Adenocarcinoma of the colon

by Jason Wasserman MD PhD FRCPC and Zuzanna Gorski MD
January 15, 2024

Invasive adenocarcinoma (also known as colonic adenocarcinoma) is the most common type of colon cancer. It is made up of cells that normally cover the inside surface of the colon. This type of cancer often starts in a polyp such as a tubular adenoma, tubulovillous adenoma, or villous adenoma.

This article will help you understand your diagnosis and pathology report for invasive adenocarcinoma of the colon.

The colon

The colon is part of the digestive system and the first part of the large intestine. It is a long hollow tube that starts at the end of the small intestine and ends at the rectum. The colon is divided into four parts: ascending (right), transverse, descending (left), and sigmoid. It plays a crucial role in the processing of waste products and the absorption of water, electrolytes, and some vitamins. Invasive adenocarcinoma can arise in any part of the colon.

What causes invasive adenocarcinoma in the colon?

Invasive adenocarcinoma in the colon is believed to be caused by a combination of environmental and genetic factors. Established risk factors include excess consumption of processed meats, red meats, and alcohol. People with excess body fat are also at increased risk of developing this type of cancer. Prolonged inflammation in the colon, which can be seen in inflammatory bowel disease (ulcerative colitis and Crohn’s disease), is also associated with an increased risk of developing invasive adenocarcinoma.

What are the symptoms of invasive adenocarcinoma of the colon?

Symptoms of invasive adenocarcinoma 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.

Where in the colon does invasive adenocarcinoma start?

Invasive adenocarcinoma of the colon arises from epithelial cells normally found on the inside surface of the colon. These epithelial cells connect to form structures called glands. The glands, together with the underlying lamina propria and muscularis mucosae, form a thin layer of tissue called the mucosa. When the tumour cells are located entirely within the mucosa, the condition is called high grade dysplasia.

High grade dysplasia is considered a noninvasive, precancerous condition, and the tumour cells cannot metastasize (spread) to other body parts. However, as the tumour grows and the cells invade the underlying layers of tissue, the diagnosis changes to invasive adenocarcinoma. In contrast to high grade dysplasia, the tumour cells in invasive carcinoma can metastasize (spread) to lymph nodes and other parts of the body.

Microscopic features of this tumour

Under microscopic examination, invasive adenocarcinoma of the colon consists of groups of abnormal epithelial cells typically arranged invariably sized glands (that may look similar to the normal glands in the colon), nests, or sheets.

What to look for in your pathology report for invasive adenocarcinoma of the colon:

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 cells and tumour cells. Extracellular means that the mucin was seen outside of the tumour cells. If more than 50% of the tumour is made up of mucin, the tumour is called mucinous adenocarcinoma.

Histologic grade

Invasive adenocarcinoma of the colon is divided into three grades – well differentiated, moderately differentiated, and poorly differentiated. The grade is based on the percentage of the tumour cells forming round structures called glands. A tumour that does not form any glands is called undifferentiated. The grade is important because poorly differentiated and undifferentiated tumours tend to behave more aggressively; for example, these tumours are more likely to spread to lymph nodes and other parts of the body.

• Well differentiated: More than 95% of the tumour comprises glands. Pathologists also describe these tumours as grade 1.
• Moderately differentiated: 50 to 95% of the tumour comprises glands. Pathologists also describe these tumours as grade 2.
• Poorly differentiated: Less than 50% of the tumour comprises glands. Pathologists also describe these tumours as grade 3.
• Undifferentiated: Very few glands are seen anywhere in the tumour.

Depth of invasion and pathologic tumour stage (pT)

In pathology, the term invasion describes the spread of cancer cells into organs or tissues surrounding the location where the tumour started. Because invasive adenocarcinoma of the colon 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 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 see how far the cancer cells have spread from the mucosa into the surrounding tissue. This is called the depth or level of invasion. The depth of invasion is important because tumours that invade deeper into the colon wall 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). The images below show the relationship between the depth of invasion and the pathologic tumour stage.

Perineural invasion​

Pathologists use the term “perineural invasion” to describe a situation where cancer cells attach to or invade a nerve. “Intraneural invasion” is a related term that specifically refers to cancer cells found inside a nerve. Nerves, resembling long wires, consist of groups of cells known as neurons. These nerves, present throughout the body, transmit information such as temperature, pressure, and pain between the body and the brain. The presence of perineural invasion is important because it allows cancer cells to travel along the nerve into nearby organs and tissues, raising the risk of the tumour recurring after surgery.

Lymphovascular invasion​

Lymphovascular invasion occurs when cancer cells invade a blood vessel or lymphatic vessel. Blood vessels are thin tubes that carry blood throughout the body, whereas lymphatic vessels carry a fluid called lymph instead of blood. These lymphatic vessels connect to small immune organs scattered throughout the body, known as lymph nodes.

Lymphovascular invasion is important because it enables cancer cells to spread to other body parts, including lymph nodes or the liver, via the blood or lymphatic vessels. In addition, the presence of cancer cells inside a large vein 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.

​Margins

In pathology, a margin is the edge of tissue removed during tumour surgery. The margin status in a pathology report is important as it indicates whether the entire tumour was removed or if some was left behind. This information helps determine the need for further treatment.

Pathologists typically assess margins following a surgical procedure like an excision or resection, aimed at removing the entire tumour. Margins aren’t usually evaluated after a biopsy, which removes only part of the tumour. The number of margins reported and their size—how much normal tissue is between the tumour and the cut edge—vary based on the tissue type and tumour location.

