Gastrin-secreting tumors (gastrinomas) are the most frequent functioning duodenopancreatic NETs in patients with MEN1 (>50 %), and ~ 20 % of patients with gastrinomas will have MEN1 [42–44]. Gastrinomas occur more often in patients with MEN1 who are older than 30 years; are associated with marked gastric acid secretion and recurrent and severe peptic ulcerations (the Zollinger-Ellison syndrome, ZES), which may perforate; and are usually metastatic at diagnosis [45, 46]. These features are responsible for the major morbidity (peptic ulcer disease, diarrhea and steatorrhea, cachexia, and abdominal pain) and mortality associated with MEN1 [47, 48].

In contrast to the sporadic gastrinomas that occur predominantly in the pancreas, in MEN1, most of these tumors develop in the proximal duodenum [49]. Gastrinomas are usually small (<5 mm) and multiple, growing slowly deep into the mucosa and metastasizing frequently to the peripancreatic lymph nodes and further to the liver [50]. Pancreatic gastrinomas or other extra-pancreatic, extra-duodenal (e.g., ovary, liver, bile duct, pylorus, spleen, mesentery), and extra-abdominal (e.g., cardiac intraventricular septum) locations in MEN1 patients are extremely rare [51, 52]. When found in the pancreas, it may be difficult to distinguish gastrinomas from concomitant nonfunctioning PNETs, and in this eventuality selective arterial secretagogue injection test (SASI test) may help in localizing the gastrin-secreting tumor [43, 53].

The diagnosis is established by demonstration of an increased fasting serum gastrin concentration (found to be elevated in 90–98 % of ZES patients) after stopping antisecretory drugs (proton pump inhibitors, PPIs, at least 1 week; histamine receptors 2 blockers, H2R, for at least 2 days) [54], in association with increased basal gastric acid secretion (gastric pH < 2) [52, 55]. However, stopping antisecretory drugs in ZES patients is often impossible due to severe symptoms of peptic disease and diarrhea and may be hazardous due to possible perforation or bleeding. Occasionally, iv provocative tests with either secretin (2 U/kg) or calcium infusion (4 mg Ca²⁺/kg∙h for 3 h) are required to distinguish patients with ZES from other patients with hypergastrinemia (e.g., those with antral G-cell hyperplasia) [50]. In two-thirds of patients with ZES, fasting serum gastrin levels overlap with values seen in other conditions. In these patients, gastrin provocative tests are needed to establish the diagnosis of ZES [56]. For unknown reasons, secretin stimulates the release of gastrin by gastrinoma cells, and therefore patients with these tumors have a dramatic rise in serum gastrin in response to a secretin infusion. In contrast, normal gastric G cells are inhibited by secretin, and therefore serum gastrin concentrations do not rise in patients with other causes of hypergastrinemia. The secretin stimulation test is performed by administering 0.4 μg of secretin per kg body weight (RepliGen Corporation, Waltham, MA) intravenously over 1 min; a baseline serum gastrin is measured twice before the secretin is administered and classically 2, 5, 10, 15, and 20 min later. An increase of ≥120 pg/mL in gastrin levels is highly suggestive of gastrinoma [56].

In some patients with MEN1, the diagnosis of ZES may be difficult, as it does not appear to develop in the absence of primary hyperparathyroidism, whereas hypergastrinemia has also been reported to be associated with hypercalcemia [54]. Moreover, successful treatment of MEN1-associated PHPT with restoration of normocalcemia is known to ameliorate clinical symptoms and biochemical abnormalities in ~ 20 % of MEN1 patients with ZES [44].

Tumor localization and determination of the tumor extent are essential to the proper management for MEN1 gastrinomas: endoscopic ultrasonography, CT, MRI, selective abdominal angiography, and mainly somatostatin-receptor scintigraphy/Ga⁶⁸-DOTA-TATE/-TOC/-NOC PET-CT are very helpful in localizing the tumor [53, 57]. Moreover, the combination of intra-arterial calcium injections with hepatic venous gastrin sampling has been shown to regionalize the gastrinomas [58]. Importantly, these tumors are often occult to conventional exploration, and their detection requires duodenotomy and meticulous evaluation of the mucosa by eversion and direct palpation [59].

