Intramucosal adenocarcinoma of the esophagus

by Jason Wasserman MD PhD FRCPC
July 2, 2023

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What is intramucosal adenocarcinoma of the esophagus?

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 on the inside of the esophagus. If left untreated, the tumour cells will spread further into the esophagus resulting in a more serious condition simply called adenocarcinoma.

Where in the esophagus does intramucosal adenocarcinoma start?

Intramucosal adenocarcinoma starts from abnormal glandular cells found in a thin layer of tissue on the inside of the esophagus called the mucosa. Most tumours start near the gastroesophageal junction (GEJ), where the esophagus meets the stomach.

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 intestinal-type cells (cells normally found in the small intestine). These intestinal-type cells are designed to protect tissue from the strong acids 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. Most patients with intramucosal adenocarcinoma of the esophagus have had Barrett’s esophagus for many years. For this reason, Barrett’s esophagus is considered a pre-cancerous condition that can lead to intramucosal adenocarcinoma.

What does it mean if intramucosal adenocarcinoma of the esophagus is described as well, moderately, or poorly differentiated?

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.

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

Why is the distance of the tumour to the gastroesophageal junction important for intramucosal adenocarcinoma of the esophagus?

Once the entire tumour is removed, your report will probably describe where in the esophagus the tumour was located. The gastroesophageal junction (GEJ) is the area where the esophagus meets the stomach. Tumours located above the GEJ, at the GEJ, or just below the GEJ are called esophageal tumours. Tumours that are located entirely below the GEJ (within the stomach) are called gastric tumours. The location of the tumour is important because esophageal and gastric tumours tend to behave differently over time and the treatment options are different.

What is HER2?

HER2 is a special type of protein called a receptor. HER2 behaves like a switch that allows cells to grow and divide. Some tumour cells produce extra amounts of HER2 which allows them to grow and divide much faster than normal cells.

Why is testing for HER2 important for intramucosal adenocarcinoma?

One out of every five cases of esophageal intramucosal adenocarcinoma produces extra HER2 and specific treatments are available for patients with HER2-producing tumours.  For this reason, your pathologist may order a test to see if the tumour is producing extra HER2.

How do pathologists test for HER2?

The most common test used to look for HER2 in intramucosal adenocarcinoma is called immunohistochemistry.

Possible HER2 immunohistochemistry results:

• Negative (0 or 1) – The tumour cells are not producing extra HER2.
• Equivocal (2) – The tumour cells may be producing extra HER2.
• Positive (3) – The tumour cells are definitely producing extra amounts of HER2.

What are mismatch repair proteins?

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

Pathologists order mismatch repair testing to see if any of these proteins are lost in a tumour. If mismatch repair testing has been ordered on your tissue sample, the results will be described in your pathology report.

Why is testing for mismatch repair proteins important?

Mismatch repair (MMR) testing is performed on intramucosal adenocarcinoma of the esophagus 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, gastric cancer, and others.

How do pathologists test for mismatch repair proteins?

The most common way to test for mismatch repair proteins is to perform a test called immunohistochemistry. This test allows pathologists to see if the tumour cells are producing all four mismatch repair proteins. A normal result will say that the protein is retained or expressed. An abnormal result will say that there is a loss of the protein or that the protein is deficient.

What does perineural invasion mean and why is it important?​

Perineural invasion is a term pathologists use to describe cancer cells attached to or inside a nerve. A similar term, intraneural invasion, is used to describe cancer cells inside a nerve. Nerves are like long wires made up of groups of cells called neurons. Nerves are found all over the body and they are responsible for sending information (such as temperature, pressure, and pain) between your body and your brain. Perineural invasion is important because the cancer cells can use the nerve to spread into surrounding organs and tissues. This increases the risk that the tumour will regrow after surgery.

What does lymphovascular invasion mean and why is it important?

Lymphovascular invasion means that cancer cells were seen inside a blood vessel or lymphatic vessel. Blood vessels are long thin tubes that carry blood around the body. Lymphatic vessels are similar to small blood vessels except that they carry a fluid called lymph instead of blood. The lymphatic vessels connect with small immune organs called lymph nodes that are found throughout the body. Lymphovascular invasion is important because cancer cells can use blood vessels or lymphatic vessels to spread to other parts of the body such as lymph nodes or the liver. The presence of cancer cells inside a large vein past 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.

What is a margin?

In pathology, a margin is the edge of a tissue that is cut when removing a tumour from the body. The margins described in a pathology report are very important because they tell you if the entire tumour was removed or if some of the tumour was left behind. The margin status will determine what (if any) additional treatment you may require.

