Pancreatic neuroendocrine tumors (NETs)
What is it?
These are neoplasms originating from endocrine cells of the pancreas (Langerhans islets). These tumors are rare (only 5-10% of pancreatic neoplasms are of endocrine origin), but in recent years their prevalence has increased significantly due to the widespread use of high-quality radiological methods (CT and MRI). In most cases, these tumors grow slowly and are not very aggressive, but sometimes they can grow rapidly and become malignant, even metastasizing at a distance. In less than 10% of cases, tumors originating from endocrine cells in the pancreas are associated with genetically determined hereditary syndromes, such as:
- multiple endocrine neoplasia type 1 (MEN1): it is characterized by primary hyperparathyroidism, pancreatic endocrine tumors, and pituitary adenomas;
- Von Hippel-Lindau syndrome (VHL): it is characterized by a predisposition to develop both benign and malignant neoplasms, including retinal and central nervous system hemangioblastomas, renal carcinomas and cysts, pheochromocytomas (adrenal tumors) and endocrine pancreatic tumors;
- neurofibromatosis type 1 (NF1);
- tuberous sclerosis (TS).
Which are the symptoms?
Endocrine pancreatic tumors (PanNETs) are divided into two groups: functioning tumors (F-PanNETs) and non-functioning tumors (NF-PanNETs). NF-PanNETs, also called “non-secretory” tumors, are the most common (70% of cases) and can become very large, causing symptoms associated with compression of adjacent organs and structures. Functioning tumors (30% of cases), on the other hand, are characterized by excess production of certain specific hormones and are often small in size, as they become visible early due to the appearance of abnormalities associated with increased hormone secretion.
- Insulinoma: this is the most common functioning tumor, the symptoms of which are caused by a decrease in blood sugar levels (glycemia) due to excessive insulin production by the tumor. The patient may experience various symptoms associated with hypoglycemia, such as headache, dizziness, blurred vision, fainting, confusion, personality changes, and in severe hypoglycemia, loss of consciousness, seizures and coma. Nausea, palpitations, tremors, profuse sweating, and, since eating prevents hypoglycemia, there may also be marked weight gain. In 90% of cases, these are single benign neoplasms; patients with MEN1 syndrome are more likely to develop multiple insulinomas.
- Gastrinoma: if the tumor produces gastrin, a hormone that regulates acid secretion in the stomach, there is excessive production of acidic gastric juice, resulting in gastric and/or duodenal ulcers that do not respond to drug therapy. Diarrhea is also present in many patients. They are often multiple tumors (60%) and are sometimes associated with MEN1 syndrome.
- Glucagonoma: if the tumor produces glucagon, a hormone with the opposite function to that of insulin, the main clinical manifestation is hyperglycemia with the development of diabetes mellitus. Weight loss, anemia, venous thrombosis, and a characteristic chronic rash called “erythema migrans necrolyticum” may also occur.
- Somatostatinoma: a very rare functioning tumor characterized by increased somatostatin production and the occurrence of diarrhea, diabetes and gallstones.
- VIPoma: this is a functioning tumor characterized by increased production of vasoactive intestinal peptide (VIP), a hormone responsible for controlling secretion and absorption of water in the intestine. Patients usually have profuse watery diarrhea (up to 20 excretions per day), hypokalemia (low blood potassium levels) and hypo-/achlorhydria (decreased/absent gastric acid secretion).
- Non-functioning tumors: they are not characterized by the clinical syndrome associated with abnormal hormone secretion. For this reason, these tumors are often diagnosed when they reach a significant size, such that they compress or invade adjacent organs and/or structures, or when they have already metastasized to other organs (primarily the liver). However, the picture is changing nowadays, as the use of increasingly accurate radiological techniques has made the accidental finding of small asymptomatic non-functioning neuroendocrine tumors increasingly frequent. The main clinical manifestations of these tumors are: pain, usually not very intense, called heaviness in the upper abdomen; nausea or vomiting if the tumor compresses the stomach or duodenum; jaundice (i.e. yellow skin and eyes) if the tumor compresses the choledochus; and weight loss.
How is it diagnosed?
In the case of F-PanNET, special laboratory tests can detect a hormone produced in excess in the blood (insulin, gastrin, VIP...).
Insulinoma can be diagnosed by measuring blood glucose and insulin levels. A fasting test (prolonged fasting for 72 hours in the absence of symptoms of hypoglycemia) can be useful for diagnosis.
