Well differentiated neuroendocrine tumour of the pancreas

by Stephanie Reid MD FRCPC
January 30, 2025

---

A well differentiated neuroendocrine tumour is a type of pancreatic cancer that starts from neuroendocrine cells in the hormone-producing (endocrine) part of the pancreas. These tumours are more common in people with a genetic syndrome called multiple endocrine neoplasia type 1 (MEN1), but most people with this tumour do not have any known genetic condition.

Where in the pancreas do these tumours start?

Well differentiated neuroendocrine tumours start in the endocrine part of the pancreas. This part of the pancreas is made up of small, round structures called islets of Langerhans. The cells in these islets act like both nerve cells (neurons) and hormone-producing (endocrine) cells. They receive signals from the nervous system and the bloodstream and respond by producing hormones. These hormones help regulate many body functions, including blood sugar levels. The pancreas makes several hormones, including:

• Insulin – Lowers blood sugar.
• Glucagon – Raises blood sugar.
• Gastrin – Helps with digestion.
• Somatostatin – Regulates other hormones.
• Vasoactive intestinal peptide (VIP) – Controls water and salt balance.

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

The symptoms of a well differentiated neuroendocrine tumour of the pancreas depend on whether the tumour is functioning or non-functioning.

Functioning tumours

Some well differentiated neuroendocrine tumours produce hormones that cause specific symptoms. These tumours are called functioning and are named based on the type of hormone they produce. Symptoms occur when the tumour releases excess amounts of a hormone into the bloodstream, leading to a hormonal syndrome.

Common types of functioning well differentiated neuroendocrine tumours include:

• Insulinoma – Produces insulin, leading to low blood sugar (hypoglycemia), dizziness, sweating, and confusion.
• Glucagonoma – Produces glucagon, leading to high blood sugar (hyperglycemia), weight loss, a specific type of skin rash (necrolytic migratory erythema), and anemia.
• Gastrinoma – Produces gastrin, leading to excessive stomach acid, ulcers, abdominal pain, and diarrhea. This condition is known as Zollinger-Ellison syndrome.
• VIPoma – Produces vasoactive intestinal peptide (VIP), leading to severe watery diarrhea, dehydration, and electrolyte imbalances.
• Somatostatinoma – Produces somatostatin, leading to diabetes, gallstones, and digestive problems due to reduced pancreatic enzyme secretion.
• ACTH-secreting tumour – Produces adrenocorticotropic hormone (ACTH), which stimulates the adrenal glands and leads to Cushing’s syndrome, causing weight gain, high blood pressure, and muscle weakness.

Less common functioning well differentiated neuroendocrine tumours can also produce hormones such as serotonin, growth hormone-releasing hormone (GHRH), parathyroid hormone-related peptide (PTHrP), or cholecystokinin (CCK), leading to other metabolic imbalances.

Non-functioning tumours

Non-functioning, well differentiated neuroendocrine tumours do not produce hormones that cause noticeable symptoms. However, many of these tumours still produce substances like pancreatic polypeptide (PP), somatostatin, and chromogranins, which can be detected in blood tests or by immunohistochemistry but do not cause a specific clinical syndrome.

Because non-functioning tumours do not produce symptoms related to hormone excess, they are often discovered later when they have grown large. Symptoms are usually caused by the tumour pressing on nearby structures in the pancreas. These symptoms include:

• Abdominal pain.
• Nausea.
• Unexplained weight loss.
• Jaundice (yellowing of the skin and eyes) if the tumour is in the head of the pancreas and blocks the bile duct.

At least 15% of non-functioning well differentiated neuroendocrine tumours are found incidentally during imaging studies performed for unrelated reasons. Sometimes, a non-functioning tumour is not diagnosed until it has metastasized (spread) to other body parts, such as the liver. Even in these cases, symptoms may be mild or go unnoticed.

Genetic changes found in well differentiated neuroendocrine tumours

Most well differentiated neuroendocrine tumours of the pancreas occur sporadically, meaning they develop without a known inherited cause. However, in 10–20% of cases, these tumours arise in people with a genetic syndrome that increases the risk of developing tumours in multiple organs.

