Adenocarcinoma of the colon

by Jason Wasserman MD PhD FRCPC and Zuzanna Gorski MD
July 20, 2025

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Adenocarcinoma is the most common type of colon cancer. It starts from the glandular cells that normally line the inside of the colon. These cells are responsible for producing mucus to help move stool through the large intestine. When these cells become abnormal and start to grow in an uncontrolled way, they can form a tumour called adenocarcinoma.

What causes adenocarcinoma of the colon?

Most cases of colonic adenocarcinoma develop slowly over time through a series of changes in the DNA of cells lining the colon. These changes may occur randomly or may be influenced by lifestyle or inherited risk factors. In many cases, the tumour begins as a small non-cancerous growth called an adenoma or polyp.

Some key risk factors include:

• A personal or family history of colorectal polyps or cancer.

• Inherited conditions such as Lynch syndrome or familial adenomatous polyposis (FAP).

• Chronic inflammation in the colon, such as ulcerative colitis or Crohn’s disease.

• A diet high in red or processed meat and low in fiber.

• Lack of physical activity, smoking, and heavy alcohol use.

What are the symptoms of colonic adenocarcinoma?

In its early stages, colonic adenocarcinoma may not cause any symptoms. As the tumour grows, it may lead to:

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

• Rectal bleeding or blood in the stool.

• Abdominal discomfort, bloating, or pain.

• Unexplained weight loss.

• Fatigue or weakness due to anemia (low red blood cell count).

Symptoms often depend on the size and location of the tumour. Any persistent changes in bowel habits or signs of bleeding should be discussed with your doctor.

How is this diagnosis made?

Colonic adenocarcinoma is usually diagnosed after a small tissue sample is removed during a colonoscopy. This procedure allows a doctor to examine the inside of the colon and rectum and take samples (biopsies) of any abnormal areas. If cancer is found, additional imaging studies and surgery may be done to determine the full extent of the tumour.

What does colorectal adenocarcinoma look like under the microscope?

When examined under the microscope, colonic adenocarcinoma is made up of abnormal glandular structures. These glands may appear disorganized, irregular, and may invade deep into the surrounding tissue layers. The tumour cells typically have enlarged, irregularly shaped nuclei and may produce mucin (a type of mucus), although not in the large amounts seen in mucinous adenocarcinoma.

Tumour grade

Tumour grade describes how closely the tumour cells resemble normal cells. In colonic adenocarcinoma, grade is based on how much of the tumour forms gland-like structures:

• Grade 1 (well differentiated): more than 95% of the tumour forms glands.

• Grade 2 (moderately differentiated): 50–95% of the tumour forms glands.

• Grade 3 (poorly differentiated): less than 50% of the tumour forms glands.

• Grade 4 (undifferentiated): no gland formation.

Higher-grade tumours behave more aggressively and are more likely to spread.

The most recent World Health Organization guidelines propose a simplified two-tier system:

• Low grade: This includes well- and moderately differentiated tumours (grades 1 and 2) that still form gland-like structures.
• High grade: This includes poorly differentiated and undifferentiated tumours (grades 3 and 4) with little gland formation.

Mucinous differentiation

Pathologists use the term mucinous differentiation to describe tumours that contain a large amount of extracellular mucin. Mucin is a specialized type of protein made by both normal and tumour cells. Extracellular means that the mucin was seen outside of the tumour cells. If more than 50% of the tumour is composed of mucin, the tumour is classified as a mucinous adenocarcinoma.

Level of invasion

Invasion refers to how deeply the tumour has grown into the wall of the colon. Colonic adenocarcinoma starts from gland-forming cells located in a thin layer of tissue on the inner surface of the colon called the mucosa. As the tumour grows, it can spread beyond the mucosa into deeper layers of tissue.

Beneath the mucosa are several important layers of the colon wall:

• Submucosa – a supportive layer made of connective tissue located just beneath the mucosa.

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

• Subserosal tissue – a layer of fat beneath the muscle.

• Serosa – the outermost layer that covers the outside surface of the colon.

As adenocarcinoma grows, it can invade into these deeper layers. In more advanced cases, the tumour may grow all the way through the wall of the colon and spread directly into nearby organs or tissues.

The level of invasion refers to the deepest layer that the tumour has reached. This can only be determined after the tumour is examined under the microscope by a pathologist. The level of invasion is very important because tumours that grow deeper into the colon wall are more likely to spread to lymph nodes or other parts of the body. The level of invasion is also used to determine the pathologic tumour stage (pT), which helps doctors plan further treatment and estimate the risk of the cancer coming back.

