Intramucosal adenocarcinoma of the esophagus

by Jason Wasserman MD PhD FRCPC
April 21, 2022

What is intramucosal adenocarcinoma of the esophagus?

Intramucosal adenocarcinoma is a type of esophageal cancer. It is considered an early-stage cancer because the tumour cells have not spread any further than the mucosa on the inside of the esophagus.

What causes intramucosal adenocarcinoma of the esophagus?

Intramucosal adenocarcinoma arises from a condition called Barrett’s esophagus which is caused by 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 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.

How do pathologists make the diagnosis of intramucosal 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. Most patients are then offered surgery to remove the tumour entirely. Some patients may be offered radiation before or after the tumour is removed.

How do pathologists grade intramucosal carcinoma in the esophagus?

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 tumour cells forming round structures called glands. A well-differentiated tumour (grade 1) is more than 95% glands. A moderately differentiated tumour (grade 2) is 50 to 95% glands. A poorly differentiated tumour (grade 3) is less than 50% glands. The grade is important because less differentiated tumours (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 invasion mean?

All intramucosal adenocarcinomas in the esophagus start in a thin layer of tissue on the inside of the esophagus called the epithelium. Below the epithelium are five additional layers of tissue: lamina propria, muscularis mucosa, submucosa, muscularis propria, and adventitia (see picture below). The epithelium and lamina propria combine to form a barrier called the mucosa. Pathologists use the word invasion to describe the spread of tumour cells from the epithelium into the layers of tissue below. Most pathology reports will describe the deepest level of invasion. In order to make the diagnosis of intramucosal adenocarcinoma, tumour cells cannot pass the muscularis mucosa.

normal esophagus histology

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. 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 cancer cells 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.

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

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 tumour cells are producing all four mismatch repair proteins.

If the tumour 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 tumour 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?

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 a term pathologists use to describe tumour cells attached to a nerve. Perineural invasion is important because tumour cells that have become attached to a nerve can grow along the nerve and into surrounding tissues. This increases the risk that the tumour will re-grow after treatment.

perineural invasion

What does lymphovascular invasion mean?

Blood moves around the body through long thin tubes called blood vessels. Another type of fluid called lymph which contains waste and immune cells moves around the body through lymphatic channels. The term lymphovascular invasion is used to describe tumour cells that are found inside a blood vessel or lymphatic channel. Lymphovascular invasion is important because once the tumour cells are inside a blood vessel or lymphatic channel they are able to metastasize (spread) to other parts of the body such as lymph nodes or the lungs.

lymphovascular invasion

What is a margin?

In the esophagus, a margin is any tissue that was cut by the surgeon in order to remove the tumour from your body. The types of margins present will depend on the type of procedure that was performed.

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. Anither 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.

In the esophagus, a margin is considered positive when there are cancer cells at the very edge of the cut tissue. A positive margin is associated with a higher risk that the tumour will re-grow in the same site after treatment.


What are lymph nodes?

Lymph nodes are small immune organs located throughout the body. Tumour cells can travel from the tumour to a lymph node through lymphatic channels located in and around the tumour (see Lymphovascular invasion above). The movement of tumour cells from the tumour to a lymph node is called metastasis.

Lymph node

Your pathologist will carefully examine each lymph node for tumour cells. Lymph nodes that contain tumour cells are often called positive while those that do not contain any tumour cells are called negative. Most reports include the total number of lymph nodes examined and the number, if any, that contain tumour cells.

Finding tumour cells in a lymph node is associated with an increased risk that the tumour cells will spread to other parts of the body. The number of lymph nodes with tumour cells is also used to determine the nodal stage (see Pathologic stage below).

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.​

How do pathologists determine 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.

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