Well Differentiated Neuroendocrine Tumour of the Pancreas: Understanding Your Pathology Report

by Stephanie Reid MD FRCPC
June 15, 2026

A well differentiated neuroendocrine tumor is a type of pancreatic cancer that starts from neuroendocrine cells in the hormone-producing (endocrine) part of the pancreas. These cells are found in small, round clusters called islets of Langerhans, and they produce hormones such as insulin and glucagon that help regulate body functions like blood sugar levels. “Well differentiated” means the tumor cells still look and behave much like normal neuroendocrine cells, which is why these tumors usually grow slowly. They are also called pancreatic neuroendocrine tumors, or PanNETs.

This article will help you understand the findings in your pathology report, what each term means, and why it matters for your care.

What causes a well differentiated neuroendocrine tumor of the pancreas?

Most well differentiated neuroendocrine tumors of the pancreas occur sporadically, meaning they develop without a known inherited cause. However, in about 10 to 20 percent of cases, the tumor arises in a person with an inherited syndrome that raises the risk of tumors in several organs. Because some of these conditions run in families, your doctor may recommend genetic counseling and testing, which can also help relatives understand their own risk. The syndromes most often linked to these tumors include:

Multiple endocrine neoplasia type 1 (MEN1) — The most common inherited cause. People with MEN1 have a change in the MEN1 gene, which raises the risk of tumors in the pancreas, parathyroid glands, and pituitary gland.
Von Hippel-Lindau (VHL) syndrome — Caused by changes in the VHL gene, leading to tumors in the pancreas, kidneys, adrenal glands, and brain.
Tuberous sclerosis complex (TSC) — Caused by changes in the TSC1 or TSC2 genes, leading to tumors in the brain, kidneys, skin, and pancreas.
Neurofibromatosis type 1 (NF1) — Caused by changes in the NF1 gene, leading to nerve tumors and an increased risk of pancreatic neuroendocrine tumors.

Rarer inherited conditions associated with these tumors include Mahvash disease, familial insulinomatosis, Lynch syndrome, and familial atypical multiple mole melanoma (FAMMM) syndrome. Even in people without one of these syndromes, certain inherited DNA-repair gene changes, such as in MUTYH, CHEK2, or BRCA2, have been found in some cases.

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

The symptoms depend on whether the tumor is functioning (making a hormone that causes symptoms) or non-functioning.

Functioning tumors

Some of these tumors release excess amounts of a hormone into the bloodstream, which causes a specific group of symptoms called a hormonal syndrome. Functioning tumors are named for the hormone they make:

Insulinoma — Makes insulin, leading to low blood sugar (hypoglycemia), dizziness, sweating, and confusion.
Glucagonoma — Makes glucagon, leading to high blood sugar, weight loss, a specific skin rash, and anemia.
Gastrinoma — Makes gastrin, leading to too much stomach acid, ulcers, abdominal pain, and diarrhea (known as Zollinger-Ellison syndrome).
VIPoma — Makes vasoactive intestinal peptide (VIP), leading to severe watery diarrhea, dehydration, and salt imbalances.
Somatostatinoma — Makes somatostatin, leading to diabetes, gallstones, and digestive problems.
ACTH-secreting tumor — Makes adrenocorticotropic hormone (ACTH), leading to Cushing’s syndrome, with weight gain, high blood pressure, and muscle weakness.

Non-functioning tumors

Non-functioning tumors do not make enough hormone to cause a clear set of symptoms. Because of this, they are often found later, after they have grown large enough to press on nearby structures, causing abdominal pain, nausea, unexplained weight loss, or jaundice (yellowing of the skin and eyes) if a tumor in the head of the pancreas blocks the bile duct. At least 15 percent of non-functioning tumors are found by chance during imaging done for another reason. Sometimes a non-functioning tumor is not found until it has already metastasized (spread) to another part of the body, such as the liver.

How is the diagnosis made?

The diagnosis is usually made after a small tissue sample is examined under the microscope by a pathologist. The sample is most often obtained by a fine needle aspiration biopsy (FNAB) or a needle core biopsy during an endoscopic ultrasound.

Under the microscope, these tumors form organized clusters of cells that resemble normal neuroendocrine cells. The cells are usually round or oval with finely granular cytoplasm, and their nuclei have a characteristic “salt-and-pepper” pattern, meaning the DNA inside is arranged in small, even clumps. The cells most often grow in a solid (nest-like) or trabecular (ribbon-like) pattern, supported by delicate connective tissue and small blood vessels. Most tumors show little nuclear atypia (variation in nuclear size and shape).

To confirm that the tumor is made of neuroendocrine cells, the pathologist usually performs a test called immunohistochemistry. This test uses antibodies linked to colored dyes to highlight specific proteins. Neuroendocrine tumors typically stain positive for proteins such as synaptophysin, chromogranin, and INSM1, which confirms the neuroendocrine origin. The pathologist also measures a protein called Ki-67, which marks dividing cells and is used to assign the tumor’s grade (described in the next section).

