Adenocarcinoma of the stomach

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What is adenocarcinoma of the stomach?

Adenocarcinoma is a type of stomach cancer. The tumour starts from the cells that line the inside of the stomach. In many cases, adenocarcinoma starts from a pre-cancerous condition called intestinal metaplasia. Intestinal metaplasia occurs when tissue that lines the inside of the stomach becomes damaged and is replaced by the type of tissue that is normally found in a part of the gastrointestinal tract called the small bowel.

What cells are normally found in the stomach?

The stomach is a hollow organ found near the middle of your abdomen. Food that you eat travels down your esophagus into the stomach. The stomach is responsible for breaking down and absorbing food so that it can be used by your body.

The wall of the stomach is made up of six layers of tissue:

• Epithelium – The epithelium is the tissue that lines the inside surface of the stomach. The epithelium is made up of specialized epithelial cells that connect together to form structures called glands. Some of these cells produce acid which helps your stomach break down food. Other cells produce mucus which protects the lining of the stomach from the acid inside.
• Lamina propria – The lamina propria is a thin layer of connective tissue directly below the epithelium. The lamina propria is a type of connective tissue that supports the glands.
• Muscularis mucosa – The muscularis mucosa is a thin layer of muscle cells below the lamina propria.
• Submucosa – The submucosa sits directly below the muscularis mucosa. It contains large blood vessels and lymphatic channels.
• Muscularis propria – The muscularis propria is a thick bundle of muscle in the middle of the wall. The muscularis propria allows the stomach to mix and break down the food you eat.
• Subserosal soft tissue – This is a layer of tissue near the outer surface of the stomach. Most of the subserosal soft tissue is made up of fat.
• Serosa– The serosa is a thin layer of tissue on the outside surface of the stomach. It surrounds the stomach and separates it from nearby tissues and organs such as the spleen, colon, liver, diaphragm, pancreas, adrenal gland, kidney, and small intestine. Another name for the serosa is the visceral peritoneum.

How do pathologists make this diagnosis?

The diagnosis of adenocarcinoma is usually made after a small sample of tissue is removed in a procedure called a biopsy. A test called immunohistochemistry may be performed to confirm the diagnosis. Your doctors will use the information found in your pathology report to plan treatment such as surgery, radiation, and chemotherapy.

After the tumour has been removed completely, it will be sent to a pathologist who will prepare another pathology report. This report will confirm or revise the original diagnosis and provide additional important information such as the tumour size, depth of invasion, and spread of tumour cells to lymph nodes. This information is used to determine the cancer stage and to decide if additional treatment is required.

Types of adenocarcinoma

Pathologists divide adenocarcinoma of the stomach into two different groups based on how the cells look when examined under the microscope. These groups are called histologic types and the two most common histologic types are intestinal-type and diffuse-type. Diffuse type is also called signet cell type. The histologic type is important because the diffuse type has a higher chance of spreading to other parts of the body and is associated with a worse prognosis.

• Intestinal type – When examined under the microscope, intestinal-type adenocarcinomas of the stomach look similar to the tumours that normally start in a part of the gastrointestinal tract called the intestine. This type of adenocarcinoma usually starts from the pre-cancerous condition called intestinal metaplasia.
• Diffuse (signet cell ) type – When examined under the microscope, diffuse-type adenocarcinomas are made up of cells that do not stick together as the tumour grows. The tumour cells are round and the inside of the cell is filled with a material called mucin. Pathologists call these cells signet cells. This type of tumour can be harder to diagnosis because the individual tumour cells are harder to see under the microscope.

Tumour grade

Pathologists use the term grade to describe how different the tumour cells look and grow compared to non-cancerous cells. For adenocarcinoma in the stomach, the tumour cells are compared to the non-cancerous cells in other parts of the gastrointestinal tract which normally form glands and the grade is based on how much of the tumour is made up of glands. The grade is important because poorly differentiated tumours grow faster and are more likely to spread to other parts of the body.

1. Well-differentiated – More than 95% of the tumour is made up of glands.
2. Moderately differentiated – 50% to 95% of the tumour is made up of glands.
3. Poorly differentiated or undifferentiated – Less than 50% of the tumour is made up of glands. All diffuse-type adenocarcinomas are considered poorly differentiated.

