PanNENs are usually sporadic, but they can belong to an inherited syndrome, mainly multiple endocrine neoplasia type 1 (MEN1), which is an autosomal dominant syndrome due to a germline mutation in the MEN1 gene, located on chromosome 11q13 [7]. Other classical features of this syndrome are parathyroid and pituitary tumor/hyperplasia. PanNENs are a frequent manifestation in MEN1, are diagnosed a decade earlier than their sporadic counterpart, and are reported as the cause of death in at least one third of MEN1 patients.

The most common PanNENs in MEN1 are non-functioning forms, with a prevalence ranging from 80 to 100%, whereas gastrinomas and insulinomas, the most frequently functioning tumors, occur with a mean prevalence of 54% (range 20–61%) and 18% (range 7–31%) respectively [8]. PanNENs are often multiple and NF-PanNENs can coexist with insulinomas and gastrinomas in the same patient.

In our experience, in 16 out of 31 (52%) patients with PanNENs associated with MEN1, PanNEN was the manifestation that led to the diagnosis of MEN1, since the almost constant presence of hyperparathyroidism is either very often unrecognized or considered sporadic [9]. Thus, if biochemical screening for MEN1 was performed in all patients with PanNENs, an increased number of sporadic PanNENs would be diagnosed as MEN1. Although the prevalence of PanNENs in MEN1 patients has been assessed in several series, the prevalence of MEN1 in PanNENs has not been evaluated, except in the Italian survey, in which the association of NENs with MEN1 occurred in 1 of every 14 patients [5]. Accordingly, clinical and biochemical screening is mandatory in every PanNEN patient in order to determine whether it represents MEN1 syndrome, especially in patients with co-existing primary hyperparathyroidism and/or pituitary adenoma, in the presence of multiple lesions, and/or patients of young age. The clinical suspicion of MEN1 should always be confirmed by a MEN1 mutational analysis. In the event of a positive result, screening can be performed on all relatives and an early diagnosis of the neoplasms made.

The autosomal dominantly inherited von Hippel Lindau (VHL) syndrome is caused by mutations in the VHL gene, located on chromosome 3p25-26. It is associated with PanNENs in 12.3–30% of cases, as well as with other neoplasms, such as renal cell carcinoma, pheochromocytoma, spinal, central nervous system and retinal hemangioblastoma, endolymphatic sac neoplasm, and epididymal cystadenoma [10]. VHL-associated PanNENs are usually non-functioning and can be malignant in 17% of cases, mainly in tumors > 3 cm in size.

Rarely, PanNENs occur as a component of tuberous sclerosis, another genetic disorder.

From a clinical point of view, NF-PanNENs are defined as tumors without clinical symptoms arising from hormonal hypersecretion. Small incidental NFPanNENs are increasingly being recognized because of the more widespread use of new and more sensitive imaging procedures [11]. Most neoplasms ≤ 2 cm are likely to be benign or intermediate-risk lesions and only 6% of these are malignant when incidentally discovered [12].

However, when NF-PanNENs are diagnosed because they have become symptomatic, they are frequently in an advanced stage, with liver metastases. In these cases, the most frequent presenting symptoms are abdominal pain, weight loss, anorexia, and nausea; less frequently, patients present with intraabdominal hemorrhage, jaundice, or a palpable mass [13]. At first diagnosis, the incidence of liver metastases ranges from 32% to 73%. The median overall survival of patients with NF-PanNENs is 38 months, with a 5-year survival rate of 43%. Factors that are more significantly associated with poor survival are the presence of distant metastases, mainly in liver and bone, and the degree of tumor differentiation [13].

Insulinomas are the most common F-PanNENs, with an annual incidence of four cases in one million people. Moreover, these tumors are the most frequent cause of hyperinsulinemic hypoglycemia in adults. Whereas the mean age of patients presenting with sporadic insulinomas is 45 years (range 8–82), MEN1-associated tumors are typically diagnosed at a younger age (25 years or less). A slight female preponderance (female to male ratio 1.4:1) has also been reported [14].

Malignant insulinomas are seen in < 10% of patients and multiple insulinomas in about 10%, most typically in association with MEN1 syndrome. Extrapancreatic localizations (mainly in the ileum, spleen, and duodenal wall) account for < 1% of the cases.