Pathologists examine margins to check if tumour cells are present at the tissue’s cut edge. A positive margin, where tumour cells are found, suggests that some cancer may remain in the body. In contrast, a negative margin, with no tumour cells at the edge, suggests the tumour was fully removed. Some reports also measure the distance between the nearest tumour cells and the margin, even if all margins are negative.

Tumour budding

Tumour budding is a term pathologists use to describe either single cancer cells or small groups of cancer cells seen at the edge of the tumour. It is believed to be a sign that the tumour is becoming less differentiated. Based on the number of buds seen under the microscope, a score is assigned, either low, intermediate, or high. A high score is associated with an increased risk that cancer cells will spread to another part of the body.

Treatment effect

​If you received cancer treatment (either chemotherapy or radiation therapy or both) before the tumour was removed, your pathologist will carefully examine the area of the tissue where the tumour was previously identified to see if any cancer cells are still alive (viable). The most commonly used system describes the treatment effect on a scale of 0 to 3, with 0 being no viable cancer cells (all the cancer cells are dead) and 3 being extensive residual cancer with no apparent regression of the tumour (all or most of the cancer cells are alive).

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 also determine the pathologic tumour stage (pT).

Lymph nodes​

Small immune organs, known as lymph nodes, are located throughout the body. Cancer cells can travel from a tumour to these lymph nodes via tiny lymphatic vessels. For this reason, doctors often remove and microscopically examine lymph nodes to look for cancer cells. This process, where cancer cells move from the original tumour to another body part like a lymph node, is termed metastasis.

Cancer cells usually first migrate to lymph nodes near the tumour, although distant lymph nodes may also be affected. Consequently, surgeons typically remove lymph nodes closest to the tumour first. They might remove lymph nodes farther from the tumour if they are enlarged and there’s a strong suspicion they contain cancer cells.

Pathologists will examine any removed lymph nodes under a microscope, and the findings will be detailed in your report. A “positive” result indicates the presence of cancer cells in the lymph node, while a “negative” result means no cancer cells were found. If the report finds cancer cells in a lymph node, it might also specify the size of the largest cluster of these cells, often referred to as a “focus” or “deposit.” Extranodal extension occurs when tumour cells penetrate the lymph node’s outer capsule and spread into the adjacent tissue.

Examining lymph nodes is important for two reasons. First, it helps determine the pathologic nodal stage (pN). Second, discovering cancer cells in a lymph node suggests an increased risk of finding cancer cells in other body parts later. This information guides your doctor in deciding whether you need additional treatments, such as chemotherapy, radiation therapy, or immunotherapy.

Mismatch repair proteins

Mismatch repair (MMR) is a system inside all normal, healthy cells that fixes mistakes in our genetic material (DNA). The system is made up of different proteins, and the four most common are 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, and the risk of developing cancer increases.

How do pathologists test for mismatch repair proteins?

The most common way to test for mismatch repair proteins is immunohistochemistry. This test allows pathologists to see if the tumour cells produce all four mismatch repair proteins. The results of this test are typically reported as follows:

• Normal result: Retained protein expression.
• Abnormal result: Loss of protein expression.

Why is testing for mismatch repair proteins important?

Mismatch repair testing is important because it can help predict how well certain treatments may work. For instance, cancers with a loss of mismatch repair protein expression are more likely to respond to immunotherapy treatments like PD-1 or PD-L1 inhibitors. This is because the high number of mutations often found in deficient tumors can produce new antigens that make the tumor more visible and vulnerable to the immune system.

Mismatch repair testing is also performed 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 esophageal cancer, colon cancer, endometrial cancer, ovarian cancer, and stomach cancer.

Other genetic changes found in invasive adenocarcinoma of the colon and rectum

• APC (Adenomatous Polyposis Coli) gene mutations: Almost ubiquitous in sporadic colon cancer cases, mutations in the APC gene are often an early event in the development of colorectal cancer. The APC gene is a tumour suppressor gene, and its inactivation leads to abnormal cell growth.
• KRAS and NRAS mutations: Mutations in the KRAS and NRAS genes, part of the RAS gene family, occur in approximately 40-45% of colorectal cancers. These mutations lead to uncontrolled cell division and growth. The presence of KRAS mutations, particularly, is associated with resistance to certain anti-EGFR (epidermal growth factor receptor) therapies.
• BRAF mutations: The BRAF gene mutation, particularly V600E, is found in about 10% of colorectal cancers. It is often associated with a poor prognosis and resistance to some therapies. BRAF mutations are more common in cancers that have developed through the serrated pathway.
• PIK3CA mutations: Mutations in the PIK3CA gene, which codes for a subunit of phosphatidylinositol 3-kinase (PI3K), occur in approximately 10-20% of colorectal cancers. These mutations can activate the AKT signalling pathway, promoting cell proliferation and survival.

Tests used to detect genetic changes

• Next-generation sequencing (NGS): NGS allows for the simultaneous examination of multiple genes to detect mutations, deletions, and amplifications. This comprehensive approach can assess all the common genetic alterations in colorectal cancer, including APC, KRAS, NRAS, BRAF, and PIK3CA mutations.
• Polymerase chain reaction (PCR): This technique amplifies segments of DNA, making it possible to analyze specific genetic changes, such as KRAS, NRAS, and BRAF mutations.
• Fluorescence in situ hybridization (FISH): FISH can identify genetic abnormalities such as amplifications or deletions within specific genes. It’s less commonly used for the routine detection of the genetic changes mentioned but can be helpful in specific contexts.

About this article

Doctors wrote this article to help you read and understand your pathology report. Contact us if you have questions about this article or your pathology report. For a complete introduction to your pathology report, read this article.

Other helpful resources

Atlas of pathology