HER2

HER2 is a protein made by cells throughout the body. 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.

One out of every five tumours in the stomach produces extra HER2. For this reason, your pathologist will order a test to look for HER2 in the cancer cells. The most common test used to look for HER2 in cancer cells is called immunohistochemistry. Another test that is used to look for HER2 is called fluorescence in situ hybridization (FISH).

If immunohistochemistry was performed on the tumour, your report will describe the results as:

• 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.

Some treatments are only offered to patients with HER2 producing (positive) tumours. Talk to your doctor about the treatment options available for you.

Mismatch repair testing

​Each cell in your body contains a set of instructions that tell the cell how to behave. These instructions are written in a language called DNA and the instructions are stored on 46 chromosomes in each cell. The instructions are broken up into sections called genes and each gene tells the cell how to produce a protein. Proteins allow cells to live and to work properly.

If the DNA becomes damaged or if it cannot be read accurately, the cell will be unable to produce normal proteins and the cell may not function normally. An area of damaged DNA is called a mutation and mutations are one of the most common causes of cancer in humans.

When DNA becomes damaged, there are proteins that try to fix the damaged areas/mutations. Mismatch repair proteins are a set of proteins that normally function to remove certain types of damage/mutations from the DNA in your cells. The four main mismatch repair proteins are MLH1, PMS2, MSH2, and MSH6. When one of these proteins does not work properly, mutations in other genes can start to accumulate and a normal cell can eventually turn into a cancer cell. Pathologists can test the mismatch repair proteins to see if they are working properly. If one or more of the mismatch repair proteins is not working properly this is called mismatch repair deficiency.

In most tumours, mismatch repair deficiency is somatic, which means the mutation is only present in your tumour cells. Somatic mutations can result from both environmental and complex genetic factors, and it is very difficult to determine the exact reason why the mismatch repair protein stopped working properly.

Sometimes mismatch repair protein mutations are inherited. Inherited mutations are also called germline mutations. Germline mutations are mutations that are present in all of the cells in your body as well as your tumour cells. They can be passed down/inherited from your parents and they can also be passed down/inherited to your children. A person who inherits a mismatch repair protein that does not work properly has a higher risk of developing certain cancers and is said to have a cancer syndrome called Lynch syndrome.

In adenocarcinoma of the stomach, mismatch repair deficiency occurs in a small percentage of cases (about 10%). Most of these are due to somatic mismatch repair protein mutations. A small number of adenocarcinomas of the stomach with mismatch repair deficiency are related to germline mismatch repair protein mutations (Lynch syndrome).

In some hospitals, these tumours are tested for mismatch repair deficiency by immunohistochemistry. 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. Tumour cells that show normal production of the protein are called “intact”.

If mismatch repair deficiency is identified in the tumour, additional testing may be done to assess your risk for Lynch syndrome. Because Lynch syndrome results from an inherited gene mutation, the diagnosis of Lynch syndrome is important not only for you but also for your family. If additional testing confirms you have Lynch syndrome, your family members may want to have additional testing to see if they also have Lynch syndrome.

What to look for in your report after the tumour has been removed

Tumour size

This is the size of the tumour measured in centimetres. The tumour is usually measured in three dimensions but only the largest dimension is described in your report. For example, if the tumour measures 4.0 cm by 2.0 cm by 1.5 cm, your report will describe the tumour as being 4.0 cm.

Tumour extension​

Adenocarcinoma starts in the epithelium on the inner surface of the stomach. The spread of cancer cells from the epithelium into the tissue below is called invasion. Pathologists use the term tumour extension to describe how far the cancer cells have spread from the epithelium into the layers of tissue below.

Tumour extension is important because it is used to determine the pathologic tumour stage (see Pathologic stage below). Cancer cells that have spread further into the wall of the stomach or surrounding organs are more likely to come back after treatment in the area of the original tumour or spread to another part of the body.

