Your pathology report for well differentiated neuroendocrine tumor of the appendix

by Ipshita Kak MD FRCPC
September 18, 2025

A well differentiated neuroendocrine tumor (NET) is the most common type of appendiceal cancer. It starts from specialized neuroendocrine cells in the lining of the appendix. These cells normally help regulate digestion by releasing hormones in response to signals from the nervous system. Most well differentiated NETs are small, slow growing, and curable with surgery.

What are the symptoms of a well differentiated neuroendocrine tumor of the appendix?

In most people, an appendiceal NET does not cause symptoms. In fact, up to 80% are discovered by accident when the appendix is removed for another reason, usually appendicitis. Rarely, a person may have abdominal pain, nausea, or other digestive symptoms.

A very uncommon complication is carcinoid syndrome, which causes flushing of the skin, diarrhea, and difficulty breathing. Carcinoid syndrome rarely occurs unless the tumor has already spread (metastasized) to other parts of the body, such as the liver.

What causes a well differentiated neuroendocrine tumor of the appendix?

The exact cause is not known. These tumors develop from neuroendocrine cells found in the lining of the appendix, but why they begin to grow abnormally is not fully understood. Unlike many other cancers, appendiceal NETs typically do not exhibit common mutations found in other tumors, and there is no strong association with family history or inherited genetic syndromes.

Is well differentiated neuroendocrine tumor a cancer?

Yes. A well differentiated neuroendocrine tumor is considered a type of cancer. This is because the tumor cells can invade the wall of the appendix and, in some cases, spread to lymph nodes or other parts of the body. However, compared to many other cancers, appendiceal NETs typically grow very slowly and have an excellent prognosis, especially when they are small and completely removed. Some very small tumors behave almost like benign growths, but they are still classified as malignant because of their potential to spread.

How common is a well differentiated neuroendocrine tumor of the appendix?

Well differentiated NETs of the appendix are rare. They occur in about 1–2% of appendectomies and are more common in younger people, especially under the age of 40. They affect women slightly more often than men. Despite being rare overall, appendiceal NETs are the fifth most common gastrointestinal neuroendocrine tumor after those in the small intestine, rectum, pancreas, and stomach. They are also seen in children and teenagers, where the outcome is almost always excellent.

How is this diagnosis made?

The diagnosis is usually made after surgery to remove the appendix. The tissue is sent to a pathologist, who examines it under a microscope.

Pathologists look for:

• Small, uniform tumor cells arranged in nests, ribbons, or glands.

• A growth pattern that often extends into the muscular wall of the appendix or into the fatty tissue surrounding it (the mesoappendix).

• Rare or absent mitotic figures (dividing cells) and very little necrosis (cell death).

To confirm the diagnosis, pathologists often perform immunohistochemistry (IHC). This test uses antibodies to highlight proteins made by the tumor cells. Well differentiated NETs typically show staining for chromogranin and synaptophysin.

Histologic grade

Pathologists categorize well-differentiated neuroendocrine tumors of the appendix into three grades using a classification system established by the World Health Organization (WHO). The grade tells us how quickly the tumor cells are dividing and growing. Tumors with a higher grade (grades 2 and 3) are more likely to spread than those with a lower grade (grade 1).

The grade can only be determined after the tumor has been examined under a microscope. Your pathologist looks for cells that are in the process of dividing, called mitotic figures. The number of mitotic figures observed in a given area is referred to as the mitotic index or mitotic rate.

Another test, called immunohistochemistry for Ki-67, may also be performed. This test highlights cells that can divide, and the result is reported as a Ki-67 index, which is the percentage of tumor cells producing Ki-67.

The WHO grade for well differentiated NETs is based on the mitotic rate and/or Ki-67 index:

• Grade 1 (G1) – Mitotic rate less than 2 or Ki-67 index less than 3%.

• Grade 2 (G2) – Mitotic rate between 2 and 20 or Ki-67 index between 3% and 20%.

• Grade 3 (G3) – Mitotic rate greater than 20 or Ki-67 index greater than 20%.

Tumor extension

The appendix is a small finger-shaped pouch connected to the beginning of the colon. Its wall has several layers, starting with the inner lining (mucosa) and ending with the outer surface (serosa). On the outside, the appendix is surrounded by fatty tissue called the mesoappendix, which supports and protects it.

