Well Differentiated Neuroendocrine Tumor: Definition


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A well differentiated neuroendocrine tumor is a cancer made of neuroendocrine cells that still look much like normal neuroendocrine cells. Doctors often abbreviate it as NET. These tumors can start in many organs, including the pancreas, the digestive tract, and the lungs. Many grow slowly, but some grow faster, and some spread to other parts of the body.

This article explains what a well differentiated neuroendocrine tumor is, where these tumors start, and how pathologists diagnose and grade them. It also explains how a NET differs from a poorly differentiated neuroendocrine carcinoma, a different and faster-growing cancer.

What are neuroendocrine cells?

Neuroendocrine cells make hormones and release them into the blood. These hormones act as chemical signals that help control body functions such as digestion and blood sugar. Neuroendocrine cells occur throughout the body. They sit in the lining of the digestive tract, in the pancreas, and in the lungs, among other places.

What does well differentiated mean in a neuroendocrine tumor?

A tumor is well differentiated when its cells closely resemble the normal cells they came from. In a well differentiated neuroendocrine tumor, the cells look uniform and often form neat nests or ribbons. Under the microscope, they look much like normal neuroendocrine cells.

The World Health Organization (WHO) groups all tumors of neuroendocrine cells into one family, called neuroendocrine neoplasms. The family has two main branches. Pathologists call the well differentiated tumors neuroendocrine tumors. They call the poorly differentiated tumors neuroendocrine carcinomas. Doctors treat these as separate diseases.

Older reports may use the word carcinoid for a well differentiated neuroendocrine tumor. Your report may use either name.

Are well differentiated neuroendocrine tumors cancer?

Pathologists consider all well differentiated neuroendocrine tumors to be cancers. They are malignant, which means they can spread. However, many grow slowly. The chance of spread depends on the organ where the tumor started, its size, and its grade.

Where do well differentiated neuroendocrine tumors start?

These tumors can start almost anywhere neuroendocrine cells are found. Each location has its own article:

How is a well differentiated neuroendocrine tumor diagnosed?

A pathologist diagnoses a well differentiated neuroendocrine tumor by examining a tissue sample under the microscope. The sample comes from a biopsy or from surgery. The pathologist looks for cells with a neuroendocrine appearance, usually arranged in nests, ribbons, or small clusters.

The pathologist then confirms the diagnosis with immunohistochemistry. This test uses antibodies to detect proteins that neuroendocrine cells make. The most common stains are synaptophysin, chromogranin, and INSM1. A positive result for these stains confirms that the tumor has neuroendocrine features. Pathologists also use the Ki-67 stain to help assign the grade.

How are well differentiated neuroendocrine tumors graded?

Pathologists assign a grade to a well differentiated neuroendocrine tumor to show how fast it is growing. Two measurements determine the grade. The first is the mitotic count, which is the number of dividing cells in a set area of tumor. The second is the Ki-67 proliferation index, which is the percentage of tumor cells that are preparing to divide.

For tumors of the pancreas and digestive tract, the WHO classification of digestive system tumours (5th edition, 2019) uses three grades:

  • Grade 1 (G1). The tumor has fewer than 2 mitoses per 2 square millimeters (mm²) and a Ki-67 index of 2% or lower. This is the slowest-growing grade.
  • Grade 2 (G2). The tumor has 2 to 20 mitoses per 2 mm² and a Ki-67 index of 3% to 20%. This grade grows at an intermediate pace.
  • Grade 3 (G3). The tumor has more than 20 mitoses per 2 mm² and a Ki-67 index above 20%. This is the fastest-growing grade.

Your report may show slightly different cut-offs, depending on the organ and the classification the laboratory uses. Lung tumors follow a different system. Pathologists call them typical or atypical carcinoids, based on the mitotic count and whether necrosis (dead tissue) is present. They do not use Ki-67 to separate the two.

What is the difference between a grade 3 neuroendocrine tumor and a neuroendocrine carcinoma?

Both can have a Ki-67 index above 20%. The difference lies in how the cells look. In a grade 3 neuroendocrine tumor, the cells are still well differentiated. In a neuroendocrine carcinoma, the cells look very abnormal, and pathologists call them poorly differentiated.

This distinction matters because the two tumors behave differently and doctors treat them differently. The pathologist makes it by examining the tumor under the microscope. Ki-67 alone does not decide it.

What does the grade mean for prognosis?

The grade is one of the main factors that predicts how a well differentiated neuroendocrine tumor will behave. Higher-grade tumors grow faster and are more likely to spread. Doctors also consider the tumor’s size, its location, and its stage. Stage describes how far the tumor has spread. Each organ has its own staging system. Your care team uses all of these findings to estimate your prognosis and plan follow-up.

Some of these tumors make hormones that cause symptoms, and others make none. Your doctor can tell you whether hormone testing applies to your tumor.

Questions to ask your doctor

  • What organ did my neuroendocrine tumor start in?
  • What is the grade of my tumor, and what are the mitotic count and Ki-67 index?
  • Is my tumor a neuroendocrine tumor or a neuroendocrine carcinoma?
  • Which grading system did the pathologist use?
  • What stage is my tumor?
  • Does my tumor make hormones, and do I need hormone tests?
  • Should I be tested for an inherited condition such as MEN1?
  • What follow-up will I need?

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