Your pathology report will describe the tumour extension as follows:

• Intramuscosal – The tumour is called intramucosal if the cancer cells have not spread any further than the lamina propria or muscularis mucosa.
• Submucosal – Submucosal means that the cancer cells have passed the muscularis mucosa and are into the submucosa.
• Muscularis propria – The muscularis propria is the thick bundle of muscle in the middle of the stomach. This amount of tumour extension can usually only be seen after the entire tumour has been removed.
• Subserosal soft tissue – Cancer cells in the subserosal soft tissue are near the outer surface of the stomach.
• Serosa – Cancer cells that pass the serosa on on the outside surface of the stomach. From here, cancer cells are able to spread to nearby organs such as the spleen, pancreas, small intestine, colon, adrenal gland, or kidney.

Perineural invasion​

Nerves are like long wires made up of groups of cells called neurons. Nerves send information (such as temperature, pressure, and pain) between your brain and your body. Perineural invasion means that cancer cells were seen attached to a nerve.

Cancer cells that have attached to a nerve can use the nerve to travel into tissue outside of the tumour. This increases the risk that the tumour will grow back in the same area of the body after treatment.

Lymphovascular invasion​

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. Cancer cells can use blood vessels and lymphatics to travel away from the tumour to other parts of the body. The movement of cancer cells from the tumour to another part of the body is called metastasis.

Before cancer cells can metastasize, they need to enter a blood vessel or lymphatic. This is called lymphovascular invasion. Lymphovascular invasion increases the risk that cancer cells will be found in a lymph node or a distant part of the body such as the lungs. In particular, cancer cells seen inside a large vein outside of the tumour is associated with a high risk that the cancer cells will eventually be found in the lung or liver.

Lymph nodes

Lymph nodes are small immune organs located throughout the body. Cancer 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 cancer cells from the tumour to a lymph node is called metastasis.

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

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

Margins

A margin is any tissue that was cut by the surgeon in order to remove the tumour from your body. Whenever possible, surgeons will try to cut tissue outside of the tumour to reduce the risk that any cancer cells will be left behind after the tumour is removed.

The margins described in your report will depend on how much tissue was removed with the tumour. If the tumour was small and located in the middle of the stomach, all of the margins may be within the stomach. If the tumour was larger or located near the esophagus or small bowel, there may also be a margin in the esophagus or in an area of the small bowel called the duodenum.

Your pathologist will carefully examine all the margins in your tissue sample to see how close the cancer cells are to the edge of the cut tissue. Margins will only be described in your report after the entire tumour has been removed.

A negative margin means that no tumour cells were seen at any of the cut edges of tissue. A margin is called positive when there are tumour cells at the very edge of the cut tissue. A positive margin is associated with a higher risk that the tumour will recur in the same site after treatment.

Pathologic stage

​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) for adenocarcinoma of the stomach

Your pathologist will give a tumour stage from Tis to T4 based on how far the cancer cells have spread from the epithelium on the inner surface of the stomach into the tissue below.

• Tis – The cancer cells are seen only within the epithelium on the inner surface of the stomach. This stage is also known as carcinoma in situ or high-grade dysplasia.
• T1a – The cancer cells have spread into the lamina propria or muscularis mucosa just below the epithelium.
• T1b – The cancer cells have spread into the submucosa.
• T2 – The cancer cells have spread into the muscularis propria.
• T3 – The cancer cells are in the tissue just below the outer surface of the stomach in the subserosal soft tissue.
• T4a – The cancer cells have gone through the serosa and are on the outer surface of the stomach.
• T4b – The cancer cells have spread into organs near the stomach.​

Nodal stage (pN) for adenocarcinoma of the stomach

Adenocarcinoma is given a nodal stage between N0 and N3 based on the number of lymph nodes with cancer cells.

• 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.
• N3a – Cancer cells are seen in seven to fifteen lymph nodes.
• N3b – Cancer cells are seen in more than fifteen lymph nodes.
• NX – No lymph nodes were sent to pathology for examination.

Metastatic stage (pM) for adenocarcinoma of the stomach

Adenocarcinoma is given a metastatic stage between 0 and 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 MX.

by Jason Wasserman, MD PhD FRCPC (updated September 17, 2021)