Insulinomas represent between 10 and 30 % of all MEN1-related PNETs, and rarely (in 10 % of patients with MEN1), they may coexist with a gastrinoma or with other nonfunctioning PNETs at the time of diagnosis, in the same patient [9, 68]. In MEN1 patients, insulinomas occur more often at an age younger than 40 years (in many patients even younger than 20 years and in some as young as 5 years), in contrast to the sporadic insulinoma patients in whom the disease occurs usually after the age of 40 years [9, 69]. Insulinoma is the first manifestation of MEN1 in 10 % of patients, whereas ~ 4 % of patients with insulinomas will have MEN1 [5, 66]. The clinical presentation, biochemical and anatomical diagnosis of MEN1-related insulinomas, and the medical and surgical treatment of these patients are similar to those in the sporadic insulinoma patients and are addressed in detail in the “Insulinomas” chapter of this textbook [70, 71].

Glucagon-secreting pancreatic tumors occur in fewer than 3 % of patients with MEN1 (Table 20.1) [5, 50], are highly malignant, and frequently are localized at the tail of the pancreas [5, 72]. Importantly, in MEN1-associated glucagonomas, the characteristic clinical manifestations (such as the necrolytic migratory erythema, weight loss, anemia, or stomatitis) [73, 74] may be absent, and the tumor may be detected in a completely asymptomatic patient with MEN1 undergoing routine pancreatic imaging or detected by glucose intolerance and concomitant increase in glucagon levels [75, 76].

Surgical removal is the treatment of choice. However, up to 80 % of glucagonoma patients have metastatic disease at the time of diagnosis [77], and therefore systemic therapy using SSAs, PRRT, chemotherapy (streptozotocin and 5-fluorouracil), or hepatic artery embolization has been successful in some patients [63, 78–81].

The vasoactive intestinal peptide (VIP) secreting tumors (VIPomas) are rare in MEN1, occur commonly in the tail of the pancreas, and produce a clinical syndrome (Verner-Morrison syndrome) with watery diarrhea, hypokalemia, and achlorhydria (WDHA) [80, 82]. The diagnosis requires excluding laxative and diuretic abuse, demonstration of a large fasting stool volume (0.5–1 l/day) during a fast, and an elevated serum VIP concentration [50].

Surgical excision of VIPomas is the main therapeutic intervention in these patients, with a curative purpose. However, in patients with unresectable or metastatic tumor, systemic treatment with SSAs, chemotherapy (streptozotocin and 5-fluorouracil), corticosteroids, indomethacin, metoclopramide, lithium carbonate, and hepatic artery embolization has been used with different efficacy [37, 38].

NF PNETs represent a heterogeneous group of tumors being increasingly identified as the result of increasing sensitivity of radiological screening methods [40, 41, 83]. Importantly, NF PNETs have been reported to occur in young asymptomatic patients who are even less than 15 years of age. NF PNETs are not associated with a clinical syndrome and may be associated with minor elevation of specific pancreatic hormones (e.g., pancreatic polypeptide) but without clinical symptoms [38].

Identification of NF PNETs is of outmost importance, as they are the most common NETs occurring in the MEN1 setting, they have a well-recognized malignant potential, they are associated with a worse prognosis, and they are the most common cause of death in MEN1 patients [47, 55, 84, 85]. In the absence of specific clinical and biochemical abnormalities, the diagnosis of NF PNETs may be delayed, and therefore radiological screening for enteropancreatic NET in MEN1 is mandatory and should begin at the age of 10 years. The optimal screening method and its timing interval are still controversial and depend on method availability and skills of the performer [48, 83]: endoscopic ultrasound is probably the most sensitive, whereas somatostatin-receptor scintigraphy/gallium-68-DOTA-TATE/-TOC/-NOC PET-CT is the most specific method for detecting metastatic disease. The clinical significance of small NF PNETs (e.g., <1 cm) in asymptomatic individuals is still not fully understood [86].

NETs occur in ~ 3 % of MEN1 patients (Table 20.1), with the lungs, intestinal tract, or thymus being frequent sites of origin. In MEN1 patients, these tumors may be gender related, with a woman predominance for lung NETs and a male predominance for thymic NETs, cigarette smokers having an increased risk for developing these tumors [66, 115, 116]; moreover, there are no hormonal or biochemical abnormalities consistently reported in MEN1 patients with thymic or lung NETs. Importantly, MEN1-associated thymic NETs seem to be particularly aggressive, with a median survival time of approximately 9.5 years and with 70 % of patients dying as a direct result of the tumor [116].