The genetic syndromes most commonly associated with well differentiated neuroendocrine tumours include:

• Multiple endocrine neoplasia type 1 (MEN1) – The most common inherited cause. People with MEN1 have a mutation in the MEN1 gene, which increases the risk of tumours in the pancreas, parathyroid glands, and pituitary gland.
• Von Hippel-Lindau (VHL) syndrome – A condition caused by mutations in the VHL gene, leading to tumours in the pancreas, kidneys, adrenal glands, and brain.
• Tuberous sclerosis complex (TSC) – A disorder caused by mutations in the TSC1 or TSC2 genes, leading to tumours in the brain, kidneys, skin, and pancreas.
• Neurofibromatosis type 1 (NF1) – A condition caused by mutations in the NF1 gene, leading to nerve tumours and an increased risk of pancreatic neuroendocrine tumours.
• Mahvash disease (glucagon cell hyperplasia and neoplasm syndrome) – A rare genetic disorder that causes excessive growth of glucagon-producing cells in the pancreas.
• Familial insulinomatosis – A rare inherited condition that leads to multiple insulin-producing tumours (insulinomas) in the pancreas.
• Lynch syndrome – A condition caused by mutations in DNA repair genes, increasing the risk of colorectal, uterine, and pancreatic cancers.
• Familial atypical multiple mole melanoma (FAMMM) syndrome – A genetic disorder associated with an increased risk of melanoma and pancreatic cancer.

Even in people without these syndromes, certain inherited DNA repair gene mutations have been found in some cases of well differentiated neuroendocrine tumours. These include mutations in MUTYH, CHEK2, and BRCA2, which are also linked to other types of cancer.

If a genetic syndrome is suspected, your doctor may recommend genetic testing to determine if you have an inherited mutation that increases your risk of developing other tumours.

How is the diagnosis of well differentiated neuroendocrine tumour of the pancreas made?

A well differentiated neuroendocrine tumour of the pancreas is usually diagnosed by taking a small tissue sample. This can be done with a fine needle aspiration biopsy (FNAB) or a needle core biopsy. If the tumour is in a part of the pancreas that is hard to reach with a needle, a special imaging test called an Octreotide scan may help make the diagnosis.

Once the tumour is diagnosed, surgery is often performed to remove it. The type of surgery depends on the tumour’s location:

• Distal pancreatectomy – Removes a tumour from the end of the pancreas.
• Whipple procedure – Removes the tumour and part of the pancreas, small intestine, and stomach.

Microscopic features of this tumour

When viewed under a microscope, well differentiated neuroendocrine tumours of the pancreas have a distinctive growth pattern. These tumours form organized clusters of cells that look similar to normal endocrine cells.

The two most common growth patterns are:

• Solid pattern – Tumour cells form compact, nest-like structures.
• Trabecular pattern – Tumour cells are arranged in thin, ribbon-like strands.

Some tumours combine both patterns. The spaces between the tumour cells (called the stroma) vary, ranging from delicate connective tissue with small blood vessels to dense, fibrous areas. In some cases, the stroma may contain calcium deposits called psammoma bodies.

The tumour cells are usually round or oval with finely granular cytoplasm. Their nuclei contain a characteristic “salt-and-pepper” chromatin pattern, meaning the DNA is arranged in small, irregular clumps. In solid-pattern tumours, the nuclei are centered within the cell, while in trabecular tumours, they are positioned toward the edges.

Most tumours show very little nuclear atypia, meaning the cells resemble normal pancreatic endocrine cells. However, some tumours may contain enlarged nuclei or cells with a clear or rhabdoid (eccentric, irregular) appearance.

A key feature of well differentiated neuroendocrine tumours is their low rate of cell division. Pathologists count the number of mitotic figures (cells undergoing division) to assess how aggressive the tumour is. Most tumours have less than 20 dividing cells per 2mm² of tissue, which places them in the low to intermediate grade range.

Some tumours may also contain small, non-cancerous ducts, acini, or normal pancreatic endocrine islets mixed within the tumour tissue.

