Adenocarcinoma of the esophagus

by Catherine Forse MD FRCPC and Jason Wasserman MD PhD FRCPC
July 30, 2024

Background:

Adenocarcinoma of the esophagus is a type of cancer that forms in the glandular cells of the esophagus, the tube that carries food from the mouth to the stomach. It typically develops in a part of the esophagus called the gastroesophageal junction (GEJ) near the stomach. This type of cancer is often associated with a condition called Barrett’s esophagus, where the normal lining of the esophagus changes due to chronic acid reflux (GERD).

The esophagus

The esophagus is a hollow muscular tube that connects the throat (pharynx) to the stomach. Its primary function is to transport food and liquids from the mouth to the stomach for digestion. When you swallow, the walls of the esophagus contract in a coordinated way—this movement, called peristalsis, pushes the food downward. The esophagus also has sphincters at both ends; these muscular valves open to allow food and liquids to pass into the stomach and close to prevent stomach contents from refluxing back up into the esophagus and mouth.

What are the symptoms of adenocarcinoma in the esophagus?

The most common symptoms of adenocarcinoma of the esophagus are difficulty swallowing (especially solid foods), chest pain, worsening acid reflux, and weight loss.

What causes adenocarcinoma of the esophagus?

Adenocarcinoma of the esophagus most commonly arises from a condition called Barrett’s esophagus which is caused by the long-term reflux of stomach acids into the esophagus (acid reflux disease). For this reason, adenocarcinoma in the esophagus often develops after many years of acid reflux.

When the inside of the esophagus is exposed to stomach acid over a long period of time, the squamous cells that normally cover it are replaced by glandular cells similar to those found on the inside of the small intestine. These intestinal-type cells are more resistant to injury from the strong acids arising in the stomach. The change from squamous cells to intestinal-type cells is called intestinal metaplasia.

Doctors use the term Barrett’s esophagus to describe intestinal metaplasia in the esophagus. It is named after Dr. Norman R. Barrett, a surgeon who practiced in London, England, in the 1950s. People who have Barrett’s esophagus for many years can develop a type of abnormal growth called dysplasia, which is associated with an increased risk of developing adenocarcinoma.

Histologic grade

Adenocarcinoma of the esophagus is divided into three histologic grades: well differentiated, moderately differentiated, and poorly differentiated. The grade is based on the percentage of the tumour forming round structures called glands. A tumour that is not forming any glands is called undifferentiated. The histologic grade is important because poorly differentiated and undifferentiated tumours behave in a more aggressive manner and are more likely to spread to other parts of the body, such as lymph nodes.

Adenocarcinoma of the esophagus is graded as follows:

• Well differentiated adenocarcinoma: More than 95% of the tumour comprises glands. Pathologists also describe these tumours as grade 1.
• Moderately differentiated adenocarcinoma: 50 to 95% of the tumour comprises glands. Pathologists also describe these tumors as grade 2.
• Poorly differentiated adenocarcinoma: Less than 50% of the tumour comprises glands. Pathologists also describe these tumours as grade 3.

Depth of invasion and pathologic tumour stage (pT)

Adenocarcinoma starts in a thin layer of tissue inside the esophagus called the mucosa. When the tumour is located entirely within the mucosa, it is called intramucosal. Patients with intramucosal adenocarcinoma of the esophagus have a better overall prognosis because the cancer cells are less likely to spread to other parts of the body, such as lymph nodes.

In pathology, invasion describes the spread of cancer cells into organs or tissues surrounding the location where the tumour started. As the tumour in the esophagus grows, the cancer cells can spread into the layers of tissue below the mucosa. At this point, the disease is referred to as invasive adenocarcinoma.

When examining the tumour under the microscope, your pathologist will see how far the cancer cells have spread from the mucosa into the underlying layers of tissue. This is called the depth or level of invasion, and it is important because tumours that invade deeper are more likely to spread to other body parts, 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.

HER2

HER2 is a type of protein that functions as a receptor, acting like a switch that controls cell growth and division. In some tumour cells, an excess of HER2 is produced, leading to much faster growth and division than normal cells.

Approximately one in five cases of esophageal adenocarcinoma involve an overproduction of HER2. Specific treatments target tumours that produce extra HER2. Therefore, your pathologist may recommend testing the tumour for excess HER2 to determine the best treatment approach.

