Stages of Gastric Neuroendocrine Tumors

Neuroendocrine tumors (NETs) are rare cancers that can occur anywhere in the body. Those that originate from neuroendocrine cells located in the mucosal lining of the stomach are called gastric NETs. These specialized cells produce hormones controlling the release of gastric juices and how quickly food moves through the stomach.

Slow-growing NETs that do not spread are often described as low-grade carcinoid tumors, while rapidly-growing NETs that can invade nearby organs and tissues are called high-grade neuroendocrine carcinomas (NECs). While most gastric NETs are low-grade carcinoid tumors, some can become aggressive and behave in a similar way to NECs.

Staging is the process of describing where a cancer is located and how far it has spread to other parts of the body, if at all. This determines the severity and extent of your cancer, which helps doctors predict the course of your condition (prognosis) and decide on the best treatment options for you.

When your doctor first suspects that you may have a NET, they will order a series of diagnostic tests to confirm whether you have the condition. If the tumor is confirmed to be a gastric NET, these tests will give some information that determines the stage of your cancer. This includes the size of the tumor and which parts of the body the cancer has spread to.

While cancer is typically staged when it is first diagnosed and before any treatment, in some cases, it can be staged again over the course of your treatment journey.

If surgery is done to remove the tumor, doctors can determine the tumor’s pathological (or surgical) stage. This is derived from the results of earlier tests as well as those from the surgery. The pathological stage often gives more precise information about the cancer, which can make it a more accurate indicator of its actual progression within the body.

Doctors use classification systems to determine the stage of cancers. Most commonly used is the TNM staging system designed by the American Joint Committee on Cancer (AJCC). TNM is an acronym for tumor (T), nodes (N) and metastasis (M), which are also the three broad categories of this system.

The TNM system uses different stage descriptions for different types of cancer. This means that each cancer type has its own version of the TNM categories. The system described below is primarily for low- to intermediate-grade carcinoid tumors of the gastrointestinal (GI) tract. It does not include high-grade NECs and other types of gastrointestinal cancers, such as gastric adenocarcinomas or GISTs.

While the broad T, N and M categories are the same across all NETs, there are four different staging groups based on which part of the GI tract the main (primary) tumor started in:

• The stomach
• The small intestine (jejunum or ileum)
• The appendix
• The colon or rectum

The following covers the staging of gastric NETs specifically, which start in the innermost lining of the stomach or GI tract wall called the mucosa.

> Find out more about the anatomy of the stomach

Tumor (T)

TThe T category describes the extent of the main (primary) tumor, which is where the cancer originates. This includes its size, location, how far it has grown into the layers of the stomach wall, and if it has reached nearby structures and organs. Stages in this category are assigned a number (from 0 to 4) or the letter ‘X’. The higher the number after the T, the more deeply the tumor has invaded into/through the stomach or the larger the size of the tumor. If the number after the T is followed by a number in parentheses or the letter “m”, this indicates the number of primary tumors found or that there are multiple primary tumors. In this case, the number after the T should indicate the stage of the largest or most advanced tumor. For instance, T2(3) would mean that the largest tumor found is of T2 size and that there are three primary tumors.

TX means the primary tumor cannot be assessed due to a lack of information.

T0 means there is no evidence of a primary tumor in the stomach (i.e., it cannot be found).

T1 means the tumor is no more than 1 cm wide and has grown into deeper layers of the stomach wall beyond the mucosa, like the connective tissue layer (lamina propria) or submucosa.

T2 means the tumor is larger than 1 cm wide or has grown into the muscle layer (muscularis propria) of the stomach wall.

T3 means the tumor has grown through the muscularis propria and into the subserosa, without penetrating the overlying serosa (still within the stomach wall).

T4 means the tumor has grown into the outer layer of tissue covering the stomach, called the serosa or peritoneum, or into nearby structures or organs.

Nodes (N)

The N category describes any cancer spread to lymph nodes near the stomach. Lymph nodes are small, bean-shaped structures that form a network throughout the body. They drain away waste products and damaged cells and contain lymphocytes that fight infection and disease. Stages in the N category are also assigned a letter (X) or number (0 to 3). The higher the number after the N, the greater the spread of the cancer to nearby lymph nodes. For this cancer, only three categories exist.

