BRAF testing can help doctors determine whether a case of MSI is likely due to Lynch syndrome or not.

How is the diagnosis of medullary carcinoma made?

The diagnosis is usually made after a small tissue sample called a biopsy is taken during a colonoscopy. The tissue is then examined under the microscope by a pathologist.

Medullary carcinoma is diagnosed based on its characteristic appearance:

• The cancer cells grow in large sheets or clusters.

• The cells have round or oval nuclei, prominent nucleoli, and abundant pink (eosinophilic) cytoplasm.

• The tumor is usually filled with immune cells, especially lymphocytes.

• Unlike most colon cancers, medullary carcinoma often does not form gland-like structures.

• Special stains (immunohistochemistry) may show loss of CDX2 and CK20 and may help confirm the diagnosis.

Once the tumor is removed by surgery, your pathologist will examine the entire specimen to provide important information about the tumor’s size, depth of invasion, margins, lymph node involvement, and any signs of spread beyond the colon.

What does medullary carcinoma look like under the microscope?

Under the microscope, medullary carcinoma has a distinct appearance. The cancer cells tend to be large and round with open (vesicular) nuclei and noticeable nucleoli. The cytoplasm is often abundant and pink. The tumor typically grows in solid sheets or nests and lacks the glandular structures seen in typical adenocarcinoma. There is often a striking presence of lymphocytes, a type of immune cell, scattered throughout the tumor and surrounding tissues.

Pathologists may use special stains to help confirm the diagnosis. These tests often show that the tumor does not produce typical colon markers like CDX2 or CK20. Instead, it may express markers like SATB2 and shows loss of mismatch repair proteins in most cases.

What grade is medullary carcinoma?

Tumor grade is a way for pathologists to describe how different the cancer cells look compared to normal cells and how much the tumor resembles normal tissue under the microscope. For most types of colon cancer, tumors are graded based on the formation of gland-like structures. However, medullary carcinoma is different.

Medullary carcinoma is typically considered a high grade tumor because it does not form the typical glandular structures seen in well-differentiated colon cancers. Instead, it grows in solid sheets of cells and has features that would normally suggest an aggressive cancer. Despite this, medullary carcinoma often behaves less aggressively than other high-grade colon cancers, especially when it shows microsatellite instability and a strong immune response.

Because of this unique combination—high grade appearance but often favorable behavior—medullary carcinoma is recognized as a distinct subtype of colorectal cancer with its own classification, rather than being graded using the traditional system. Your pathology report may describe it as “poorly differentiated” or “high grade,” but this does not necessarily mean a worse prognosis compared to other types of colon cancer. The overall behavior depends on many factors, including the tumor’s genetic features and how far it has spread.

Level of invasion

In medullary carcinoma, invasion refers to how deeply the tumour has grown into the layers of the colon wall. Like other colorectal cancers, medullary carcinoma starts from cells in the innermost layer of the colon, called the mucosa.

As the tumour grows, it can extend into deeper layers:

• Submucosa – a layer of supportive tissue just beneath the mucosa

• Muscularis propria – a thick layer of muscle that helps move stool through the colon

• Subserosa – a layer of fat around the colon

• Serosa – the outermost surface of the colon

The deepest layer the tumour has reached is called the level of invasion. This is important because tumours that grow deeper into the wall are more likely to spread to other parts of the body. This information is also used to determine the tumour stage (pT).

Tumour budding

Tumour budding describes the presence of small clusters of tumour cells at the edge of the tumour. However, medullary carcinoma typically does not show tumour budding. In fact, the absence of tumour budding is one of the features that helps distinguish medullary carcinoma from other, more aggressive types of colorectal cancer. Because of this, tumour budding is usually not a concern for medullary carcinoma.

Lymphatic invasion

Lymphatic invasion means that tumour cells have entered small channels called lymphatics, which are part of the body’s drainage and immune system. This feature increases the risk that cancer has spread to nearby lymph nodes. While lymphatic invasion can be seen in medullary carcinoma, it tends to be less common than in other types of colorectal cancer.

Vascular invasion

Vascular invasion means that tumour cells have entered blood vessels. When this happens, there is a higher risk that cancer may spread to distant organs like the lungs or liver. In medullary carcinoma, vascular invasion is possible but is not seen as often as in other subtypes. However, when present, it is still considered an important risk factor.

Perineural invasion

Perineural invasion means that tumour cells were found growing around or along nerves. This is usually a sign of more aggressive disease. In medullary carcinoma, perineural invasion is not common, and its absence is often associated with a better outcome.

