Pancreatic Neuroendocrine Tumors

Signs and symptoms differ between functional and non-functional pancreatic NETs.

Symptoms of functional pancreatic NETs

• Insulinomas: Symptoms of low blood sugar including, blurred vision, headache, lightheadedness, fatigue, weakness, irritability, confusion, hunger and increased sweating.
• Gastrinomas: Chronic stomach ulcers, abdominal pain, gastric reflux and diarrhea.
• Glucagonomas: Symptoms of high blood sugar (including headaches, frequent urination, dry skin and mouth, and feeling hungry, thirsty or tired), rashes on the face, stomach or legs, blood clots, diarrhea, unexplained weight loss or sores on tongue or corners of the mouth.
• Somatostatinomas: Symptoms of high blood sugar (including, headaches, frequent urination, dry skin and mouth, and feeling hungry, tired or thirsty), diarrhea, foul-smelling stool that floats, gallstones, jaundice or unexplained weight loss.
• VIPomas: Excess diarrhea, dehydration, muscle ache, weakness or cramps due to low potassium in the blood, abdominal pain or cramps and unexplained weight loss.

Symptoms of non-functional pancreatic NETs

Non-functional pancreatic NETs do not produce large amounts of hormones. This means that these tumors can grow or spread without causing noticeable symptoms. When symptoms do occur, they can include:

• Diarrhea
• Indigestion
• Weight loss
• Pain in the abdomen or back, and possibly a lump in the abdomen
• Jaundice, or yellowing of the skin and whites of the eyes

These symptoms do not always mean you have a pancreatic NET. However, it is important to discuss any of these symptoms with your doctor.

A biopsy, in which a piece of the suspected tumor is removed and then studied, is almost always required to definitively diagnose pancreatic NETs. Several other diagnostic tests may also be used to identify, locate and stage (determine extent of) the disease.

Blood tests

Unusual levels of certain substances may indicate the presence of a pancreatic NET. Blood tests are used to check the levels of these substances, which include:

• Hormones made by functional pancreatic NETs. These include insulin, gastrin, glucagon, somatostatin, pancreatic polypeptide (PP) or vasoactive intestinal peptide (VIP).
• A protein called Chromogranin A (CgA). Levels of this protein can be raised by many medications and conditions, including non-functional pancreatic NETs. It’s sometimes evaluated when a pancreatic NET is suspected, but isn’t definitively diagnostic of the disease.

Imaging tests

Many of the imaging tests and methods that are used to detect and biopsy pancreatic adenocarcinomas are used to diagnose pancreatic NETs. The most common diagnostic imaging method for pancreatic NETs is a CT scan.

In some cases, somatostatin receptor imaging can be used to visualize pancreatic NETs. This method uses a substance called octreotate, which attaches to most pancreatic NETs and can then be seen on imaging tests. These tests are more commonly used in pancreatic NET staging, rather than diagnosis.

Several other specific tests can be used to help diagnose functional pancreatic NETs. The particular tests your doctor orders will be based on your symptoms.

Pancreatic neuroendocrine tumor staging

If you’re diagnosed with a pancreatic NET, your doctor will determine the stage of the disease. Staging is a way of classifying cancer by how much disease is in the body and if it has spread. This helps the doctor plan the best way to treat your pancreatic NET. Once the staging classification is determined, it stays the same even if treatment is successful or the cancer spreads.

(Source: American Joint Committee on Cancer (AJCC) 2018 Staging Manual)

Stage I: The tumor is less than 2 cm and is contained within the pancreas.

Stage II: The tumor is 2 cm or larger and may have grown into nearby organs. This stage is divided into IIA and IIB.

• IIA: The tumor is less than 4 cm and is contained within the pancreas.
• IIB: The tumor is larger than 4 cm and is either still contained within the pancreas or has grown into the small intestine or bile duct.

Stage III: The tumor has grown into nearby organs or blood vessels, or spread to the lymph nodes. This stage is divided into IIIA and IIIB.