NX means nearby lymph nodes cannot be assessed due to a lack of information.

N0 means the cancer has not spread to any nearby lymph nodes.

N1 means the cancer has spread to nearby lymph nodes.

Metastasis (M)

The M category describes any cancer spread to distant parts of the body. This is known as metastasis. For this cancer, the most common sites of metastasis are the liver, lungs and bones. There are two stages in this category.

M0 means that the cancer has not spread to distant parts of the body.

M1 means that the cancer has spread to distant organs or tissues. This stage can be further divided into three subcategories:

• M1a means the cancer has spread only to the liver.
• M1b means the cancer has spread to at least one area aside from the liver, such as a lung, ovary, the peritoneum, or bone.
• M1c means the cancer has spread to both the liver and areas beyond the liver.

If the staging was completed without surgery and based on the clinical information, each of the T, N, and M categories may have a lowercase ‘c’ written in front of it (e.g., cT3). To show that the staging is a result of pathological classification after surgery, each of the T, N, and M categories might have a lowercase ‘p’ written in front of it (e.g., pT2). If chemotherapy or other systemic therapy was used prior to surgery, a lowercase ‘y’ may be used to show that the pathologic classification is after receipt of prior or neoadjuvant therapy. (e.g., ypT1).

Grade (G)

The G category describes how abnormal the cancer cells look under the microscope and now frequently they are dividing as a proxy for how aggressive the cancer may behave. This is known as the grade. It is a composite score composed of three factors: differentiation, mitotic rate, and the Ki-67 index. All of these factors are determined by the pathologist who examines the tumor cells under the microscope.

Differentiation refers to how normal or abnormal the cells look compared to normal stomach mucosa cells. Mitotic rate refers to how many cells in the sample are in the process of dividing within a specific area. The Ki-67 index refers to a measurement of a protein present in cells that are preparing to divide. A higher index corresponds to a more rapid growth rate. By definition, all gastric NETs are well-differentiated.

G1 (low grade) means <2 dividing cells per 2mm² and a Ki-67 index of <2%.

G2 (intermediate grade) means either 2–20 dividing cells per 2mm² or a Ki-67 index of 3–20%.

G3 (high grade) means either >20 dividing cells per 2mm² or a Ki-67 index of >20%.

Once the tumor’s T, N, M and G categories have been determined, this information is combined in a process called stage grouping to assign an overall stage. For gastric NETs, there are four stages — stages I (1) through IV (4).

Stage I (Stage 1)

A stage I gastric NET is no more than 1 cm wide and has grown into the lamina propria or submucosa of the stomach wall. There has been no spread of the cancer to nearby lymph nodes or other distant body parts (TNM: T1, N0, M0).

Stage II (Stage 2)

For Stage II gastric NETs, the tumor

• is larger than 1 cm wide or has grown into the muscularis propria of the stomach wall. The cancer has not spread to nearby lymph nodes or distant parts of the body (TNM: T2, N0, M0), or
• has grown through the muscularis propria and into the subserosa, without penetrating the overlying serosa. There has been no spread of the cancer has to nearby lymph nodes or other distant body parts (TNM: T3, N0, M0).

Stage III (Stage 3)

For Stage III gastric NETs, the tumor

• has grown into the serosa or peritoneum, or into nearby structures or organs. There has been no spread of the cancer to nearby lymph nodes or other distant body parts (TNM: T4, N0, M0), or
• is of any size and may have spread into nearby structures. The cancer has spread to nearby lymph nodes but not distant parts of the body (TNM: any T, N1, M0).

Stage IV (Stage 4)

For Stage IV gastric NETs, the tumor is of any size and might or might not have grown into nearby structures. It might or might not have spread to nearby lymph nodes but the cancer has spread to distant parts of the body (TNM: any T, any N, M1).

The higher the number of the stage, the more the cancer has spread. This means that early-stage gastric NETs are less advanced and usually have a better prognosis. Meanwhile, higher-stage tumors have generally spread farther, so they might require different kinds of treatments that are more intense. If you have any questions about cancer staging, don’t hesitate to approach your doctors. They may be able to explain more about the stage of your gastric NET and what that means for you.