Tumour budding

Tumour budding refers to small clusters or single cancer cells seen at the edge of the tumour. The number of buds seen under the microscope is used to assign a score: low, intermediate, or high. A high tumour budding score is associated with a greater risk of the cancer spreading.

Lymphatic invasion

Lymphatic invasion means that cancer cells have entered small vessels called lymphatic channels, which are part of the body’s immune and drainage system. These channels are lined by thin endothelial cells and usually do not contain red blood cells. When tumour cells are found inside them, it suggests a higher chance that the cancer may spread to nearby lymph nodes. Sometimes, additional special stains (immunohistochemistry) are used by pathologists to identify cancer cells in these tiny vessels.

Vascular invasion

Vascular invasion means that cancer cells have entered blood vessels. This can happen inside the wall of the colon (intramural vascular invasion) or outside the wall in surrounding tissues (extramural vascular invasion). Both types are associated with a higher risk that the cancer will spread to other parts of the body, such as the lungs or liver, but extramural vascular invasion is considered particularly important.

In some cases, pathologists may use special stains to highlight the blood vessels and confirm the presence of tumour cells inside them. Recognizing this type of invasion helps guide treatment decisions and provides important information about prognosis.

Perineural invasion

Perineural invasion means that cancer cells are growing along or around a nerve. This is most often seen in advanced tumours and is associated with a higher risk of the cancer spreading or coming back after treatment. Under the microscope, pathologists look for tumour cells that wrap around at least one-third of the outside surface of a nerve. Perineural invasion can occur in any part of the colon and is more common when other high-risk features, such as vascular invasion or lymphatic invasion, are also present.

Immune response

The body’s immune system often tries to fight back against cancer by sending immune cells like lymphocytes to the area around the tumour. When a strong immune response is seen under the microscope, it may be a sign that the body is trying to contain or slow the growth of the cancer. A particular type of immune response called a Crohn-like reaction involves groups of immune cells clustered near the tumour and is generally associated with a better outcome.

In some cases, pathologists may use immunohistochemistry to assess specific types of immune cells in the tissue. While not always reported in standard pathology reports, immune response is increasingly being recognized as an important part of cancer biology.

Margins

Margins refer to the edges of tissue removed during surgery. In colon cancer surgery, pathologists examine different types of margins:

• Proximal and distal margins: These are the ends of the colon segment removed during surgery.
• Circumferential resection margin (CRM): The outermost edge of the resected tissue, which is particularly important in rectal cancer.
• Mesocolic margin: This margin is important for tumours in the cecum. A margin is considered positive if cancer cells are found at the edge, meaning some cancer may have been left behind. A negative margin means no cancer was found at the edge, indicating the tumour was removed entirely.

Treatment effect

The tumour may shrink or disappear completely if a patient receives treatment before surgery, such as chemotherapy or radiation therapy. Pathologists assess the tumour to determine how much remains after treatment.

The response is classified as:

• No viable cancer cells (complete response, score 0).
• Single cells or rare small groups of cancer cells (near complete response, score 1).
• Residual cancer with evidence of tumour regression, but more than single cells or rare small groups (partial response, score 2).
• Extensive residual cancer with no evident tumour regression (poor or no response, score 3).

Tumour deposits

Tumour deposits are small groups of cancer cells found in the fat surrounding the colon or rectum. They are located in the lymphatic drainage area of the primary tumour but do not contain identifiable lymph node tissue or blood vessels. If a tumour focus is found in a vessel, it is classified as vascular invasion rather than a tumour deposit. Similarly, if a tumour focus is found near a nerve, it is classified as perineural invasion.

Tumour deposits are important because their presence increases the risk of cancer spreading. If tumour deposits are present but no lymph nodes contain cancer, the cancer is classified as N1c, regardless of the tumour (T) stage. If positive lymph nodes are also found, the cancer is classified based on the number of involved lymph nodes (N1a or N1b), but the presence and number of tumour deposits are still noted in the pathology report. Tumour deposits are considered an adverse prognostic factor, and their presence may influence treatment decisions, such as the need for chemotherapy.

Lymph nodes​

Lymph nodes are small immune organs found throughout the body. Cancer cells can spread from a tumour to these nodes via lymphatic vessels, prompting doctors to remove and examine them for cancer. This process is known as metastasis. Typically, cancer cells first migrate to lymph nodes nearest to the tumour, but more distant nodes can also be affected. Surgeons often remove the closest lymph nodes first and may take additional ones if they appear enlarged and potentially cancerous.

