Adenocarcinoma of the esophagus

by Jason Wasserman MD PhD FRCPC
September 22, 2022


What is adenocarcinoma of the esophagus?

Adenocarcinoma is a type of esophageal cancer. It is the most common type of esophageal cancer in developed countries and it is more common in men than women.

What causes adenocarcinoma of the esophagus?

The most common cause of adenocarcinoma in the esophagus is long-standing acid reflux from the stomach. 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 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 adenocarcinoma.

How do pathologists make the diagnosis of adenocarcinoma in the esophagus?

The diagnosis is usually made after a small piece of the tumour is removed in a procedure called a biopsy. The tissue is sent to a pathologist for examination under a microscope.

What does differentiated mean and why is it important?

Pathologists use the term differentiated to divide 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.

The grade is important because moderately and poorly differentiated tumours behave in a more aggressive manner and are more likely to spread to other parts of the body.

What does well differentiated adenocarcinoma mean?

For adenocarcinoma of the esophagus, well differentiated means that more than 95% of the tumour is made up of glands. Pathologists also describe these tumours as grade 1.

What does moderately differentiated adenocarcinoma mean?

For adenocarcinoma of the esophagus, moderately differentiated means that 50 to 95% of the tumour is made up of glands. Pathologists also describe these tumours as grade 2.

What does moderately differentiated adenocarcinoma mean?

For adenocarcinoma of the esophagus, poorly differentiated means that less than 50% of the tumour is made up of glands. Pathologists also describe these tumours as grade 3.

What does invasion mean and why is the level of invasion important for adenocarcinoma of the esophagus?

In pathology, the term invasion is used to describe the spread of cancer cells into organs or tissues surrounding the location where the tumour started. Because adenocarcinoma in the esophagus starts in a thin layer of tissue on the inside of the esophagus called the epithelium, invasion is defined as the spread of cancer cells into the other layers of tissue in the esophagus (see picture below) or any other organs outside of the esophagus. Invasion can only be seen after the tumour has been examined under a microscope by a pathologist.

 

normal esophagus histology

When examining the tumour under the microscope, your pathologist will look to see how far the cancer cells have spread from the epithelium into the surrounding tissue. This is called the level of invasion. The level of invasion is important because tumours that invade deeper into the wall of the esophagus 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).

Why is the location of the tumour important for 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 cancer cells produce extra amounts of HER2 which allows them to grow and divide much faster than normal cells. Your pathologist may order a test to see if the tumour is producing extra HER2.

One out of every five cases of esophageal adenocarcinoma produces extra HER2 and specific treatments are available for patients with HER2-producing tumours. Talk to your doctor about the HER2 status of the tumour and the treatment options available for you.

How do pathologists test for HER2?

The most common test used to look for HER2 in cancer cells is called immunohistochemistry.

Possible HER2 immunohistochemistry results:

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

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 cancer cells are producing all four mismatch repair proteins.

If the cancer cells are not producing one of the proteins, your report will describe this protein as “lost” or “deficient”. Because the mismatch repair proteins work in pairs (MSH2 + MSH6 and MLH1 + PMS2), two proteins are often lost at the same time.

If the cancer cells in your tissue sample show a loss of one or more mismatch repair proteins, your doctor may refer you to a genetic specialist for additional tests and advice.

What does perineural invasion mean?

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.

Perineural invasion
Perineural invasion
What does lymphovascular invasion mean?

Lymphovascular invasion means that cancer cells were seen inside of 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.

Lymphovascular invasion
Lymphovascular invasion
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. The number of margins described in a pathology report depends on the types of tissues removed and the location of the tumour. The size of the margin (the amount of normal tissue between the tumour and the cut edge) depends on the type of tumour being removed and the location 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. The decision to offer additional treatment and the type of treatment options offered will depend on a variety of factors including the type of tumour removed and the area of the body involved. For example, additional treatment may not be necessary for a benign (non-cancerous) type of tumour but may be strongly advised for a malignant (cancerous) type of tumour.

Margin

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.

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.
  • Deep margin – This tissue is inside the wall of the esophagus. It is located below the tumour.

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. For this reason, lymph nodes are commonly removed and examined under a microscope to look for cancer cells. The movement of cancer cells from the tumour to another part of the body such as a lymph node is called a metastasis.

Lymph node

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.

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 (often described as “focus” or “deposit”) 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 (either chemotherapy or 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 adenocarcinoma of the esophagus?

The pathologic stage for 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)

Adenocarcinoma of the esophagus is given a tumour stage between 1 and 4 based on the distance the tumour cells have spread from the epithelium on the inner surface of the esophagus into the wall of the esophagus.​

  • T1a – The cancer cells have broken out of the epithelium and have entered the lamina propria, muscularis mucosae, or submucosa. This stage is often given the special name intramucosal adenocarcinoma.
  • T1b – The cancer cells have entered the submucosa.
  • T2 – The cancer cells have entered the muscularis propria in the middle of the wall.
  • T3 – The cancer cells are in the adventitia on the outer surface of the esophagus.
  • T4 – The cancer cells have spread beyond the esophagus into surrounding organs or tissues such as the lungs or aorta.
Nodal stage (pN)

Adenocarcinoma of the esophagus is given a nodal stage between 0 and 3 based on the presence of cancer cells in a lymph node and the number of lymph nodes involved.

  • N0 – No cancer cells are seen in any of the lymph nodes examined.
  • N1 – Cancer cells are seen in one or two lymph nodes.
  • N2 – Cancer cells are seen in three to six lymph nodes.
  • N3 – Cancer cells are seen in more than six lymph nodes.
  • NX – No lymph nodes were sent to the pathologist for examination.​
Metastatic stage (pM)

Adenocarcinoma of the esophagus is given a metastatic stage of 0 or 1 based on the presence of cancer 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.

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