Your pathology report for poorly differentiated neuroendocrine carcinoma of the appendix

By Jason Wasserman MD PhD FRCPC
September 19, 2025

A poorly differentiated neuroendocrine carcinoma (NEC) is a rare and aggressive type of appendix cancer. It begins with neuroendocrine cells in the appendix, which normally help regulate digestion by releasing hormones in response to signals from the nervous system.

Unlike well differentiated neuroendocrine tumors (NETs), which are slow-growing and often discovered by chance, poorly differentiated NECs are high-grade cancers that typically behave aggressively and require more intensive treatment.

What are the symptoms of poorly differentiated neuroendocrine carcinoma of the appendix?

Most people with poorly differentiated NECs of the appendix do not have specific symptoms until the cancer is advanced. Many cases are discovered when the appendix is removed for appendicitis. Symptoms may include abdominal pain, nausea, or swelling.

Because these tumors are aggressive, they may already have spread to nearby lymph nodes or distant organs at the time of diagnosis.

Unlike some NETs, carcinoid syndrome (flushing, diarrhea, wheezing) is very rare in NEC of the appendix and usually occurs only if the cancer has spread to the liver.

What causes poorly differentiated neuroendocrine carcinoma of the appendix?

The cause is not fully understood. Poorly differentiated NECs start from neuroendocrine cells in the appendix that grow abnormally. Unlike well differentiated NETs, which usually do not have common cancer-associated mutations, NECs often show changes in genes that drive aggressive tumor growth, similar to other high grade cancers of the colon.

Is poorly differentiated neuroendocrine carcinoma a cancer?

Yes. Poorly differentiated NEC is classified as a high grade cancer. The tumor cells invade through the wall of the appendix and can spread quickly to lymph nodes and distant sites such as the liver. Compared to well differentiated NETs, NECs grow faster, spread earlier, and are associated with a worse prognosis.

How common is poorly differentiated neuroendocrine carcinoma of the appendix?

This diagnosis is extremely rare. Poorly differentiated NECs account for only a very small fraction of all appendix cancers. They are much less common than well differentiated NETs and are seen mostly in adults.

How is this diagnosis made?

The diagnosis is usually made after surgery to remove the appendix. The tissue is examined under a microscope by a pathologist.

Under the microscope, poorly differentiated NECs are made up of abnormal cells that look very different from normal appendix tissue. They may grow in sheets, nests, or trabeculae (cord-like structures). The cells have irregular, darkly stained nuclei, and there is typically a high number of mitotic figures (cells in the process of dividing) and areas of necrosis (dead cells).

Pathologists divide poorly differentiated NECs into two main types:

• Small cell NEC – These tumors are made up of small, round tumor cells with minimal cytoplasm.

• Large cell NEC – These tumors are made up of larger tumor cells with abundant cytoplasm and prominent nucleoli.

To confirm the diagnosis, pathologists often use immunohistochemistry (IHC), a special test that highlights proteins made by the tumor cells. Poorly differentiated NECs typically stain positive for neuroendocrine markers such as synaptophysin and chromogranin, but may be weaker or more variable than in well differentiated NETs.

Histologic grade

All poorly differentiated NECs are considered high grade (grade 3). This means they have a high mitotic rate (many dividing cells) and a high Ki-67 index (a test that measures how many tumor cells are actively dividing). High grade tumors are much more likely to spread and are associated with a worse outcome.

Tumor extension

Pathologists use the term tumor extension to describe how far the cancer has grown from the inner lining of the appendix into the deeper layers or beyond.

• A tumor confined to the appendix wall has a lower stage.

• A tumor that has spread into the mesoappendix (the fatty tissue surrounding the appendix) or through the serosa (the outermost layer) has a higher stage and a greater risk of metastasis.

Because poorly differentiated NECs grow quickly, many already extend into the mesoappendix or beyond by the time they are diagnosed.

Perineural invasion

Perineural invasion (PNI) refers to the growth of cancer cells along or around a nerve. This allows the tumor to spread into surrounding tissues. Perineural invasion is often reported in poorly differentiated NEC and is a sign of more aggressive behavior.

Lymphovascular invasion

Lymphovascular invasion (LVI) means cancer cells are found inside a blood vessel or lymphatic vessel. This provides a pathway for the cancer to spread to lymph nodes or distant organs. Lymphovascular invasion is common in poorly differentiated NEC.

Margins

A margin is any edge of tissue cut by the surgeon to remove the tumor. For appendiceal tumors, this is usually where the appendix was attached to the colon.

• A negative margin means that no cancer cells are visible at the cut edge, suggesting that the tumor was entirely removed.

• A positive margin means cancer cells are present at the cut edge, which increases the risk of the cancer coming back.

Because these tumors are aggressive, margins are very important in guiding whether further surgery may be recommended.

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 poorly differentiated NEC 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 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 cancer cells are seen in distant organs.

• M1 – Cancer 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 poorly differentiated neuroendocrine carcinoma of the appendix?

Poorly differentiated NEC of the appendix has a much worse prognosis than well differentiated NET. These tumors tend to grow quickly and spread early to lymph nodes and distant organs.

• The outcome depends on tumor size, stage, and whether the cancer has spread to lymph nodes or distant organs.

• Even with surgery, many patients require additional treatments such as chemotherapy.

• Long-term survival rates are significantly lower than for well differentiated NETs.

Questions for your doctor

If you have been diagnosed with poorly differentiated neuroendocrine carcinoma of the appendix, you may wish to ask your doctor the following questions:

• What type of poorly differentiated NEC do I have (small cell or large cell)?

• How extensive was the tumor, and did it spread into the mesoappendix or beyond?

• Were any lymph nodes involved?

• Were the surgical margins clear, or will more surgery be needed?

• What stage is my cancer, and what does that mean for my treatment?

• Will I need chemotherapy or other treatments in addition to surgery?

• How often will I need follow-up visits or scans?

• What is my long-term outlook with this type of cancer?