Medullary Carcinoma of the Large Intestine: Understanding Your Pathology Report

by Jason Wasserman MD PhD FRCPC
April 1, 2026

Medullary carcinoma is a rare subtype of colorectal cancer. Like other types of colon and rectal cancer, it starts from the cells lining the inner surface of the bowel. However, medullary carcinoma has a very distinctive appearance under the microscope. Instead of forming the gland-like structures typical of most colorectal cancers, the tumor cells grow in solid sheets and are usually surrounded by large numbers of immune cells. Medullary carcinoma is most often found in the right side of the colon and tends to occur more frequently in older adults.

Although medullary carcinoma is technically a type of adenocarcinoma, it behaves quite differently from more common colorectal cancers. It is strongly associated with a condition called mismatch repair deficiency, which affects how cells repair mistakes in their DNA. This molecular feature is one reason why medullary carcinoma often has a better prognosis than other high-grade colorectal cancers.

What are the symptoms of medullary carcinoma?

The symptoms of medullary carcinoma are similar to those of other types of colorectal cancer. They include a change in bowel habits such as diarrhea or constipation, abdominal pain or cramping, rectal bleeding or blood in the stool, unexplained weight loss, and fatigue caused by anemia (a low red blood cell count). In some cases, there are no symptoms at all, and the cancer is found incidentally during routine screening, such as a colonoscopy.

What causes medullary carcinoma?

Medullary carcinoma is closely linked to a condition called microsatellite instability (MSI), which occurs when the body’s system for repairing small errors in DNA does not work properly. This DNA repair system is called the mismatch repair system, and when it fails, errors accumulate in the DNA of dividing cells, leading to cancer.

There are two main reasons the mismatch repair system can fail in medullary carcinoma:

• Sporadic (non-inherited) cases — In most patients, the problem is caused by a chemical change that silences the MLH1 gene, one of the key mismatch repair genes. This process is called MLH1 promoter hypermethylation. It occurs only in tumor cells during a person’s lifetime and is not inherited.
• Lynch syndrome (inherited) cases — In a smaller number of patients, the mismatch repair deficiency is caused by an inherited condition called Lynch syndrome. People with Lynch syndrome are born with a mutation in one of the mismatch repair genes — most commonly MLH1, MSH2, MSH6, or PMS2 — that they inherited from a parent. Lynch syndrome significantly increases the lifetime risk of colorectal cancer as well as cancers of the uterus, stomach, ovaries, and urinary tract. It can also be passed on to children, so the implications extend to the whole family.

Determining whether a mismatch repair deficiency is due to Lynch syndrome or a sporadic methylation change is an important part of the workup after a diagnosis of medullary carcinoma, which is why molecular testing is routinely performed.

How is the diagnosis made?

The diagnosis of medullary carcinoma is usually made after a tissue sample — called a biopsy — is taken during a colonoscopy. The sample is examined under the microscope by a pathologist.

Under the microscope, medullary carcinoma has several characteristic features that distinguish it from other colorectal cancers:

• The cancer cells grow in solid sheets or nests, without forming the glandular structures typical of ordinary colorectal adenocarcinoma.
• The cells are large and round, with open, nuclear-appearing nuclei, prominent nucleoli, and abundant pink cytoplasm.
• There is usually a striking immune cell infiltrate — large numbers of lymphocytes are scattered throughout and around the tumor, a sign that the immune system is actively responding to the cancer.

The pathologist may also perform additional staining tests, such as immunohistochemistry, to help confirm the diagnosis. Medullary carcinoma typically does not produce the standard colon markers CDX2 and CK20, which can help distinguish it from other tumor types. It often shows loss of mismatch repair proteins on immunohistochemistry, a finding with direct implications for treatment and genetic counseling

Once the tumor is surgically removed, your pathologist will examine the entire specimen and provide information about how deeply the tumor has grown, whether the margins are clear, whether lymph nodes are involved, and the results of molecular testing. If you have had a colonoscopy procedure where the tumor was biopsied, you may also find it helpful to read our guide to understanding your colonoscopy biopsy report.

