Adenocarcinoma of the stomach

by Jason Wasserman MD PhD FRCPC
February 9, 2023

What is adenocarcinoma of the stomach?

Adenocarcinoma (also called invasive adenocarcinoma) is the most common type of stomach cancer. The tumour starts from the cells that line the inside of the stomach. In many cases, adenocarcinoma develops from a precancerous condition dysplasia.

What causes adenocarcinoma in the stomach?

Environmental factors associated with adenocarcinoma in the stomach include Helicobacter pylori infection, Epstein-Barr virus (EBV) infection, tobacco smoking, and dietary factors. Genetic mutations involving the genes CDH1 or APC are also associated with an increased risk of developing adenocarcinoma of the stomach.

What are the symptoms of adenocarcinoma of the stomach?

Most people with adenocarcinoma of the stomach do not experience any new symptoms early in the disease. However, larger tumours can result in symptoms such as abdominal pain, bloating, early satiety (feeling full earlier than normal), vomiting, and weight loss.

How is the diagnosis of adenocarcinoma in the stomach made?

The diagnosis 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.

What are the histologic subtypes of adenocarcinoma in the stomach?

Several systems have been created to classify adenocarcinoma of the stomach into groups based on the way the tumour cells look when examined under the microscope. Each group is called a histologic subtype. Historically, the two most commonly used systems were the Lauren classification and the Japanese Gastric Cancer Association (JGCA) classification. In 2019, the World Health Organization (WHO) created a system that combined elements of both the Lauren and JGCA classifications.

Lauren classification

The Lauren classification system is used frequently by pathologists in North America. This system divides adenocarcinoma of the stomach into two histologic subtypes, intestinal-type adenocarcinoma and diffuse-type adenocarcinoma. Pathologists use the term signet-ring cells to describe a diffuse-type adenocarcinoma made up of large round cells filled with a protein called mucin.

Japanese Gastric Cancer Association

The Japanese Gastric Cancer Association (JGCA) classification system is used frequently by pathologists in Asia and Europe. This system divides adenocarcinoma of the stomach into more than 10 histologic subtypes. The most common histologic subtype of adenocarcinoma in the stomach according to this system is called tubular-type adenocarcinoma. Other less common histologic subtypes of adenocarcinoma include papillary-type adenocarcinoma, signet ring cell-type adenocarcinoma, papillary-type adenocarcinoma, mucinous-type adenocarcinoma, poorly differentiated, and hepatoid-type adenocarcinoma.

World Health Organization (WHO)

The World Health Organization (WHO) classification system was introduced in 2019. This system divides adenocarcinoma of the stomach into 5 main histologic subtypes. The most common histologic subtype of adenocarcinoma in the stomach according to this system is called tubular-type adenocarcinoma. Other less common histologic subtypes of adenocarcinoma include papillary-type adenocarcinoma, poorly cohesive-type adenocarcinoma, mucinous-type adenocarcinoma, and mixed-type adenocarcinoma adenocarcinomas. According to this system, tumours with signet ring cells are considered a subtype of poorly cohesive adenocarcinoma.

Why is the histologic subtype of adenocarcinoma important?

The histologic subtype is important because some subtypes such as diffuse-type adenocarcinoma, poorly cohesive-type, papillary-type adenocarcinoma, and micropapillary-type adenocarcinoma are more likely to metastasize (spread) to lymph nodes and other organs such as the liver. Some histologic subtypes such as diffuse-type adenocarcinoma may also be less likely to respond to chemotherapy.

What does differentiated mean and why is it important?

Pathologists use the term differentiated to divide adenocarcinoma of the stomach 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 poorly differentiated tumours behave in a more aggressive manner and are more likely to metastasize (spread) to other parts of the body.

What is HER2 and why is it important?

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.

How do pathologists test for HER2?

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.

What are mismatch repair (MMR) proteins and why are they important?

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.

For adenocarcinoma of the stomach, a loss of one or more mismatch repair proteins is associated with a better prognosis compared to tumours without a loss. In addition, tumours with loss of mismatch repair proteins may be more sensitive to a group of medications called immune checkpoint inhibitors.

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

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 starts in a thin layer of tissue on the inside surface of the stomach called the mucosa, invasion is defined as the spread of cancer cells into the other layers of tissue in the stomach or any other organs outside of the stomach. Invasion can only be seen after the tumour has been examined under a microscope by a pathologist.

When examining the tumour under the microscope, your pathologist will look to see how far the cancer cells have spread from the mucosa 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 stomach 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).

Most pathology reports for adenocarcinoma of the stomach will describe the level of invasion as follows:

• Intramuscosal – The tumour is called intramucosal if the cancer cells have not spread outside of the mucosa. The mucosa include 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 level of invasion 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 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.

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.

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.

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

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.

Most reports include the total number of lymph nodes examined and the number, if any, that contain cancer cells. Your pathologist will carefully examine all lymph nodes 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.

Finding cancer cells in a lymph node is important because it is associated with a higher risk that the cancer cells will be found in other lymph nodes or in a distant organ such as the lungs. The examination of lymph nodes is also used to determine the nodal stage (pN).

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. 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 intestine, there may also be a margin in the esophagus or in an area of the small intestine called the duodenum. The size of the margin (the amount of normal tissue between the tumour and the cut edge) also 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.

What is the pathologic stage for adenocarcinoma of the stomach?

​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 T1 to T4 based on how far the cancer cells have spread from the mucosa on the inner surface of the stomach into the tissue below.

• T1a – Cancer cells were only found in the mucosa. This is also called intramucosal adenocarcinoma.
• 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 M0 and M1 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.