Insulin-secreting pancreatic tumor is the most common functional pancreatic NEN. In approximately 1 % of patients, extra-pancreatic location is possible (duodenum, stomach, bile ducts, lungs) [4]. Clinical symptoms result from hypoglycemia and neuroglycopenia: skin pallor, increased perspiration, trembling of hands, nausea, palpitations, hunger, headache and vertigo, blurred vision, double vision, changed behavior, confusion, concentration disorders, retrograde amnesia, drowsiness, hallucinations, delusions, convulsions, and loss of consciousness (sometimes accompanied by grandmal convulsions).

Insulinoma is characterized by Whipple’s triad:

They are tumors oversecreting gastrin and thus causing Zollinger-Ellison syndrome (ZES). The most common symptoms of gastrinoma include persistent pain in the upper abdomen, nausea, vomiting, and diarrhea, which disappears after the use of proton pump inhibitors (PPIs) – a very characteristic feature, body weight loss, and gastrointestinal bleeding. There are no differences between the clinical symptoms of pancreatic and duodenal gastrinoma [7].

Helicobacter pylori infection is less frequent in ZES patients compared to idiopathic peptic ulcer disease. Therefore, negative results of Helicobacter pylori tests in pat)ZESients with recurrent peptic ulcer disease who do not receive NSAIDs or acetylsalicylic acid should be suggestive of gastrinoma [2, 8].

VIPoma (Verner-Morrison syndrome, pancreatic cholera, WDHA syndrome): symptoms: diarrhea, hypokalemia, dehydration, acidosis, rarely skin reddening, hypercalcemia, glucose intolerance, and functional gallbladder disorders.

Symptoms of glucagonoma are migrating necrolytic erythema, glucose intolerance, body weight loss, stomatitis, diarrhea, and hypoaminoacidemia.

Symptoms of somatostatinoma include cholelithiasis, diabetes, diarrhea, and body weight loss [2, 9–11].

Biochemical diagnostics of hormones and markers secreted by neuroendocrine neoplasms may be helpful in:

Biochemical diagnosis of functional NENs (F-NENs) requires the evidence of increased serum concentrations of specific hormonal markers, e.g., gastrin in the ZES or insulin in insulinoma (in combination with 72-h fasting assay), etc. If clinical symptoms indicating the hypersecretion of a given hormone occur, other tests may be performed, for instance, demonstration of excessive secretion of gastric juice in ZES, or secretin test can be done in justified cases [12, 13].

Biochemical diagnostics of rare F-PNEN include confirmation of increased serum concentrations of specific biochemical markers, e.g., glucagon in suspected glucagonoma (positive result > 1,000 pg/ml), vasoactive intestinal peptide (VIP) (positive result >170 pg/ml), and somatostatin (positive result in pancreatic tumor location is over 50 times higher than the reference values).

Chromogranin A, which is a nonspecific marker, may only be used to confirm the presence of a neuroendocrine tumor and to monitor the course of the disease, but it cannot constitute the basis for the diagnosis of functioning NENs [3, 9].

Detailed guidelines for laboratory diagnostics are discussed in Chapter 7.

Pathomorphological diagnostics necessary to diagnose GEP NENs are discussed in other chapters.

It is worth emphasizing that demonstrating expression of specific hormones in an immunohistochemical assay does not justify the diagnosis of functional NEN. Only evidence of high blood concentrations of particular hormones confirms such diagnosis.

In the diagnostics of GEP NENs, both anatomic imaging techniques and nuclear medicine tools are used. The choice of imaging examination depends on the primary focus location and the stage of the disease: USG/EUS, CT, MRI, and endoscopy. One of the functional examinations is the somatostatin receptor expression test with ⁶⁸Ga or ⁹⁹Tc-DOTA TOC, which enables the location of the primary lesion, but also assessment of the stage of the disease and qualification for treatment with “hot” somatostatin analogs. PET/CT scan with ¹⁸FDOPA may be an alternative diagnostic method, if the results of the above functional tests are negative. In the diagnostics of insulinoma, the role of a new isotope-labeled GLP-1 analog in detecting small lesions of less than 1 cm is considered [9, 14].

Surgical treatment is the treatment of choice in GEP NENs [1, 2]. Primary tumor resection should be considered even in the presence of metastases, including hepatic metastases, if they are potentially resectable and the patient meets the criteria for the surgery. In advanced functional NENs, cytoreduction is intended to reduce the symptoms and the tumor mass.

Surgical treatment is the therapy of choice in the case of pancreatic neuroendocrine neoplasms (PNENs), as it is associated with a significantly prolonged patient survival. The development of diagnostic methods has improved the detection of small, asymptomatic tumors. Most nonfunctional neoplasms of ≤ 2 cm in diameter are benign and demonstrate a moderate risk of becoming malignant. Only 6 % of the nonfunctional, accidentally diagnosed PNENs present histopathological characteristics of malignancy. In certain cases, accidentally diagnosed tumors of ≤ 2 cm in diameter may be observed for the first year, with tests performed at 3-month intervals, then every 6 months for the next 3 years. Due to the lack of clear recommendations, the decision on the course of treatment should be taken by a multidisciplinary team of doctors experienced in the management of PNENs, and the surgical procedure should be performed in a center specializing in pancreatic surgery [2, 3].

In multiple endocrine neoplasia type 1 (MEN1), if multiple lesions occur, it is recommended to remove them preventively before they become malignant; however, this approach in the case of small, nonfunctional tumors is still controversial [15].

Liver transplantation is conducted in selected groups of patients with exacerbated symptoms associated with hormonal secretion. Patients who may benefit from transplantation are those under the age of 50 years, without metastases outside the liver, and with a low expression of Ki-67 [16–19].

In MEN1 syndrome, surgical resection of the parathyroids in primary hyperparathyroidism reduces excessive secretion of hydrochloric acid [2].

In each case when resection of hepatic metastases is impossible, the recommended palliative treatment methods include hepatic artery embolization (HAE), transarterial chemoembolization (TACE), or HAE with the use of isotope. Radiofrequency thermoablation (RFA), cryoablation, and microwave ablation (MWA) can be used for tumors ≤5 cm. With these different modalities, symptoms improve in 40–80 % of patients [2, 17, 20, 21].

It is of significant importance, and it may be used for symptomatic treatment of:

Recently, single cases of using EUS for ablation of functional pancreatic tumors secreting insulin have been reported [22–24]. It is possible that in the future, endoscopic EUS-controlled ablation of pancreatic NENs, involving administration of cytotoxic agents, alcohol, or using thermoablation, will become an alternative, minimally invasive therapeutic method for patients who cannot be treated surgically [9, 17, 19].

It is the main course of action in the management of hormonal syndromes. The main purpose of pharmacological treatment is maintaining the patient’s good quality of life for the longest possible time, reduction of clinical symptoms, and, if achievable, prolongation of the patient’s survival [8].

Prior to planning the treatment, the tumor size, presence of metastases, histological grading, and the profile of secreted hormones and other markers should be determined.

The choice of the treatment method depends on the symptoms, staging of the disease, the level of radiotracer uptake in receptor scintigraphy, and histological characteristics of the tumor [8, 25].