Pathologists examine the removed lymph nodes and report results as “positive” if cancer cells are found and “negative” if not. If cancer is detected, the report may indicate the size of the largest cluster, referred to as a “focus” or “deposit.” Extranodal extension refers to tumour cells breaking through the lymph node’s outer capsule into nearby tissue.

Examining lymph nodes is important for determining the pathologic nodal stage (pN) and gauging the risk of cancer spreading to other body parts. This information helps doctors determine whether further treatments, such as chemotherapy, radiation, or immunotherapy, are necessary.

Molecular markers

Molecular markers are changes in specific genes or proteins found in cancer cells that can provide important information about how a tumour behaves and how it may respond to certain treatments. These changes are identified through specialized laboratory tests performed on the tumour tissue. The results of these tests can help guide treatment decisions, especially in cases where the disease is advanced or has spread to other parts of the body.

Mismatch repair protein testing

Mismatch repair (MMR) proteins are part of the cell’s natural system for fixing DNA damage. These proteins—MLH1, PMS2, MSH2, and MSH6—work in pairs to repair small errors that occur when cells divide. If one of these proteins is missing, the repair system does not work properly, and this can lead to cancer.

Pathologists use a test called immunohistochemistry to check if these proteins are present in the tumour. If one or more proteins are missing, this is called mismatch repair deficiency. Mismatch repair deficiency may be caused by an inherited condition such as Lynch syndrome or by a non-inherited (sporadic) change in the tumour. If the proteins are present, the result is called mismatch repair proficient, meaning the repair system appears to be working normally.

Finding mismatch repair deficiency is important because it may suggest a higher risk of other cancers in the patient or their family. It can also help doctors decide whether certain treatments, like immunotherapy, might be helpful.

MLH1 promoter hypermethylation

One common reason for mismatch repair deficiency is a change called MLH1 promoter hypermethylation. This is not a mutation in the gene itself, but a chemical change that turns off the MLH1 gene so it cannot make its protein. When MLH1 is turned off, its partner protein PMS2 is also lost, and the DNA repair system stops working.

To figure out why MLH1 is missing, doctors may test for a specific mutation in another gene called BRAF. If a BRAF mutation (specifically V600E) is found, it suggests that the tumour is sporadic, meaning it developed on its own and is not due to an inherited condition like Lynch syndrome.

In some cases, doctors may test directly for MLH1 hypermethylation. If this is found, it also supports the diagnosis of a sporadic tumour. These tests help doctors decide whether genetic testing for Lynch syndrome is needed.

KRAS and NRAS

KRAS and NRAS are genes that help control how cells grow and divide. Changes (called mutations) in these genes are common in colorectal cancer. If a tumour has a mutation in either KRAS or NRAS, it is unlikely to respond to targeted treatments such as cetuximab or panitumumab, which are drugs that block a protein called EGFR. For this reason, testing for KRAS and NRAS mutations is usually done before starting one of these therapies. The test looks at specific parts of the genes known as codons, especially codons 12, 13, 61, and 146. About half of all colorectal cancers have a mutation in either KRAS or NRAS.

BRAF

BRAF is another gene that works in the same pathway as KRAS and NRAS to help regulate cell growth. A specific mutation in BRAF, called V600E, is sometimes found in colorectal cancers, including adenocarcinomas. This mutation is associated with a more aggressive tumour and a higher chance of spreading. BRAF testing can also help determine whether the cancer might be related to Lynch syndrome. If the V600E mutation is found, Lynch syndrome is much less likely. Similar to KRAS and NRAS mutations, tumours with a BRAF mutation usually do not respond well to anti-EGFR therapy.

PIK3CA

PIK3CA is a gene that helps cells grow and survive. Mutations in PIK3CA are found in about 10 to 20 percent of colorectal cancers. These mutations may reduce how well the cancer responds to anti-EGFR therapy, especially when they occur alongside KRAS or NRAS mutations. Some studies suggest that patients with a PIK3CA mutation may benefit from taking aspirin (acetylsalicylic acid) after surgery, but this is still being researched and is not yet a standard part of treatment.

PTEN

PTEN is a gene that helps control the same growth pathway as PIK3CA. When PTEN is not working properly, tumour cells may grow more easily and may be less likely to respond to anti-EGFR treatment. Pathologists can check for PTEN loss either by testing the gene itself or by using a test called immunohistochemistry to see if the PTEN protein is missing in the tumour cells. PTEN loss is sometimes found in tumours that also have mutations in KRAS, BRAF, or PIK3CA.