Tumour grade

For most colorectal cancers, grade describes how closely the tumor cells resemble normal colon glands. Well-differentiated (low-grade) tumors closely resemble normal tissue; poorly differentiated (high-grade) tumors look very abnormal and do not form recognizable glands.

Medullary carcinoma does not form glandular structures at all, which by conventional criteria would make it high grade or poorly differentiated. You may see this language in your pathology report. However, this classification can be misleading: despite its high-grade appearance, medullary carcinoma often behaves less aggressively than other poorly differentiated colorectal cancers, particularly when it shows mismatch repair deficiency and a strong immune response. For this reason, medullary carcinoma is now recognized as a distinct subtype of colorectal cancer with its own biological identity, rather than being classified alongside other high-grade tumors. The grading terminology in the report should be interpreted in this context.

Level of invasion

Invasion refers to how deeply the tumor has grown into the layers of the colon wall. Like all colorectal cancers, medullary carcinoma starts from the innermost lining of the colon (the mucosa). As it grows, it can extend into progressively deeper layers:

• Submucosa — supportive tissue just beneath the mucosa
• Muscularis propria — the thick muscle layer that moves stool through the colon
• Pericolorectal tissues (subserosa/pericolic fat) — fatty tissue surrounding the outer wall of the colon
• Serosa — the outermost surface layer of the colon
• Adjacent organs — in advanced cases, the tumor may grow directly into nearby structures

The deepest layer the tumors reached is used to determine the tumor stage (pT). Tumors that grow deeper into or through the wall are associated with a higher risk of spread to other parts of the body.

Tumour budding

Tumor budding refers to small clusters of individual cancer cells at the invading edge of the tumor, breaking away from the main mass. In many types of colorectal cancer, tumor budding is a sign of aggressive behavior. Medullary carcinoma, however, typically does not show tumor budding. In fact, its absence is one of the features that distinguishes medullary carcinoma from more aggressive colorectal cancer types and helps explain its relatively better outcome.

Lymphatic invasion

Lymphatic invasion (LVI) means that tumor cells have entered the small lymphatic channels within the colon wall. These channels connect to nearby lymph nodes, and cancer cells that enter them can travel to them and potentially beyond. Your pathology report will state whether lymphatic invasion is present or absent. While lymphatic invasion can occur in medullary carcinoma, it is seen less often than in conventional colorectal adenocarcinoma.

Vascular invasion

Vascular invasion means that tumor cells have entered a blood vessel. Blood vessels provide a direct route for cancer cells to travel to distant organs, such as the liver or lungs. When vascular invasion is identified, it is considered a higher-risk indicator and noted in the pathology report. As with lymphatic invasion, vascular invasion is less common in medullary carcinoma than in other colorectal cancers. subtypes

Perineural invasion

Perineural invasion (PNI) means that tumor cells are growing along or around a nerve. This can allow cancer cells to spread along nerve pathways into surrounding tissues. Perineural invasion is uncommon in medullary carcinoma, and its absence is associated with a better prognosis.

Immune response

One of the most distinctive features of medullary carcinoma — and one of the main reasons it tends to behave less aggressively — is a strong immune response. The tumor is typically infiltrated by large numbers of immune cells called lymphocytes, which suggests that the immune system is actively recognizing and attacking the cancer. This immune activity is related to the mismatch repair deficiency: tumors with defective DNA repair accumulate many mutations, making them highly recognizable to immune cells.

Some medullary carcinomas also show a pattern called a Crohn-like reaction, which involves clusters of immune cells at the outer edge of the tumor. This feature is also associated with a more favorable outcome and may predict a better response to immunotherapy.

Surgical margins

Margins are the edges of the tissue removed during surgery. After the tumor is removed, the pathologist examines the margins to determine whether cancer cells extend to the edge of the specimen.