A diagnosis of gastrinoma can be made by measuring blood gastrin levels; if gastrin levels are borderline or undiagnostic, a secretin stimulation test, which causes a rapid increase in blood gastrin levels in patients with gastrinoma, can be used.
The following instrumental examinations are used to confirm the presumptive diagnosis, determine the location of the tumor, assess its relationship to the surrounding structures, and make a judgment about surgical removal:
- computed tomography (CT) with contrast agent: it allows to localize even small lesions, study the relationship with adjacent structures (especially vascular structures) and assess the presence of metastases (in lymph nodes and liver);
- magnetic resonance imaging (MRI) with contrast agent: the information obtained with this technique is similar to that obtained with CT to characterize a primary pancreatic tumor; thanks to the introduction of a hepatospecific contrast agent, it also allows the assessment of liver lesions with suspected metastases with greater precision than a CT examination;
- ecoendoscopy: this examination is similar to gastroscopy, in which an instrument called an endoscope is inserted through the mouth into the stomach and duodenum with a small ultrasound probe attached, allowing accurate visualization of the pancreas through the walls of the stomach and duodenum. It can be particularly useful for detecting very small tumors; it is also a technique that allows a small sample of the tumor (needle aspiration) to be taken for analysis and pathological diagnosis;
- PET gallium 68-DOTA-peptide: it involves the use of a radiopharmaceutical that can bind to somatostatin receptors, which are usually abundantly expressed in neuroendocrine tumors. This type of receptor study allows not only to confirm the diagnosis but also to select patients who may respond to therapy with analogue somatostatin drugs.
- 18F-FDG PET: 18FDG accumulates in neoplastic lesions with high glucose metabolism. The higher the absorption of this tracer, the more aggressive the tumor.
How is it treated?
Treatment of pancreatic neuroendocrine tumors is multidisciplinary and should be appropriate for the type of tumor, the extent of the lesion, and the associated symptoms.
All patients with PanNET who come to us are discussed collegially within the San Raffaele NET Multidisciplinary Group, which meets every two weeks to improve the diagnosis and therapy of these tumors. The multidisciplinary team includes: surgeons, endocrinologists, oncologists, radiologists, pathologists, nuclear physicians, and endoscopists.
- Active surveillance: it is offered to patients with non-functioning, asymptomatic, incidentally discovered neuroendocrine tumors less than 2 cm in size, which usually do not exhibit aggressive characteristics and tend to remain stable in size. Active surveillance includes radiologic examination (ultrasound/magnetic resonance imaging) every 6 months for the first 2 years after diagnosis and every 12 months thereafter.
- Surgery: surgical removal is the method of first choice and can permanently cure the tumor in most cases. Possible interventions are duodenocephalopancreasectomy (DCP), distal pancreasectomy, enucleation or, in rare cases, intermediate pancreasectomy and total pancreasectomy. Some of these operations (distal pancreasectomy, intermediate pancreasectomy and enucleation) can be performed using a minimally invasive laparoscopic access.
- Somatostatin analogues (octreotide/lanreotide): these drugs can be given as monthly injections to patients with neuroendocrine neoplasms that cannot be removed surgically, provided they express somatostatin receptors. These drugs can both slow tumor growth and control symptoms in the case of functioning tumors.
- Radiotherapy: this therapy is usually given to patients with metastatic or inoperable locally spread tumors. It involves the use of a somatostatin analog drug appropriately radioactively labeled (yttrium or lutetium). The radiopharmaceutical administered intravenously recognizes its target by binding the somatostatin analog to its receptors and allows selective irradiation of tumor cells.
- Other antitumor therapies are usually reserved for patients with tumors that cannot be removed surgically or are metastatic, biologically aggressive and/or unresponsive to somatostatin analog therapy. Both conventional chemotherapy and “biological” drugs selectively affecting the mechanisms responsible for growth and metastasis of these tumors (everolimus and sunitinib) are used.
In resectable pancreatic cancer, postoperative adjuvant radiotherapy may be considered for positive lymph node metastases or resection margins. Radical radiotherapy is indicated in patients with unresectable disease. The available technologies, capable of obtaining a high dose conformation with consequent saving of the surrounding risk organs, have made it possible to develop hypofractionation protocols in 15 fractions. Currently, disease control even in advanced cases with combined treatment is around 27 months. In selected cases it is possible to use a hypofractionation with stereotaxic technique in 5 sessions for curative or even symptomatic purposes.
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