Imaging tests are an important part of the workup. A special scan called a gallium-68 DOTATATE PET scan uses a tracer that attaches to neuroendocrine tumor cells, helping doctors locate the tumor and find any areas where it has spread. CT and MRI are also used to measure the tumor and to check whether it has spread to nearby organs or distant sites. If the tumor is found to be removable, surgery is often performed.

Histologic grade

Histologic grade describes how quickly the tumor is likely to grow, based on the number of tumor cells actively dividing. The pathologist measures this in two ways: by counting dividing cells (called mitotic figures) in a set area of tissue, and by measuring the Ki-67 labeling index, which is the percentage of cells that stain positive for Ki-67. If the two measurements give different grades, the higher value is used. The grade is one of the most important factors in predicting how the tumor will behave.

Grade 1 — Fewer than 2 mitoses per 2 mm² and a Ki-67 index below 3 percent. These tumors grow very slowly.
Grade 2 — 2 to 20 mitoses per 2 mm² or a Ki-67 index between 3 and 20 percent.
Grade 3 — More than 20 mitoses per 2 mm² or a Ki-67 index above 20 percent. These tumors grow more quickly.

It is important to know that a grade 3 well differentiated neuroendocrine tumor is not the same as a pancreatic neuroendocrine carcinoma. A neuroendocrine carcinoma is a separate, poorly differentiated cancer that looks very abnormal under the microscope and tends to grow much faster. Even at grade 3, a well differentiated tumor generally has a better outlook than a neuroendocrine carcinoma.

Tumor size

After the tumor is removed, the pathologist measures it, usually in centimeters. Size matters because larger tumors are more likely to spread, and size is used to assign the tumor stage (pT). Size also affects treatment decisions: small tumors (less than 2 cm) that cause no symptoms and are low-grade may sometimes be monitored with regular imaging rather than removed right away. Tumor size is usually reported only after surgery, not on a small biopsy.

Perineural invasion

Perineural invasion means that cancer cells are found inside or around nerves. Cancer cells can use nerves as a pathway to spread into nearby tissue, and this finding is linked to a higher risk of the tumor returning after surgery. If it is present, it will be described in your pathology report.

Lymphovascular invasion

Lymphovascular invasion means that cancer cells are found inside blood vessels or lymphatic vessels. Cancer cells can use these vessels to travel to lymph nodes or distant organs, so this finding is associated with a higher risk of spread.

Surgical margins

A margin is the edge of the tissue that is cut during surgery to remove the tumor. The pathologist examines these edges under the microscope to see whether any tumor cells reach them.

Negative margin — No tumor cells are seen at the cut edge. This suggests the tumor was completely removed.
Positive margin — Tumor cells are seen right at the cut edge. This raises concern that some tumor may have been left behind, and it may lead the treatment team to consider further surgery.

In pancreatic surgery, the margins commonly examined include the pancreatic margin (where the pancreas was cut), the common bile duct margin, and, depending on the operation, the edges of the duodenum (small intestine) and stomach.

Lymph nodes

Lymph nodes are small, bean-shaped organs that are part of the immune system, and they can be one of the first places a neuroendocrine tumor spreads. When surgery is performed, nearby lymph nodes are often removed and examined. Your pathology report may describe the number of lymph nodes examined, the number that contain tumor, and whether extranodal extension is present. Extranodal extension means that tumor cells have broken through the outer capsule of a lymph node into the surrounding tissue. The number of involved lymph nodes is used to assign the nodal stage (pN), described in the staging section below.

Biomarker and molecular testing

Biomarkers are measurable changes within tumor cells, usually involving specific genes or proteins, that help the treatment team understand how a tumor behaves and which treatments may be effective. For well differentiated neuroendocrine tumors, the most useful biomarkers relate to the tumor’s hormone receptors and to a few genetic changes that affect outlook or point to an inherited condition.

Somatostatin receptor status

Most well differentiated neuroendocrine tumors carry large numbers of somatostatin receptors on their surface, especially a type called SSTR2. These receptors are important because they are the target of two treatments: somatostatin analog drugs (such as octreotide and lanreotide) and a radioactive treatment called peptide receptor radionuclide therapy (PRRT). Somatostatin receptor status is most often assessed with a gallium-68 DOTATATE PET scan, and sometimes by immunohistochemistry on the tissue sample. A tumor that shows strong receptor activity is more likely to respond to these treatments.

DAXX and ATRX

DAXX and ATRX are genes that help maintain DNA structure. Loss of the DAXX or ATRX protein is found in a portion of pancreatic neuroendocrine tumors and is linked to a higher risk of the tumor returning or spreading. This information is mainly used to help predict the outlook. It can be assessed by immunohistochemistry or by next-generation sequencing, which reads many genes at once.

MEN1 and inherited gene changes

The MEN1 gene is the most commonly altered gene in these tumors. A change found only in the tumor (somatic) is common and does not affect family members. A change found in every cell of the body (germline) signals the inherited condition MEN1 syndrome and has implications for relatives. For this reason, germline genetic testing and counseling are often recommended, particularly for younger patients, those with more than one tumor, or those with a family history. Rarely, these tumors show mismatch repair deficiency, a change in the cell’s ability to repair DNA that can make immunotherapy an option and may point to an inherited syndrome.