EGFR

EGFR stands for epidermal growth factor receptor. It is a protein found on the surface of many cancer cells that helps them grow and divide. Drugs like cetuximab and panitumumab work by blocking EGFR to slow tumour growth. However, EGFR testing is not routinely used in colorectal cancer to decide whether these drugs will be helpful. Instead, treatment decisions are usually based on whether the tumour has mutations in KRAS or NRAS, since these mutations are more reliable indicators of how the tumour will respond to anti-EGFR therapy.

PD-L1

PD-L1 is a protein that some cancer cells use to hide from the immune system. A test for PD-L1 may be done to help identify patients who could benefit from immunotherapy. The test result is often given as a CPS score, which stands for Combined Positive Score. This score compares the number of tumour and immune cells producing PD-L1 to the total number of tumour cells. A higher CPS score means more cells are expressing PD-L1, which in some cancers may suggest a better response to immunotherapy. However, the usefulness of PD-L1 testing in colorectal cancer is still being studied and is not currently a routine part of treatment planning.

HER2

HER2, also called ERBB2, is a gene commonly tested in breast and stomach cancers, but it can also be relevant in colorectal cancer. Some colorectal cancers show HER2 overexpression or amplification, particularly those that do not have mutations in KRAS or BRAF. In certain situations, HER2-positive colorectal cancers may respond to HER2-targeted therapies. HER2 testing may be considered when other treatments are no longer effective or as part of a clinical trial.

Pathologic stage (pTNM)

Pathologic staging for adenocarcinoma of the colon describes how far the cancer has spread in your body at the time of surgery. It is based on the examination of tissue under the microscope by a pathologist after the tumor has been removed.

The system uses three key components:

• T (Tumor): How deep the tumor has grown into the wall of the colon or surrounding areas.

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

• M (Metastasis): Whether the cancer has spread to distant parts of the body (this is usually assessed by imaging and not by the pathologist).

The sections below focus on the T and N stages, which are determined by the pathologist.

Tumor stage (pT)

The tumor stage (pT) tells us how deeply the tumor has grown into the wall of the colon or nearby tissues. The colon wall is made up of several layers, starting from the inner surface and moving outward:

• Mucosa – The inner lining where the cancer starts.

• Submucosa – A layer of tissue under the mucosa.

• Muscularis propria – A thick muscle layer that helps move stool.

• Subserosa and surrounding fat – A layer of fat around the outside of the colon.

• Serosa – The outermost surface (not present everywhere in the colon).

pT categories

• pT1: The cancer has grown into the submucosa, which is the layer just beneath the inner lining.

• pT2: The cancer has grown into the muscularis propria, the thick muscle layer of the colon.

• pT3: The cancer has gone all the way through the muscle layer and into the fat and tissue surrounding the colon.

• pT4a: The cancer has reached the outer surface of the colon (called the serosa) or has caused a perforation through the colon wall.

• pT4b: The cancer has directly invaded nearby organs or structures, such as the bladder, uterus, or abdominal wall.

Nodal stage (pN)

The nodal stage (pN) for adenocarcinoma of the colon tells us whether the cancer has spread to nearby lymph nodes, which are small immune structures that help the body filter and fight infections. Cancer often spreads to these nodes first.

pN categories

• pN0: No cancer is found in any of the lymph nodes that were examined.

• pN1: Cancer is found in 1 to 3 lymph nodes, or there are tumor deposits in surrounding tissues, even if all the lymph nodes are negative.

  • pN1a: One lymph node has cancer.

  • pN1b: Two or three lymph nodes have cancer.

  • pN1c: No lymph nodes have cancer, but tumor deposits are found in the fat or tissue near the colon.

• pN2: Cancer is found in 4 or more lymph nodes.

  • pN2a: Four to six lymph nodes are involved.

  • pN2b: Seven or more lymph nodes are involved.

If no lymph nodes were sent to the lab or could not be evaluated, the nodal stage may be listed as pNX (not assessable).

Why is staging important?

The pathologic stage helps your doctor understand how advanced the cancer is and what kind of treatment may be most effective. In general:

• Lower stages (like pT1 or pN0) suggest an earlier cancer with a better chance of cure.

• Higher stages (like pT4 or pN2) suggest a more advanced cancer with a higher risk of recurrence.

This information, combined with other features such as tumor grade, lymphovascular invasion, and molecular markers, helps guide decisions about chemotherapy and follow-up care.

Questions to ask your doctor

• What is the stage and grade of my tumour?

• Were lymph nodes or blood vessels involved?

• Was the tumour fully removed with negative margins?

• Do I need more treatment, such as chemotherapy?

• Was my tumour tested for mismatch repair deficiency?

• Were any other molecular markers tested?

• What follow-up tests or procedures do I need?