Most well differentiated NETs start in the mucosa. Tumor extension describes how far the tumor has grown into the wall of the appendix and whether it has spread into the mesoappendix or beyond the serosa.

Tumors that break through the serosa can spread into nearby organs such as the colon, small intestine, or abdominal wall. Because of this, tumor extension is important both for understanding prognosis and for determining the pathologic tumor stage (pT).

Perineural invasion

Perineural invasion (PNI) means tumor cells were seen attached to or growing along a nerve. Nerves are thin structures found throughout the body that carry signals such as pain, pressure, and temperature. When tumor cells grow along nerves, they can spread deeper into surrounding tissues. This finding increases the risk that the tumor could return after treatment.

Lymphovascular invasion

Lymphovascular invasion (LVI) means tumor cells were seen inside a blood vessel or a lymphatic vessel. Blood vessels carry blood throughout the body, while lymphatic vessels carry a clear fluid called lymph. Finding tumor cells in these vessels is important because it means they have a potential pathway to spread to lymph nodes or distant organs such as the liver or lungs.

Margins

A margin is any cut surface where the surgeon divided the tissue to remove the appendix. For appendiceal tumors, this is usually where the appendix attaches to the colon. In some cases, if part of the colon is also removed, the margin may include the cecum or other surrounding tissue.

Margins are only described in your report after the entire tumor has been removed.

• A negative margin means no tumor cells are seen at the cut edge, suggesting the tumor was completely removed.

• A positive margin means tumor cells are seen at the edge, which increases the risk that the tumor could grow back in the same area.

Lymph nodes

Lymph nodes are small immune organs located throughout the body. Tumor cells can travel from the appendix to lymph nodes through lymphatic vessels, a process called metastasis.

Your pathologist will carefully examine any lymph nodes removed during surgery.

• Lymph nodes that contain tumor cells are called positive.

• Lymph nodes without tumor cells are called negative.

Your report will usually state how many lymph nodes were examined and how many, if any, contained tumor cells. This information is used to determine the pathologic nodal stage (pN). Finding tumor cells in a lymph node raises the nodal stage and is associated with a higher risk of spread.

Stage

The pathologic stage for well differentiated NETs of the appendix is based on the TNM system, which looks at the size and growth of the primary tumor (T), spread to lymph nodes (N), and spread to distant sites such as the liver (M). In general, a higher stage means more advanced disease and a higher risk of recurrence.

Tumor stage (pT):

• T1 – Tumor is 2 cm or less.

• T2 – Tumor is greater than 2 cm but less than or equal to 4 cm.

• T3 – Tumor is greater than 4 cm or has spread into the subserosa or mesoappendix.

• T4 – Tumor has grown through the serosa or into nearby organs.

Nodal stage (pN):

• N0 – No cancer cells are seen in any lymph nodes.

• N1 – Cancer cells are seen in at least one lymph node.

• NX – No lymph nodes were sent for examination.

Metastatic stage (pM):

• M0 – No tumor cells are seen in distant organs.

• M1 – Tumor cells are seen in a distant organ (such as the liver).

• MX – No distant tissue was sent for examination, so the metastatic stage cannot be determined.

What is the prognosis for someone with a well differentiated neuroendocrine tumor of the appendix?

The prognosis is excellent for most people. Small tumors are usually cured by appendectomy alone.

The risk of spread depends mainly on size:

• Tumors less than 1 cm almost never spread.

• Tumors between 1–2 cm have a small risk (about 10–20%) of spread to lymph nodes.

• Tumors greater than 2 cm have a higher risk and may require more extensive surgery.

Even when lymph nodes are involved, survival rates are still very high. Distant spread (to the liver or elsewhere) is rare, but when it occurs, the prognosis is less favorable. Overall, the 10-year survival rate for appendiceal NETs is over 90%.

Questions for your doctor

• How does the size and grade of my tumor affect my risk of spread?

• Did the tumor extend into the mesoappendix or beyond the appendix wall, and what does that mean for treatment?

• Were any lymph nodes involved, and does that change my stage or prognosis?

• Do I need additional surgery, such as a right hemicolectomy, or is appendectomy enough?

• How often should I have follow-up visits or imaging after surgery?

• What signs or symptoms should I watch for in the future?