Immune response

One of the most distinctive features of medullary carcinoma is a strong immune response. These tumours are typically surrounded by large numbers of immune cells, particularly lymphocytes. This response suggests that the body is actively trying to fight the cancer, and it is associated with a more favorable prognosis.

Some patients with medullary carcinoma may also show a pattern called a Crohn-like reaction, which involves clusters of immune cells around the tumour. This immune activity is one reason why patients with medullary carcinoma may respond well to immunotherapy.

Margins

Margins are the edges of the tissue removed during surgery. Pathologists examine these margins to ensure that the entire tumour has been removed. A negative margin means no cancer was found at the edge, which is the goal. A positive margin means cancer cells were found at the edge, suggesting that some tumour may still be present in the body.

In medullary carcinoma, margins are assessed the same way as in other types of colon cancer. If the tumour is located in the rectum, the circumferential resection margin (CRM) is especially important. For tumours in the cecum, the mesocolic margin is more relevant.

Treatment effect

Some patients receive chemotherapy or radiation before surgery to shrink the tumour. After surgery, the pathologist looks at the tissue to see how much of the tumour remains. This is called treatment effect. The response is scored from 0 (no cancer left) to 3 (tumour still present with no signs of shrinking).

While pre-surgical treatment is less commonly used for medullary carcinoma due to its typically favorable behavior, the same scoring system applies if treatment is given.

Tumour deposits

Tumour deposits are small groups of cancer cells found outside the main tumour, often in the fat near the colon or rectum. They are different from lymph node deposits because they do not have the structure of a lymph node and are not found in blood vessels or nerves.

In medullary carcinoma, tumour deposits are less common but can still occur. If tumour deposits are found and no lymph nodes contain cancer, the cancer is staged as N1c. If both tumour deposits and positive lymph nodes are present, the nodal stage is based on the number of involved lymph nodes.

Lymph nodes

Lymph nodes are small structures that filter fluids and are part of the immune system. In colon cancer, tumour cells may spread to nearby lymph nodes through lymphatic vessels. Pathologists examine all removed lymph nodes to see if they contain cancer.

In medullary carcinoma, lymph node involvement is possible, but not always present. The presence or absence of cancer in the lymph nodes helps determine the nodal stage (pN) and guides decisions about treatment, including whether chemotherapy is needed.

Molecular markers for medullary carcinoma

Molecular markers are changes in genes or proteins found in cancer cells that help doctors understand how the tumour behaves and how it might respond to treatment. These markers are especially important in medullary carcinoma, which often shows distinctive molecular features compared to other types of colon cancer.

Mismatch repair protein testing

Most medullary carcinomas show mismatch repair deficiency. This means the tumour cells have lost the ability to fix small mistakes in their DNA. The mismatch repair system includes four proteins: MLH1, PMS2, MSH2, and MSH6. These proteins work in pairs, and if even one is missing, the repair system does not work properly.

Pathologists test for these proteins using a method called immunohistochemistry. If one or more proteins are missing in the tumour, the result is called mismatch repair deficient (MMR-deficient). This is a hallmark feature of medullary carcinoma and helps support the diagnosis.

Finding MMR deficiency is important because:

• It can suggest an inherited condition like Lynch syndrome, especially if the patient is younger or has a family history of colon cancer.

• It helps identify patients who may benefit from immunotherapy, a type of cancer treatment that helps the immune system attack cancer cells.

MLH1 promoter hypermethylation

One of the most common reasons for mismatch repair deficiency in medullary carcinoma is a chemical change called MLH1 promoter hypermethylation. This change turns off the MLH1 gene, which also leads to loss of its partner protein PMS2.

To help determine if the tumour is caused by a sporadic (non-inherited) change or by Lynch syndrome, doctors may test for a mutation in another gene called BRAF. If the BRAF V600E mutation is present, it suggests the tumour is sporadic and not inherited.

In some cases, doctors may test directly for MLH1 promoter hypermethylation. If this is found, it also supports a sporadic origin. These tests are important for deciding whether further genetic testing is needed.

KRAS and NRAS

Mutations in KRAS and NRAS are common in many types of colon cancer, but they are typically absent in medullary carcinoma. This is helpful because it supports the diagnosis and also affects treatment. Tumours with KRAS or NRAS mutations usually do not respond to anti-EGFR therapies like cetuximab or panitumumab. Since medullary carcinoma often lacks these mutations, other treatment strategies may be considered.

BRAF

Medullary carcinoma is often associated with a mutation in the BRAF gene, especially a specific change called V600E. This mutation is found in a high percentage of sporadic medullary carcinomas and is a key molecular feature.