Most pathology reports only describe margins after a surgical procedure called an excision or resection has been performed for the purpose of removing the entire tumour. For this reason, margins are not usually described after a procedure called a biopsy is performed for the purpose of removing only part of the tumour.

Pathologists carefully examine the margins to look for tumour cells at the cut edge of the tissue. If tumour cells are seen at the cut edge of the tissue, the margin will be described as positive. If no tumour cells are seen at the cut edge of the tissue, a margin will be described as negative. Even if all of the margins are negative, some pathology reports will also provide a measurement of the closest tumour cells to the cut edge of the tissue.

A positive (or very close) margin is important because it means that tumour cells may have been left behind in your body when the tumour was surgically removed. For this reason, patients who have a positive margin may be offered another surgery to remove the rest of the tumour or radiation therapy to the area of the body with the positive margin.

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 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.

Were lymph nodes examined and did any contain cancer cells?​

Lymph nodes are small immune organs found throughout the body. Cancer cells can spread from a tumour to lymph nodes through small vessels called lymphatics. The movement of cancer cells from the tumour to another part of the body such as a lymph node is called a metastasis.

Cancer cells typically spread first to lymph nodes close to the tumour although lymph nodes far away from the tumour can also be involved. For this reason, the first lymph nodes removed are usually close to the tumour. Lymph nodes further away from the tumour are only typically removed if they are enlarged and there is a high clinical suspicion that there may be cancer cells in the lymph node. Lymph nodes are not always removed for intramucosal adenocarcinoma, however, if any lymph nodes were removed from your body, they will be described in your pathology report.

If any lymph nodes were removed from your body, they will be examined under the microscope by a pathologist and the results of this examination will be described in your report. Most reports will include the total number of lymph nodes examined, where in the body the lymph nodes were found, and the number (if any) that contain cancer cells. If cancer cells were seen in a lymph node, the size of the largest group of cancer cells will also be included.

The examination of lymph nodes is important for two reasons. First, this information is used to determine the pathologic nodal stage (pN). Second, finding cancer cells in a lymph node increases the risk that cancer cells will be found in other parts of the body in the future. As a result, your doctor will use this information when deciding if additional treatment such as chemotherapy, radiation therapy, or immunotherapy is required.

What does it mean if a lymph node is described as positive?

Pathologists often use the term “positive” to describe a lymph node that contains cancer cells. For example, a lymph node that contains cancer cells may be called “positive for malignancy” or “positive for metastatic carcinoma”.

What does it mean if a lymph node is described as negative?

Pathologists often use the term “negative” to describe a lymph node that does not contain any cancer cells. For example, a lymph node that does not contain cancer cells may be called “negative for malignancy” or “negative for metastatic carcinoma”.

What does extranodal extension mean?

All lymph nodes are surrounded by a thin layer of tissue called a capsule. Extranodal extension means that cancer cells within the lymph node have broken through the capsule and have spread into the tissue outside of the lymph node. Extranodal extension is important because it increases the risk that the tumour will regrow in the same location after surgery. For some types of cancer, extranodal extension is also a reason to consider additional treatment such as chemotherapy or radiation therapy.

What does treatment effect mean?

​If you received treatment (such as radiation therapy) for your cancer prior to the tumour being removed, your pathologist will examine all of the tissue submitted to see how much of the tumour is still alive (viable).

The treatment effect will be reported 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). Lymph nodes with cancer cells will also be examined for treatment effects.​

What is the pathologic stage for intramucosal adenocarcinoma of the esophagus?

The pathologic stage for intramucosal adenocarcinoma is based on the TNM staging system, an internationally recognized system originally created by the American Joint Committee on Cancer. This system uses information about the primary tumour (T), lymph nodes (N), and distant metastatic disease (M)  to determine the complete pathologic stage (pTNM). Your pathologist will examine the tissue submitted and give each part a number. In general, a higher number means more advanced disease and a worse prognosis.

Tumour stage (pT)

All intramucosal adenocarcinomas of the esophagus are given a tumour stage of T1a.

Nodal stage (pN)

Intramucosal adenocarcinoma is given a nodal stage between 0 and 3 based on the presence of tumour cells in a lymph node and the number of lymph nodes involved.

• 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.​

Metastatic stage (pM)

Intramucosal adenocarcinoma is given a metastatic stage of 0 or 1 based on the presence of tumour cells at a distant site in the body (for example the lungs). The metastatic stage can only be determined if tissue from a distant site is submitted for pathological examination. Because this tissue is rarely present, the metastatic stage cannot be determined and is listed as X.