Adenocarcinoma of the esophagus

by Catherine Forse MD FRCPC and Jason Wasserman MD PhD FRCPC
November 27, 2023


Adenocarcinoma (also known as invasive 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. Adenocarcinoma of the esophagus typically starts from glandular cells lining the lower part of the esophagus. The lower part of the esophagus, near the junction with the stomach, is an area 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 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 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 adenocarcinoma.

Your pathology report for adenocarcinoma of the esophagus

The information found in your pathology report for adenocarcinoma in the esophagus will depend on the procedure performed. For small procedures such as a biopsy, your report may only include the diagnosis, the grade (for example well differentiated), and the depth of invasion (how far the tumour has spread from its starting point on the inside surface of the esophagus). The results of additional biomarker or molecular tests may also be described. For larger procedures such as an excision or resection performed to remove the entire tumour, additional information such as the size of the tumour and the assessment of margins may also be described. Please see the sections below for more details.

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

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. 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.

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.

Tumour grade adenocarcinoma of the esophagus

What does it mean if my report says the tumour invades the muscularis mucosa?

The muscularis mucosa is a thin layer of muscle just under the epithelium on the inside surface of the esophagus. Adenocarcinoma starts in the epithelium but as the tumour grows, the cells can spread into the muscularis mucosa. Pathologists describe this as invasion and it is important because tumours that invade the muscularis mucosa are more likely to metastasize (spread) to lymph nodes. A tumour that invades the muscularis mucosa indicates a pathologic tumour stage of at least pT1a.

Adenocarcinoma of the esophagus: Invasion into the muscularis mucosa

What does it mean if my report says the tumour invades the submucosa?

The submucosa is a thin layer of connective tissue just under the muscularis mucosa. Tumours that invade the submucosa come in contact with more blood vessels and lymphatic channels. As a result, these tumours are more likely to metastasize (spread) to lymph nodes and other parts of the body. A tumour that invades the submucosa indicates a pathologic tumour stage of at least least pT1b.

Adenocarcinoma of the esophagus: Invasion into the submucosa

What does it mean if my report says the tumour invades the muscularis propria?

The muscularis propria is a thick layer of muscle in the middle of the wall of the esophagus. Tumours that invade the muscularis propria are usually quite large and tend to behave in a more aggressive manner compared to tumours that only involve the muscularis mucosa or submucosa. A tumour that invades the muscularis propria indicates a pathologic tumour stage of at least pT2.

Adenocarcinoma of the esophagus: Invasion into the muscularis propria

What does it mean if my report says the tumour invades the adventitia?

The adventitia is a thin layer of tissue on the outside surface of the esophagus. Tumours that invade the adventitia are much more likely to metastasize (spread) to lymph nodes and other parts of the body. Tumours that involve the adventitia are also more likely to spread directly to nearby organs such as the trachea which can make them very difficult to remove surgically. A tumour that invades the adventitia indicates a pathologic tumour stage of at least pT3.

Adenocarcinoma of the esophagus: Invasion into the adventitia

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.

Biomarkers

A biomarker is a genetic change, protein, or other chemical that can be tested for in order to predict how a disease will behave over time or how it will respond to a given treatment. For adenocarcinoma of the esophagus, biomarkers tested for include HER2, mismatch repair (MMR) proteins, and PD-L1.

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.

One out of every five cases of esophageal 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.

The most common test used to look for HER2 in 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. 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 (MMR) 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.

Mismatch repair (MMR) testing is performed on 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.

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.

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 acts to turn down the activity of immune cells called T cells which 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 (IHC) on a tissue sample from the tumour. 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 level of protein expression is then counted and scored based on the intensity and percentage of positive cells. For cancers of the esophagus, the result is reported as a combined positive score (CPS) with a score > 1 being considered positive.

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.

Perineural invasion

What does lymphovascular invasion mean and why is it important?

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

What is a margin and why are margins important?

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.

Margin

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.

What are lymph nodes and why are they important?

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 information is used to determine the pathologic stage for adenocarcinoma of the esophagus?

The pathologic stage for adenocarcinoma of the esophagus 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 mucosa on the inner surface of the esophagus into the wall of the esophagus.​

  • T1a – The tumour cells are still located entirely within the mucosa on the inside surface of the esophagus. This stage is often given the special name intramucosal adenocarcinoma.
  • T1b – The tumour cells have entered the submucosa.
  • T2 – The tumour cells have entered the muscularis propria in the middle of the wall.
  • T3 – The tumour cells are in the adventitia on the outer surface of the esophagus.
  • T4 – The tumour 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 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)

Adenocarcinoma of the esophagus 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 Mx.

About this article

This article was written by doctors 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
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