• Negative margin — No cancer cells are present at the cut edge. This is the goal of surgery and suggests the tumor was fully removed.
• Positive margin — Cancer cells are present at the cut edge, raising the concern that some tumor remains in the body. This may lead to a recommendation for additional treatment.

For rectal tumors, the circumferential resection margin (CRM) — the distance from the tumor to the closest non-mucosal surface — is particularly important and is often specifically mentioned in the report. For right-sided colon tumors, the relevant margin is the mesocolic (mesenteric) margin.

Treatment effect

Some patients receive chemotherapy or radiation therapy before surgery (called neoadjuvant treatment) to shrink the tumor. After surgery, the pathologist assesses how much of the tumor responded to the treatment. This is called the treatment effect or tumor regression grade. The degree of response is typically scored on a scale from complete response (no viable tumor remaining) to minimal response (most of the tumor remains).

Neoadjuvant treatment is less commonly used for medullary carcinoma than for conventional colorectal cancer, but the same assessment applies if treatment was given before surgery.

Tumour deposits

Tumor deposits are small clusters of cancer cells found in the fat surrounding the colon or rectum, located away from the main tumor and lacking the structure of a lymph node. They represent a form of local spread and are distinct from lymph node metastases.

If tumor deposits are found but no lymph nodes contain cancer, the nodal stage is recorded as pN1c. If both tumor deposits and positive lymph nodes are present, the nodal stage is based on the number of involved lymph nodes, with the deposits noted separately.

Lymph nodes

Lymph nodes are small immune organs located throughout the body. During surgery for colorectal cancer, the lymph nodes near the tumor are removed along with the bowel segment and examined by the pathologist. Your report will state the total number of lymph nodes examined and the number, if any, that contain cancer.

Lymph node involvement is used to determine the nodal stage (pN) and is one of the most important factors in deciding whether to recommend chemotherapy after surgery. In medullary carcinoma, lymph node spread is possible but tends to occur less frequently than in conventional colorectal adenocarcinoma.

If cancer is found in a lymph node, the report may also note the size of the largest tumor deposit and whether the cancer has broken through the lymph node’s outer wall into surrounding tissue — a finding called extranodal extension.

Biomarker and molecular testing

Molecular testing is a routine and essential part of the workup for medullary carcinoma. The results can influence treatment decisions, confirm the diagnosis, and determine whether the cancer is associated with an inherited syndrome.

Mismatch repair (MMR) protein testing

This is the most important molecular test for medullary carcinoma. Using a technique called immunohistochemistry, the pathologist tests for four mismatch repair proteins: MLH1, PMS2, MSH2, and MSH6. These proteins normally work in pairs to fix small errors in DNA. If one or more proteins are missing from tumor cells, the result is reported as mismatch repair-deficient (MMR-deficient) or, equivalently, microsatellite instability-high (MSI-high).

Virtually all medullary carcinomas are MMR-deficient, and this finding is among the features supporting the diagnosis. It also has direct clinical implications:

• MMR-deficient tumors are more likely to respond to immunotherapy (specifically, checkpoint inhibitor drugs such as pembrolizumab), which is not typically effective in MMR-intact colorectal cancer.
• MMR deficiency prompts further testing to determine whether the cause is an acquired (sporadic) change or an inherited one (Lynch syndrome).

MLH1 promoter hypermethylation and BRAF V600E testing

When the mismatch repair test shows loss of MLH1 and its partner PMS2, the next step is to determine why. The most common cause of medullary carcinoma is hemical silencing of the MLH1 gene, called MLH1 promoter hypermethylation. This change occurs only in the tumor cells and is not inherited — it is a sporadic event.

Testing for the BRAF V600E mutation serves a related purpose: a BRAF V600E mutation is strongly associated with sporadic MLH1 methylation and essentially rules out Lynch syndrome as the cause of the MMR deficiency. If BRAF V600E is present, further genetic testing for Lynch syndrome is generally not required. If BRAF is negative, additional testing — including direct testing for MLH1 promoter hypermethylation or germline genetic testing — is usually recommended to investigate whether Lynch syndrome is present.

