What are the causes of neuroendocrine pancreatic tumors (pNETs)?
Description of the natural history of ultra-rare paediatric tumours
Genetic origin of pNETs
As it seems, there are several risk factors that may make a child or adolescent more likely to develop a neuroendocrine pancreatic tumor or pNET. These risk factors are basically the presence of mutations in the DNA of pancreatic cells, which can lead to abnormal cell growth.
Approximately 90% of mutations related to the appearance of pNETs are known to be sporadic, meaning they are not inherited. Sporadic mutations are very complicated to detect and diagnose because they are isolated sequences of DNA that are wrongly copied. Random changes are called acquired mutations, because they are adopted after the child is born. These acquired mutations may appear due to the exposure to cancer-causing chemicals such as tobacco or the combustion of carbon, but the vast majority of them are unknown. Exposure to these chemicals may occur during pregnancy, infancy or adolescence.
The other 10% of mutations have an inherited component that increases their risk to develop a NET. These mutations are commonly related to other mutations and other health problems, so they are part of a syndrome and they rarely appear as an isolated tumor. Three different syndromes are known to be responsible for many inherited cases of pNETs. These syndromes are:
- Multiple Endocrine Neoplasia Type 1 (MEN1) syndrome. This syndrome has been related to pancreatic, parathyroid and pituitary gland cancer. Patients with a positive screening for the MEN1 gene can be diagnosed with a NET before the initiation of the symptoms. This is the mutation responsible for most of the inherited pancreatic NETs.
- Von Hipple-Lindau (VHL) syndrome. Mutations of the VHL gene have been associated to NETs, but are responsible for very few of them, especially non-functional slow growing tumors.
- Neurofibromatosis type 1 (NF1) syndrome. NF1 gene mutation has been correlated with somatostatinomas in the pancreas (a type of NET). NF1 gene mutation has also been proven to be determining in the appearance of brain and skin tumors (neurofibromas).
These tumors are interesting because these cells have a common origin in the pancreas but their manifestations are completely different. These tumors are classified in functional and non-functional ones. The main and most important difference is that functional tumors maintain the “functions” of the cell, whilst the other type of tumors are based on cells that de-differentiate or from embryonic cells in the pancreas that still haven not differentiated. These pre-mature or differentiated cells have no function, that is why these tumors are known as “non-functional”.
Symptomatology of functional pNETs
Functional NETs present symptoms that vary depending on the cell type that is affected. Here are some examples of the signs and symptoms caused by these tumors:
If we have a β-cell tumor, too much insulin will be produced and will cause very low blood sugar, leading to blurred vision, weakness, sweatiness, confusion and accelerated heartbeat. These tumors are known as insulinomas.
- Our G-cells are responsible for part of the production of gastrin in our body. If these cells start to replicate and develop into a tumor, too much gastrin will probably cause peptic ulcers due to the increased acidity inside the stomach. These tumors are known as gastrinomas.
- Αlpha cells (α-cells) are in charge of the production of glucagon, which will normally be secreted when blood glucose levels are low. A tumor in the alpha cells of the pancreas can lead to an increased production of this hormone that can lead to skin rashes in our legs and face, high blood sugar levels (which can be translated into frequent urination) and blood clots becasue of the increased glucose levels in the bloodstream. These tumors are known as glucagonomas.
- Too much vasoactive intestinal peptide (VIP), a small peptide produced by the neuroendocrine cells of the pancreas, generates severe watery diarrhea, dehydration and hypopotassemia or low levels of potassium in your blood. The latter can lead to cramps, muscle weakness and numbness. These tumors are known as VIPomas.
How to treat pNETs
Prognosis for functional pNETs is good. Surgery is the usually the best option, because fortunately functional NETs do not metastasize to other tissues because its cells do not tend to widespread. When surgery is not an option (which may be the case) treatment is symptomatic, meaning that our objective is to minimize the comorbidities caused by the tumor, such as high levels of blood-sugar.
Non-functional pNETs, on the other hand are very difficult to diagnose based on clinical knowledge, because symptoms are very vague. They are associated to abdominal pain, diarrhea, indigestion, steatorrhea, jaundice, etc, and, due to these unclear signs, patients are usually diagnosed in late stages of the disease. The treatment differs depending on the type of cell responsible for the tumor, metastasis and the patient’s state. Prognosis for these tumors is not very good, but if detected on time, surgery and the correct chemo or radiotherapy can be applied and the patients and the families can feel optimistic.
Neuroendocrine pancreatic tumors can be either easily treated or highly aggressive. There is very little knowledge about their etiology due to the small number of patients that suffer from this oncological disease and the situation is worse when dealing with children. Share4Rare wants to connect patients dealing with this disease in order to collect medical information and boost research. Join our global community and help us find an effective treatment for pNETs!