• IIIA: The tumor has grown into nearby organs, such as the stomach, spleen, colon or adrenal gland, or into large blood vessels. It has not spread to nearby lymph nodes or distant areas of the body.
• IIIB: The tumor has spread to nearby lymph nodes, but has not spread to distant areas of the body. It may or may not have grown into nearby areas outside of the pancreas.

Stage IV: The tumor has spread to distant areas of the body, and may or may not have grown to nearby areas outside of the pancreas or spread to nearby lymph nodes.

Several types of treatments are used for pancreatic NETs, including:

• Surgery
• Hormone therapy
• Chemotherapy
• Targeted therapy
• Peptide receptor radionuclide therapy (PRRT)
• Liver-directed therapy

Surgery

The best way to treat pancreatic NETs that are contained within the pancreas is through surgery. Many cases can be cured this way. The type of surgical procedure used varies depending on the type, size and location of the tumor.

If the tumor is large, either a pancreatoduodenectomy (or, more commonly, the Whipple procedure) or distal pancreatectomy may be used to remove the parts of the pancreas affected by the tumor. These operations are extremely complex. Studies have shown that they are more successful and have less risk when performed by doctors at major cancer centers with extensive experience.

A central pancreatectomy may be used if the tumor is small and confined to the pancreas. This procedure removes only the small part of the pancreas affected by the tumor.

Sometimes the surgeon can remove the tumor without removing any part of the pancreas. This is called enucleation.

For pancreatic NETs that have spread outside of the pancreas, surgery can be used to reduce some of the negative side effects. In select cases, liver surgery can be used to remove liver metastases.

Hormone therapy

Hormone therapy can be used when surgery is not possible. This therapy uses somatostatin analogues, such as octreotide or lanreotide, to slow a tumor’s growth. It can also be used to prevent the cancer from spreading.

Hormone therapy can also be used to reduce the level of hormones produced by functional pancreatic NETs. This may reduce negative side effects of these tumors.

Chemotherapy

Chemotherapy can be used to stop a tumor from growing, and to shrink larger tumors. Chemotherapy drugs commonly used to treat pancreatic NETs include:

• Doxorubicin
• Streptozocin
• Fluorouracil (5-FU)
• Temozolomide
• Capecitabine

Based on a patient’s ability to tolerate therapy, two or more of the chemotherapy drugs above are typically given in combination. The most common combinations are:

• Temozolomide with capecitabine
• Fluorouracil (5-FU) with doxorubicin and streptozocin

Targeted therapy

Targeted therapies are a type of precision medicine. They slow or stop the growth of cancer by targeting specific features on cancer cells. There are three targeted therapies that are used to treat pancreatic NETs.

• Belzutifan, a targeted therapy for pancreatic NETs caused by von Hippel-Lindau disease (VHL). This therapy blocks a protein that induces tumor growth in VHL-related tumors.
• Everolimus, which blocks one of the ways that cancer cells use to grow and divide.
• Sunitinib, which prevents the tumor from creating new blood vessels, which are needed to grow and survive.

Peptide receptor radionuclide therapy

Peptide receptor radionuclide therapy (PRRT) was recently approved to treat somatostatin-receptor positive pancreatic NETs. This type of radiation therapy uses an intravenous delivery of a radioactive drug called lutetium Lu 177 dotatate. This drug delivers radiation by attaching to the tumor directly.

Liver-directed therapy

When pancreatic NETs spread to the liver, liver-directed therapy can be used. These are procedures performed by specialized interventional radiologists. The doctors inject the therapy, such as radioactive beads, into the blood vessels feeding the liver tumors. This treatment slows the growth of liver tumors and can also shrink them.

Careful observation

Some pancreatic NETs grow so slowly that the risks of treating may outweigh the risks of not treating for a period of time. In these cases, careful observation can be used as a treatment strategy. This can apply to some tumors contained within the pancreas as well some cases of metastatic disease.