The most common method for detecting HER2 in adenocarcinoma is a test called immunohistochemistry. The results of this test are typically reported in the following way:

• Negative (0 or 1) – The tumour cells are not producing extra HER2.
• Equivocal (2) – The tumour cells may be producing extra HER2. In this case, pathologists will usually perform a laboratory test called fluorescent in situ hybridization (FISH) to see if the tumour cells have more gene copies of HER2. This can help determine if the tumour is expressing more HER2 protein.
• Positive (3) – The tumour cells are definitely producing extra amounts of HER2.

Mismatch repair proteins

Mismatch repair (MMR) is a system inside all normal, healthy cells that fixes mistakes in our genetic material (DNA). The system comprises 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.

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.

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 many 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.

PD-L1

PD-L1 (Programmed Death-Ligand 1) is a protein found on the surface of normal, healthy cells and some cancer cells. It is called an immune checkpoint protein because it turns down the activity of immune cells called T cells. These cells normally detect abnormal cells, such as cancer cells, and remove them from the body. Cancer cells that express this protein escape attack by T cells by activating a protein on the T cell called PD-1.

Doctors test for this protein to help determine which patients may benefit from treatments that target the PD-1/PD-L1 pathway, such as immune checkpoint inhibitors. To test for PD-L1 expression, pathologists typically perform a test called immunohistochemistry on a tumour tissue sample. In this test, a specific antibody against PD-L1 is applied to the tissue section and then detected using a secondary antibody attached to a dye.

The protein expression level is then counted and scored based on the intensity and percentage of positive cells. For esophageal cancers, the result is reported as a combined positive score (CPS), with a score > 1 being considered positive.

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.

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, which removes the entire tumour. Margins aren’t usually evaluated after a biopsy, which removes only part of the tumour.

For endoscopic resections where only a small piece of the inside of the esophagus has been removed, the margins will include:

• Mucosal margin – This is the tissue that lines the inner surface of the esophagus. Another name for this margin is the lateral margin.
• Deep margin – This tissue is inside the wall of the esophagus. It is located below the tumour.

For esophagectomy specimens where an entire segment of the esophagus has been removed, the margins will include:

• Proximal margin – This margin is located near the upper portion of the esophagus, closer to the mouth.
• Distal margin – This margin is located near the lower portion of the esophagus. The distal margin can be in the esophagus or the stomach.
• Radial margin – This is the tissue around the outside of the esophagus.

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.

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.

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.

Pathologic nodal stage (pN) for adenocarcinoma of the esophagus:

• N0 – No tumour cells are seen in any of the lymph nodes examined.
• N1 – Tumour cells are seen in one or two lymph nodes.
• N2 – Tumour cells are seen in three to six lymph nodes.
• N3 – Tumour cells are seen in more than six lymph nodes.
• NX – No lymph nodes were sent to the pathologist for examination.​

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).

Prognosis

The following pathologic features are associated with good prognosis for patients diagnosed with adenocarcinoma of the esophagus:

1. Low histologic grade: Well differentiated tumours tend to grow slower and are less likely to spread than poorly differentiated tumours.
2. Superficial depth of invasion: Tumours that are limited to the mucosa or submucosa are less likely to spread to other parts of the body and are associated with better overall prognosis.
3. No lymph node involvement (pN0): Cancer has not spread to nearby lymph nodes.
4. No lymphovascular invasion: Cancer cells are not present in the lymphatic or blood vessels.
5. No perineural invasion: Cancer cells are not surrounding or invading nerves.
6. Negative margins of resection: No cancer cells are present at the edges of the removed tissue.
7. Favorable molecular and genetic markers: Absence of aggressive genetic alterations such as HER2 overexpression of loss of p53 protein.

The following pathologic features are associated with poor prognosis for patients with adenocarcinoma of the esophagus.

1. High histologic grade: Poorly differentiated and undifferentiated tumours grow faster and are more likely to spread to other parts of the body.
2. Deep depth of invasion: Tumours that invade into the muscularis propria or beyond are more likely to regrow after treatment and spread to other parts of the body.
3. Lymph node involvement (N1-N3): Cancer has spread to nearby lymph nodes.
4. Lymphovascular invasion: Cancer cells are present in the lymphatic or blood vessels.
5. Perineural invasion: Cancer cells are surrounding or invading nerves.
6. Positive margins of resection: Cancer cells are present at the edges of the removed tissue, indicating incomplete removal. These tumours are more likely to regrow after treatment.
7. Unfavorable molecular and genetic markers: Presence of aggressive genetic alterations, such as overexpression of HER2 or mutations in p53.

About this article

Doctors wrote this article to help you read and understand your pathology report. Contact us with any questions about this article or your pathology report. Read this article for a more general introduction to the parts of a typical pathology report.

Other helpful resources

Atlas of Pathology