Your pathology report for mixed neuroendocrine non-neuroendocrine neoplasm of the appendix

By Jason Wasserman MD PhD FRCPC
September 20, 2025

A mixed neuroendocrine non-neuroendocrine neoplasm (MiNEN) is a rare type of appendix cancer that contains two different components:

For a tumor to be called MiNEN, each component must make up at least 30% of the cancer and be recognizable as a separate part under the microscope.

What are the symptoms of mixed neuroendocrine non-neuroendocrine neoplasm of the appendix?

Most people with MiNEN do not have specific symptoms at first. Like other appendix tumors, many cases are found when the appendix is removed for appendicitis.

Symptoms can include:

  • Abdominal pain or swelling

  • Nausea or vomiting

  • A mass seen on imaging

Because MiNEN behaves aggressively, some patients already have spread to lymph nodes or distant organs at the time of diagnosis.

What causes mixed neuroendocrine non-neuroendocrine neoplasm of the appendix?

Doctors do not know exactly why MiNENs develop. They are thought to arise when some cells in the appendix begin to grow and divide abnormally, leading to two different cancerous components within the same tumor.

In many cases, the tumor appears to come from a single group of cells that can change into different cell types. Over time, some of these cells develop features of neuroendocrine cells (cells that release hormones) while others develop features of non-neuroendocrine cells (cells that normally form glands in the lining of the intestine).

Long-standing inflammation of the appendix or colon may play a role in the development of these tumors, but in most people the exact cause cannot be identified.

Is mixed neuroendocrine non-neuroendocrine neoplasm a cancer?

Yes. MiNEN is a malignant (cancerous) tumor. Both the neuroendocrine and non-neuroendocrine components are invasive cancers, which means they can grow into nearby tissues and spread to lymph nodes and other organs.

The behavior of MiNEN is usually determined by the most aggressive component. If the neuroendocrine part is poorly differentiated (high grade), the cancer behaves like a neuroendocrine carcinoma. If the neuroendocrine part is well differentiated (low grade), the adenocarcinoma component usually determines the outcome and treatment.

How common is mixed neuroendocrine non-neuroendocrine neoplasm of the appendix?

MiNEN is extremely rare. It is much less common than both well differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs) of the appendix.

How is this diagnosis made?

The diagnosis of MiNEN is made after the appendix or a related tumor has been removed and examined by a pathologist.

Microscopic examination

When examined under the microscope, MiNENs show two separate patterns of growth. One part resembles a neuroendocrine tumor or carcinoma, and the other part resembles a non-neuroendocrine carcinoma, usually adenocarcinoma. For the diagnosis to be made, each part must make up at least 30% of the tumor.

Immunohistochemistry

Immunohistochemistry (IHC) is a special test that uses antibodies linked to colored markers to detect proteins in tumor cells. This test helps pathologists confirm the diagnosis.

  • The neuroendocrine component usually stains positive for synaptophysin and chromogranin, proteins normally made by neuroendocrine cells.

  • The non-neuroendocrine component (such as adenocarcinoma) usually stains for cytokeratins and CDX2, proteins made by gland-forming cells.

Histologic grade

Pathologists classify neuroendocrine tumors and carcinomas by their grade, which reflects how quickly the tumor cells are dividing and how abnormal they look under the microscope.

  • A well differentiated neuroendocrine tumor (NET) is made up of cells that look relatively uniform and organized. Pathologists further divide NETs into three grades based on the mitotic rate (number of dividing cells) and the Ki-67 index (the percentage of tumor cells that are actively dividing):

    • 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%.

  • A poorly differentiated neuroendocrine carcinoma (NEC) is always considered high grade. These tumors have very abnormal-looking cells, grow quickly, and usually have a very high Ki-67 index (often greater than 50%).

In MiNENs of the appendix, the neuroendocrine component is most often a poorly differentiated NEC, which means the tumor is classified and treated as a high grade cancer.

Limitations of a biopsy

Sometimes only a biopsy is performed before surgery. Because the two tumor components may not be evenly distributed, a biopsy may show only one part of the tumor. This means the diagnosis of MiNEN is often only confirmed after the entire tumor is removed and examined.

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 MiNENs 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 MiNEN 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 MiNEN.

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 MiNEN 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 mixed neuroendocrine non-neuroendocrine neoplasm of the appendix?

MiNEN of the appendix is an aggressive cancer with a prognosis similar to other high-grade appendiceal cancers.

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

  • Surgery is usually the first treatment, but many patients require additional therapies such as chemotherapy.

  • Overall, MiNENs carry a worse prognosis than well differentiated neuroendocrine tumors and often behave like poorly differentiated adenocarcinomas or NECs.

Questions for your doctor

If you have been diagnosed with a mixed neuroendocrine–non-neuroendocrine neoplasm of the appendix, you may wish to ask your doctor the following questions:

  • How much of my tumor was neuroendocrine and how much was non-neuroendocrine?

  • Did the tumor extend into the mesoappendix or nearby organs?

  • Were any lymph nodes involved?

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

  • What stage is my cancer, and how does that affect my treatment plan?

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

  • How often should I be followed after treatment, and what tests will I need?

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

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