Screening for these NETs is of major importance and their diagnosis depends on the imaging method used and the skills of the radiologist; CT and MRI are sensitive methods, whereas somatostatin-receptor scintigraphy may be useful, although there is still insufficient evidence to recommend its routine use [116, 117]. The current guidelines for the early detection of MEN1-related thymic and lung NETs recommend the use of CT or MRI imaging every 1–2 years (in favor of MRI, as repeated CT exposure to repeated doses of ionizing radiation may be harmful) [117, 118]. Noteworthy, thymic NETs have occurred also after prophylactic thymectomy, suggesting that surveillance imaging is still required [119] even after tumor excision.

Type II gastric NETs are associated with MEN1 and Zollinger-Ellison syndrome, are usually multiple and smaller than 1.5 cm, and may be detected incidentally during endoscopy in these patients [119].

Surgical excision is the treatment of choice [119]. For unresectable or metastatic disease, treatment with somatostatin analogues, such as octreotide or lanreotide, has resulted in improvement in symptoms and tumor regression [119, 120]. In addition, chemotherapeutic agents (e.g., cisplatin, etoposide) or radiotherapy may be used in patients with aggressive tumors [121].

Adrenocortical tumors occur in up to 73 % of the patients with MEN1 (Table 20.1) [83, 122–124] and include adenomas, hyperplasia, cysts, or carcinomas. Most are nonfunctioning [122], whereas functional tumors are reported to occur in less than 10 % of patients, with primary hyperaldosteronism and ACTH-independent Cushing’s syndrome most commonly reported [122]. Pheochromocytomas are rarely described in MEN1 patients, whereas adrenocortical carcinoma is reported to occur in up to 13 % of MEN1 patients, in parallel with a tumor size of more than 1 cm [122].

Biochemical investigation (e.g., plasma renin and aldosterone concentrations, low-dose dexamethasone suppression test or 24-hour urine collection for free cortisol, urinary catecholamines and metanephrines, or plasma metanephrines) should be performed as routine for adrenal tumors. It is recommended that MEN1 patients with adrenal tumors should undergo an annual imaging screening (CT or MRI) of the adrenal glands (Table 20.2) [122, 124].

The treatment of MEN1-related adrenal tumors is similar to that for tumors occurring in the sporadic context. Surgical excision is recommended for adrenal tumors that are more than 4 cm in diameter, or less than 4 cm but with suspicious radiological features, or for tumors with significant growth over a 6-month interval [124].

MEN2A is characterized by the development of MTC in 90 % of adult gene carriers, unilateral or bilateral pheochromocytoma in 50 %, and multigland parathyroid adenoma/hyperplasia with primary hyperparathyroidism (PHPT) in 20–30 % [150–152]. MEN2A accounts for over 75 % of MEN2 [153] and may present as rare variants including familial MTC (FMTC) [151, 154], MEN2A with cutaneous lichen amyloidosis [155, 156], and MEN2A or FMTC with Hirschsprung’s disease [157].

FMTC is historically diagnosed in families with four or more cases of MTC in the absence of pheochromocytoma or parathyroid adenoma/hyperplasia [153, 154] and comprises approximately 10–20 % of cases of MEN2. Because RET accounts for all clinical subtypes of MEN2, FMTC may be viewed as MEN2A with reduced organ-specific penetrance. The age of onset of FMTC is later, and the penetrance of MTC is lower than what is observed in MEN2A and MEN2B [177, 178].

MEN2B comprises approximately 5 % of cases of MEN2, and it is the most aggressive variant of MEN2 syndrome, characterized by MTC and pheochromocytoma, together with a marfanoid habitus and mucosal (lips and tongue) and intestinal ganglioneuromatosis, but not PHPT [186, 187].

CLT values (basal or stimulated by pentagastrin, calcium, or both) are nearly always elevated in MTC [201], being a specific and a sensitive marker, and elevation after surgery suggests persistent or recurrent disease [202]. In provocative testing, plasma CLT concentrations are measured before and 2 and 5 min after intravenous administration of the CLT secretagogue. Reference levels for basal calcitonin vary across laboratories, and usually levels of <10 pg/mL for adult males and <5 pg/mL for adult females are typically considered normal. Furthermore, a basal or stimulated calcitonin level of ≥100 pg/mL is considered an indication for surgery [203, 204]. Preoperative calcitonin testing may be useful for assessing CCH (C-cell hyperplasia) or tumor spread and should be considered when deciding the extent of surgery for MEN2A MTC [205].