BRAF mutations are important because:

• They support the diagnosis of medullary carcinoma.

• They are associated with mismatch repair deficiency and MLH1 promoter hypermethylation.

• Tumours with this mutation typically do not respond well to anti-EGFR therapy.

However, the presence of a BRAF mutation may help guide treatment decisions, particularly in advanced or metastatic cases.

PIK3CA and PTEN

Mutations in PIK3CA and loss of function in PTEN can also be found in some colorectal cancers, including medullary carcinoma. These genes are involved in pathways that help cancer cells grow and survive.

While these markers are less commonly tested in medullary carcinoma, they may provide helpful information in advanced disease, especially if standard treatment options are no longer effective.

EGFR

EGFR is a protein found on the surface of many cancer cells. Drugs like cetuximab and panitumumab work by blocking this protein. However, in medullary carcinoma, EGFR-targeted treatments are usually not effective, especially if the tumour has a BRAF mutation or mismatch repair deficiency. Because of this, EGFR testing is generally not used to guide treatment for medullary carcinoma.

PD-L1

PD-L1 is a protein that helps cancer cells avoid being attacked by the immune system. Medullary carcinoma often shows high levels of immune activity, and some tumours produce PD-L1.

Doctors may test for PD-L1 to help identify patients who could benefit from immunotherapy. The result may be reported as a CPS score (Combined Positive Score). A higher CPS score means that more tumour and immune cells are producing PD-L1, which may increase the likelihood of responding to immunotherapy.

While PD-L1 testing is not routine in all cases, it may be considered in patients with advanced disease or when immunotherapy is being explored as a treatment option.

Pathologic stage (pTNM)

Staging helps doctors understand how far the medullary carcinoma has spread and plays a key role in treatment planning. Pathologic staging is based on the examination of tissue after surgery.

There are three main parts to the staging system:

• T (Tumour): How deep the tumour has grown into the colon wall or nearby tissues.

• N (Nodes): Whether cancer has spread to nearby lymph nodes.

• M (Metastasis): Whether cancer has spread to other parts of the body (usually determined by imaging, not pathology).

Tumour stage (pT)

The colon wall has several layers:

• Mucosa – the innermost lining where the cancer begins.

• Submucosa – a layer of tissue beneath the mucosa.

• Muscularis propria – the thick muscle layer.

• Subserosa and fat – tissue and fat around the colon.

• Serosa – the outermost covering of the colon.

Medullary carcinoma, like other colon cancers, can grow through these layers. The pT stage is based on the deepest layer the tumour has reached:

• pT1 – Tumour has grown into the submucosa.

• pT2 – Tumour has grown into the muscularis propria.

• pT3 – Tumour has grown into the fat around the colon.

• pT4a – Tumour has reached the outer surface (serosa).

• pT4b – Tumour has invaded nearby organs or structures.

Nodal stage (pN)

The pN stage tells whether cancer has spread to lymph nodes. This is common in more advanced medullary carcinomas, although the strong immune response in some cases may help limit the spread.

• pN0 – No cancer in lymph nodes.

• pN1a – Cancer in one lymph node.

• pN1b – Cancer in two or three lymph nodes.

• pN1c – No lymph nodes involved, but tumour deposits are found nearby.

• pN2a – Cancer in four to six lymph nodes.

• pN2b – Cancer in seven or more lymph nodes.

If no lymph nodes are available for examination, the stage may be listed as pNX.

Why is staging important?

Staging helps doctors understand how far the cancer has spread and what kind of treatment is most appropriate. In medullary carcinoma, even tumours with advanced stage may behave less aggressively than expected due to strong immune responses and mismatch repair deficiency.

Lower stages (like pT1 or pN0) usually mean a better chance of cure. Higher stages (like pT4 or pN2) mean the cancer is more advanced and may require additional treatment such as chemotherapy or immunotherapy.

What is the prognosis for medullary carcinoma?

Medullary carcinoma generally has a better prognosis than other types of poorly differentiated colon cancers. This is likely due to the presence of MSI and the strong immune response seen in these tumors. However, like all colorectal cancers, the outcome depends on several factors, including how deeply the tumor has grown into the wall of the colon, whether it has spread to lymph nodes or other organs, and whether the tumor was completely removed with surgery.

Questions to ask your doctor

• Has my tumor been tested for microsatellite instability or mismatch repair protein loss?

• Do I need genetic testing for Lynch syndrome?

• What stage is my tumor and what does that mean for my treatment?

• Will I need chemotherapy or immunotherapy?

• What follow-up tests or screening will I need after treatment?