The clinical presentation of insulinoma has changed over the last few years. Although hypoglycemic symptoms usually appear during fasting, postprandial hypoglycemia, previously considered a very uncommon presentation, is increasingly being reported at the time of diagnosis [15]. In fact, in a large series from the Mayo Clinic, post-prandial hypoglycemia was described in 6% of the patients as the only symptom and in 21% it was associated with fasting hypoglycemia [16]. Symptoms of hypoglycemia can generally be classified into two major groups: neuroglycopenic, due to brain glucose deprivation, and neurogenic, due to adrenergic activation. In the first group, dizziness, tiredness, diplopia, headache, blurred vision, mental confusion, abnormal behavior, epilepsy, and coma are seen, while in the second group sweating, trembling, sensation of warmth, anxiety, weakness, nausea, vomiting, and palpitations are characteristic. Insulinoma should be suspected in the presence of Whipple’s triad (symptoms or signs consistent with hypoglycemia; glucose level < 50 mg/dl; relief of symptoms after administration of glucose). To confirm the diagnosis, the supervised 72-h fasting test is considered the “gold standard” [17], although in a few cases it can produce negative results, especially in patients with post-prandial symptoms [16]. In 2009, the Endocrine Society’s clinical practice guidelines for the management of hypoglycemic disorders established a lower cut-off of insulin of ≥ 3 μ/ml (≥ 18 pmol/l), replacing the previous cut-off of 6 μ/ml (36 pmol/l), in the presence of glycemia < 55 mg/dl, whereas the cut-offs of C-peptide and proinsulin were not modified (respectively, ≥ 0.6 ng/ml or 0.2 nmol/l and ≥ 5 pmol/l ). These new criteria were suggested when, at the end of the 1990s, a more sensitive insulin assay became available. Only after the biochemical diagnosis of insulinoma should imaging procedures be performed, with the aim of localizing the tumor as this is of paramount importance in planning the surgical strategy [15].

Zollinger-Ellison Syndrome (ZES) is a rare endocrine disorder (incidence 1–1.5 cases/million/year) caused by ectopic gastrin hypersecretion from duodenal or pancreatic gastrinomas [18]. Gastrinoma is the second most common type of F-PanNEN after insulinoma [11]. In the sporadic form, it occurs most frequently in individuals between the ages of 48 and 55 years and it is slightly more common in males (54–56%). In 20–30% of patients, ZES is part of MEN1 and symptoms occur at an earlier age (32–35 years).

Clinical presentation is characterized by severe peptic ulcer (75–98% of cases), heartburn (44–56%) nausea/vomiting (12–30%), diarrhea (30–75%), gastrointestinal bleeding (44–75%), and weight loss (7–53%) [19–21]. These symptoms correlate with the high gastric acid output due to gastrin hypersecretion. Disease manifestations have changed recently, reflecting the widespread use of proton pump inhibitors (PPIs). These drugs mask the typical symptoms, resulting in a diagnostic delay that could have a negative impact on clinical course and prognosis. In fact, multiple ulcers or ulcers located in unusual sites are seen less frequently than in the past; instead, nowadays, the majority of ZES patients harbor a single typical duodenal ulcer. Helicobacter pylori is positive in < 50% of patients. In addition, the resolution of diarrhea following PPI use by patients with duodenal ulcer has been advocated as a criterion suggestive of a ZES diagnosis [22]. Although patients with MEN1 most commonly have parathyroid hyperplasia as the initial manifestation, ZES onset can precede the diagnosis of hyperparathyroidism in 45% of cases [23]. Chronic hypergastrinemia in ZES/MEN1 can stimulate the proliferation of parietal cells and gastric enterochromaffin-like cells, leading to gastric carcinoid (type 2) development. Finally, in 6% of patients with ZES, Cushing’s syndrome, due to ectopic ACTH secretion, can complicate the clinical course and worsen the prognosis [18].

In ZES, the primary tumor is located in the duodenum (50–70%) or pancreas (25–40%). Duodenal lesions are even more prevalent in patients with MEN1 (70–90%); these tumors are generally small (< 1 cm) and multifocal. Metastases are very frequent, mainly in patients with pancreatic tumors > 2 cm, and occur firstly in regional lymph nodes and in the liver (70–80% at diagnosis) and later in bones (12%) [1]. The presence of liver metastases has a negative impact on the prognosis and in 25% of patients gastrinoma shows an aggressive behavior, with an overall 10-year survival of 30% [24].

The biochemical diagnosis of ZES requires the demonstration of an inappropriate elevation of serum gastrin in spite of hyperchlorhydria. Accordingly, in these patients autoimmune atrophic gastritis, in which hypergastrinemia is secondary to hypochlorhydria, must be ruled out. Basal gastrin levels elevated > 10-fold, in the presence of gastric pH < 2, is diagnostic of ZES [19]. Since hypochlorhydria induced by PPI is the most frequent cause of high gastrin levels, this class of drugs need to be discontinued at least 1 week before the diag- nostic work-up. In these cases, physicians should be aware of the possible complications due to acid hypersecretion. When diagnosis is equivocal, a positive secretin stimulation test, defined as a gastrin increase > 120 pg/ml over the basal level, is considered diagnostic [19].

The association of refractory diarrhea and hypokalemia was first described by Priest and Alexander [25] and Verner and Morrison [26], in 1957 and 1958, respectively. Only 15 years later, in 1973, the syndrome was correlated with elevated levels of circulating vasoactive intestinal polypeptide l (VIP) and VIPsecreting tumor (VIPoma) [27]. VIPoma is a rare tumor, with an annual estimated incidence of 0.1/million individuals [18]. Its prevalence in PanNENs is 0.6–1% (11) and the mean patient age at presentation is 48–51 years [28, 29].