Grade

Grade describes how different the cancer cells look from normal cells and how quickly the tumour is growing. The grade for well differentiated neuroendocrine tumours of the pancreas is based on the number of tumour cells actively dividing. These dividing cells are called mitotic figures, and the process is called mitosis.

Your pathologist may also use a special test called immunohistochemistry to measure Ki-67, a protein found in dividing cells. The percentage of cells that test positive for Ki-67 is called the Ki-67 labelling index. If both mitotic count and Ki-67 labelling index are measured, the higher value determines the tumour’s grade.

The grade is important because higher-grade tumours grow and spread more quickly.

Grading system:

• Grade 1: Less than 2 mitoses per 2mm² or Ki-67 index below 3%
• Grade 2: 2 to 20 mitoses per 2mm² or Ki-67 index between 3% and 20%
• Grade 3: More than 20 mitoses per 2mm² or Ki-67 index over 20%

Tumour size

After the tumour is removed, it is measured in millimetres or centimetres. The size of the tumour helps determine its pathologic tumour stage (pT). Larger tumours are more likely to metastasize (spread) to other body parts. Tumour size is usually not reported in a biopsy but is included in the pathology report after surgery.

Perineural invasion

Perineural invasion occurs when cancer cells are found inside or around nerves. Nerves transmit signals, such as pain or temperature, between the body and the brain. Cancer cells can use nerves to spread to surrounding tissues, increasing the risk of tumour recurrence after surgery.

Lymphovascular invasion

Lymphovascular invasion means cancer cells are found inside blood vessels or lymphatic vessels. Blood vessels carry blood throughout the body, while lymphatic vessels carry a fluid called lymph to small immune organs called lymph nodes. Cancer cells can use these vessels to spread to other body parts, such as lymph nodes or distant organs.

Margins

Margins refer to the edges of tissue removed during surgery. A negative margin means no cancer cells are found at the edge, while a positive margin means cancer cells are at the cut edge. Positive margins suggest that some cancer may have been left behind, and additional treatment, such as surgery or radiation therapy, may be needed.

Key margins in the pancreas include:

• Common bile duct margin: The channel connecting the liver to the pancreas.
• Pancreatic margin: The part of the pancreas that was cut to remove the tumour.
• Other margins: These may include the uncinate process (part of the pancreas), duodenum (small bowel), and stomach.

Prognosis

All well differentiated neuroendocrine tumours of the pancreas are considered malignant, meaning they can potentially metastasize (spread). However, the risk of spread varies depending on tumour size, grade, and other microscopic features.

Risk of spread and recurrence

• 55–75% of pancreatic neuroendocrine tumours are diagnosed after they have spread beyond the pancreas, most commonly to the liver, bones, or distant lymph nodes.
• Even after complete surgical removal, 26% of patients experience recurrence, meaning the tumour returns over time.
• The risk of recurrence depends on the Ki-67 labelling index:
  • 14% recurrence rate if Ki-67 is 0–5%.
  • 41% recurrence rate if Ki-67 is 6–20%.

Because of this, higher-grade tumours (those with higher Ki-67 percentages) require closer follow-up after treatment.

Survival rates

• 5-year survival rates are 62% for grade 2 tumours and 29% for grade 3 tumours.
• 91% of patients with Ki-67 0–5% survive at least 10 years after diagnosis.
• Only 26% of patients with Ki-67 6–20% survive 10 years after diagnosis.

Factors affecting prognosis

Several tumour characteristics help predict the risk of spread and long-term outcomes:

• Tumour size – Small tumours (less than 2 cm) rarely behave aggressively, while tumours larger than 3 cm are more likely to metastasize.
• Proliferative rate – The Ki-67 index and mitotic count are the most important factors in predicting tumour behaviour.
• Invasive growth – Tumours that invade blood vessels or lymphatics are at a higher risk of spreading.
• Necrosis (dead tumour tissue) – The presence of necrosis is associated with a more aggressive tumour.

Because small, low grade tumours usually grow very slowly, some experts suggest that asymptomatic tumours under 2 cm could be monitored with imaging rather than removed surgically. However, treatment decisions should always be personalized based on each patient’s situation.