For more general information about the tests in this section, visit our Biomarkers section.

Pathologic stage (pTNM)

The pathologic stage describes how far the tumor has grown and spread, based on the tissue removed during surgery. It uses the TNM system (8th edition of the American Joint Committee on Cancer, or AJCC), which combines the size and extension of the tumor (pT), the involvement of lymph nodes (pN), and spread to distant organs (pM). The M part is usually determined by imaging rather than by the pathologist and describes distant spread, most often to the liver.

Tumor stage (pT)

pT1 — The tumor is limited to the pancreas and is smaller than 2 cm.
pT2 — The tumor is limited to the pancreas and is 2 cm to 4 cm.
pT3 — The tumor is limited to the pancreas and is larger than 4 cm, or it has grown into the duodenum or common bile duct.
pT4 — The tumor has grown into nearby organs (such as the stomach, spleen, colon, or adrenal gland) or into the wall of a major blood vessel.

Nodal stage (pN)

pNX — The lymph nodes could not be assessed, or no lymph nodes were submitted.
pN0 — No tumor was found in any of the lymph nodes examined.
pN1 — Tumor was found in one or more regional lymph nodes.

What is the prognosis?

All well differentiated neuroendocrine tumors of the pancreas are considered malignant, meaning they can spread. However, the outlook is generally much more favorable than for pancreatic ductal adenocarcinoma, the most common type of pancreatic cancer. Many small, low-grade tumors that are confined to the pancreas and completely removed are associated with excellent long-term survival. The outlook is lower when the tumor has spread to distant organs; for tumors that have spread, five-year survival is in the range of 25 to 30 percent, although this varies widely with grade.

Grade is one of the strongest predictors of outcome. In published studies, the risk of tumor recurrence after complete removal increases with the Ki-67 index, from roughly 1 in 7 for tumors with a low Ki-67 to nearly 4 in 10 for tumors with a higher Ki-67. Because of this, higher-grade tumors are watched more closely after treatment.

The following features are associated with a higher risk of spread or recurrence:

Higher grade — A higher Ki-67 index or mitotic count is the most important predictor of how the tumor will behave.
Larger tumor size — Tumors smaller than 2 cm rarely spread, while tumors larger than 3 cm are more likely to spread.
Vascular or perineural invasion — Tumor growing within vessels or along nerves — is associated with a higher risk of spread.
Necrosis — The presence of necrosis (dead tumor tissue) is linked to a higher risk of spread.
Loss of DAXX or ATRX — Loss of these proteins is linked to a higher risk of recurrence.
Spread to lymph nodes or distant organs — Tumor found in lymph nodes or other organs indicates more advanced disease.

What happens after the diagnosis?

Care for a well differentiated neuroendocrine tumor of the pancreas usually involves a team that may include a surgeon, a medical oncologist, an endocrinologist, a radiologist, a pathologist, and a genetic counselor. The findings in your pathology report help the team decide on the next steps.

For tumors that are limited to the pancreas, surgery is the main treatment. The type of operation depends on the tumor’s location and may include a distal pancreatectomy (removal of the end of the pancreas), a Whipple procedure (removal of the head of the pancreas along with part of the small intestine and sometimes the stomach), or removal of just the tumor (enucleation) for small tumors. As noted above, small, low-grade tumors that cause no symptoms are sometimes watched with regular imaging instead of being removed.

For tumors that have spread or that continue to grow, several treatments may be considered, and the choice depends on the grade, the somatostatin receptor status, and the extent of disease. Options include somatostatin analog drugs (octreotide, lanreotide), peptide receptor radionuclide therapy (PRRT) for receptor-positive tumors, targeted drugs (everolimus, sunitinib, or cabozantinib), chemotherapy, and treatments aimed directly at tumor in the liver. An inherited gene change found on testing may lead to a referral for genetic counseling for the patient and their family. Supportive (palliative) care, which focuses on managing symptoms and quality of life, is offered alongside other treatments and is a standard part of care, not only an end-of-life measure. After treatment, follow-up usually includes regular imaging and blood tests to watch for any return of the tumor.

Questions to ask your doctor

Is my tumor functioning or non-functioning, and if functioning, which hormone does it make?
What is the grade of my tumor, and what was the Ki-67 index?
What was the size of the tumor, and what is the pathologic stage (pT and pN)?
How many lymph nodes were examined, and how many contained tumor?
Were the surgical margins negative or positive?
Was perineural or lymphovascular invasion seen in my tumor?
Did testing show loss of DAXX or ATRX, and what does that mean for me?
Does my tumor have somatostatin receptors, and could PRRT or somatostatin analog drugs help?
Should I have germline (inherited) genetic testing, and what would it mean for my family?
Is my tumor better treated with surgery, or could it be watched with imaging?
What treatments are being considered based on these findings?
What follow-up tests will I need to watch for the tumor returning?