Intramucosal adenocarcinoma of the esophagus

by Catherine Forse MD FRCPC and Jason Wasserman MD PhD FRCPC
April 24, 2024

Intramucosal adenocarcinoma is a type of early-stage esophageal cancer. It is called ‘intramucosal’ because the tumour cells have not spread any further than the mucosa, a thin layer of tissue inside the esophagus. Treatment options for patients with intramucosal adenocarcinoma include endoscopic mucosal resection (EMR) and sometimes endoscopic submucosal dissection (ESD).

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.

Where does intramucosal adenocarcinoma of the esophagus start?

Intramucosal adenocarcinoma of the esophagus typically starts from glandular cells lining the lower part of the esophagus, which is near the junction with the stomach. This area is known as the gastroesophageal junction. This type of cancer is often associated with a condition called Barrett’s esophagus, where the normal squamous cells of the esophagus are replaced by glandular cells.

What are the symptoms of intramucosal adenocarcinoma in the esophagus?

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

What causes intramucosal adenocarcinoma of the esophagus?

Intramucosal adenocarcinoma of the esophagus 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, intramucosal 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 the inside of the esophagus are replaced by glandular cells that are similar to the cells 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.

Barrett’s esophagus is the name doctors use 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 that is associated with an increased risk of developing intramucosal adenocarcinoma.

What to look for in your pathology report for intramucosal adenocarcinoma of the esophagus:

Histologic grade

Pathologists use the term differentiated to divide intramucosal adenocarcinoma of the esophagus into three 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 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.

Intramucosal adenocarcinoma of the esophagus is graded as follows:

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

Depth of invasion and pathologic tumour stage (pT)

Intramucosal adenocarcinoma of the esophagus starts in a thin layer of tissue on the inside surface of the esophagus called mucosa. In the esophagus, the mucosa comprises three parts: epithelium, lamina propria, and muscularis mucosae. Your pathology report may describe which parts of the mucosa are involved by tumour. By definition, all intramucosal adenocarcinomas of the esophagus are assigned the pathologic tumour stage pT1a.

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.

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.

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).

Biomarkers

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 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.

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.

About this article

Doctors wrote this article to help you read and understand your pathology report. Contact us if you have 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