KRAS and NRAS

KRAS and NRAS are genes that, when mutated, can make cancer cells grow independently of normal signals. Mutations in these genes are common in conventional colorectal adenocarcinoma and are associated with resistance to a class of targeted therapies called anti-EGFR drugs (such as cetuximab and panitumumab). Medullary carcinoma typically lacks KRAS and NRAS mutations, which distinguishes it molecularly from most other colorectal cancers. However, because medullary carcinoma does not usually respond to anti-EGFR therapy for other reasons (including its association with BRAF mutation), these results primarily serve a confirmatory and informational role.

PD-L1

PD-L1 is a protein that some tumor cells produce to help them evade immune system attack. Testing for PD-L1 expression may be performed in patients with advanced medullary carcinoma when immunotherapy is being considered. Results are often reported as a Combined Positive Score (CPS), which measures PD-L1 expression across both tumor cells and immune cells. A higher CPS score is generally associated with a greater likelihood of responding to checkpoint inhibitor immunotherapy, although MMR deficiency itself is already a strong predictor of immunotherapy response.

For detailed explanations of these and other biomarker tests used in colorectal cancer, visit our Biomarkers and Molecular Testing section.

Pathologic stage (pTNM)

The pathologic stage is determined after surgery and describes how far the cancer has spread. It is based on the internationally recognized TNM staging system, which considers three components: the primary tumor (T), lymph node involvement (N), and distant metastasis (M). Metastasis is typically assessed by imaging rather than by pathology.

Tumor stage (pT)

• pT1 — Tumor has grown into the submucosa but not the muscle layer.
• pT2 — Tumor has grown into the muscularis propria (muscle layer).
• pT3 — Tumor has grown through the muscle layer into the pericolorectal fat or tissues.
• pT4a — Tumor has reached the outermost surface of the colon (the serosa/visceral peritoneum).
• pT4b — Tumor has grown directly into or is attached to a nearby organ or structure.

Nodal stage (pN)

• pN0 — No cancer found in any of the lymph nodes examined.
• pN1a — Cancer found in 1 lymph node.
• pN1b — Cancer found in 2 to 3 lymph nodes.
• pN1c — TuTumoreposit(s) in the pericolorectal fat, but no cancer in lymph nodes.
• pN2a — Cancer found in 4 to 6 lymph nodes.
• pN2b — Cancer found in 7 or more lymph nodes.
• pNX — Lymph nodes were not assessed.

What is the prognosis for medullary carcinoma?

Medullary carcinoma generally has a more favorable prognosis than other poorly differentiated or high-grade colorectal cancers. This is largely attributed to the strong immune response and to mismatch repair deficiency, which characterize most medullary carcinomas. Patients whose tumors are MMR-deficient tend to have better outcomes than those with MMR-intact tumors of similar stage — a pattern that holds not just for medullary carcinoma but for colorectal cancer more broadly.

As with all colorectal cancers, the most important factors affecting prognosis include the pathologic stage at diagnosis (particularly lymph node involvement and depth of invasion), whether the tumor was fully removed with clear margins, and the results of molecular testing. Patients with MMR-deficient tumors may also benefit from immunotherapy in the advanced or metastatic setting, which provides additional treatment options not available for MMR-intact cancers.

Questions to ask your doctor

Your pathology report contains important information that will guide your care. The following questions may help you prepare for your next appointment.

• What stage is my cancer, and what does that mean for my treatment and outlook?
• Was my tumor tested for mismatch repair deficiency or microsatellite instability — and what was the result?
• Do I need further testing to find out whether my cancer is related to Lynch syndrome?
• Should my family members be referred for genetic counseling or testing?
• Were the surgical margins clear? Was the entire tumor removed?
• Was cancer found in any of my lymph nodes?
• Was a BRAF or KRAS mutation found in my tumor, and does this affect my treatment options?
• Am I a candidate for immunotherapy, given that my tumor is mismatch repair-deficient?
• Will I need chemotherapy after surgery?
• What follow-up tests and appointments will I need, and how often?