The four most common endocrine tumor syndromes are multiple endocrine neoplasia type 1 (MEN-1), multiple endocrine neoplasia type 2 (MEN-2a and MEN-2b), von Hippel-Lindau disease (VHL), and Carney complex (CC). Less commonly, endocrine tumors of the pancreas, parathyroids, and adrenal glands have been observed in neurofibromatosis type 1 (NF-1) and tuberous sclerosis complex (TSC) (Table 5.1) [3–10].

According to the Knudson multiple-hit hypothesis, most endocrine tumor-predisposing disorders are related to inactivation of growth suppressor genes, except MEN-2a, MEN-2b, and familial medullary thyroid carcinoma (FMTC) which occur through dominant activation of the RET tyrosine kinase receptor.

This chapter will only focus on tumor syndromes associated with NET of the digestive tract, pancreas, lung, and thymus.

MEN–1 (MIM 131100) is a multisystem autosomal dominant inherited genetic disorder characterized by hyperplasia and/or multiple adenomas of the parathyroid glands, single or multiple NET of the pancreas and/or duodenum and stomach, adenomas of the anterior pituitary, NET of the thymus and lung and functioning and nonfunctioning hyperplasia, or adenomas of the adrenal cortex. Less common lesions associated with MEN-1 include cutaneous lesions like angiofibroma, collagenoma, lipoma, and melanoma and peripheral or central nervous system (CNS) tumors such as ependymoma and meningioma [4, 11–14]. The prevalence of the MEN-1 syndrome is approximately 1 in 20,000–40,000 individuals. MEN-1 should be suspected in patients with characteristic endocrine pathology in 2 out of the 3 characteristic affected organs or with a characteristic endocrine disorder in one of these organs plus a first-degree relative affected by the MEN-1 syndrome [11–15].

In 1903, the autopsy of an acromegalic patient with a pituitary adenoma and enlarged parathyroid glands, suggestive of MEN-1, was described by Jakob Erdheim [16]. In 1927, Harvey Williams Cushing and Leo M. Davidoff reported the first patient with the classic MEN-1 tumor triad [17]. In 1953, Laurentius O. Underdahl, Lewis B. Woolner, and B. Marden Black performed the first review of cases with a syndrome of pituitary, parathyroid, and pancreatic NET [18]. Paul Wermer in 1954 was the first who reported that the MEN-1 phenotype was transmitted in an autosomal dominant inheritance pattern giving the syndrome its initial eponym “Wermer’s syndrome” [19]. The MEN-1 clinical phenotype was subsequently fully characterized in the 1960s when radioimmunoassay’s for peptides and hormones and standard imaging protocols were developed [20].

The MEN-1 syndrome is the result of an inactivating mutation of the MEN-1 tumor suppressor localized on chromosome 11q13. The 7–10 Kb MEN-1 gene was identified in 1997. It encodes for the 67 kd tumor-suppressor protein menin, consisting of 610 amino acids [21–23]. More than 1,100 unique germline mutations and more than 200 somatic mutations have now been identified in MEN-1 family probands [24]. There is no recognizable genotype/phenotype relation among germline and somatic MEN-1 mutations.

Somatic mutations have also been reported in sporadic forms of endocrine tumors with variable incidence of 20–40 % in pancreatic and lung NET [25, 26]. Clinically, mutations of the MEN-1 and DAXX/ATRX genes seem to be associated with a better prognosis of pancreatic NET [25]. Patients with pancreatic NET with mutations in both the MEN-1 gene and DAXX/ATRX survived at least 10 years, whereas patients without these mutations died within 5 years of diagnosis [25].

Clinical screening of patients remains a prerequisite of genetic analysis [11–15]. Patients with MEN-1 have a shorter life expectancy than the general population. Nowadays this is mainly caused by the malignant potential of the MEN-1-related NET. The 20-year survival of patients affected with MEN-1 is estimated to be 64 % [11–15].

Gastroenteropancreatic (GEP) NET occur in about 30–80 % of MEN-1 patients and are the second most frequent clinical manifestation of MEN-1 [11–15, 27, 28]. Unlike sporadic GEP NET, they are frequently characterized by multiple tumors that are usually diagnosed a decade earlier than sporadic GEP NET. About 2/3 of these tumors are clinically active, i.e., producing an excess of one or more peptides/hormones, which cause the distinct clinical syndromes. The most common functional pancreatic NET are insulinomas (15 %) (11–15; 17). Gastrinomas represent more than half of all functional GEP NET in MEN-1. The great majority of (multiple) gastrinomas (>90 %) in MEN-1 patients is located in the duodenum. In MEN-1 patients, these tumors can manifest with the typical symptoms of the Zollinger-Ellison syndrome before the age of 40 and a generally diagnosed when metastases have occurred [27–29]. Gastrinomas represent one of the major causes of morbidity and mortality in MEN-1 patients and are associated with a poor prognosis [29, 30]. Multiple insulinomas in MEN-1 patients are usually also diagnosed before the age of 40 – many times in association with gastrinomas – which is generally earlier than the diagnosis of sporadic insulinomas [31]. Glucagonomas have also been reported in only a few MEN-1 cases.

Thymic NET almost exclusively occur in male patients with MEN-1. Their prevalence is between 3 and 4 %, and the 10-year survival of patients with these tumors is approximately 25 %. Lung NET occur in 20–25 % of MEN-1 patients. MEN-1 patients with a lung NET, as compared to those with a thymic NET, have a much better 10-year survival (>70 %) [32, 33].

The therapy of NET and NET syndromes in MEN-1 patients is essentially not different from the therapies for their sporadic counterparts. However, there is discussion as to whether gastrinoma surgery should be generally attempted in MEN-1 patients [29, 34–36]. Gastric NET in MEN-1 patients almost exclusively develop in the presence of the Zollinger-Ellison syndrome [37, 38]. They are generally characterized as type 2 ECL-omas, or gastric carcinoids. These generally well-differentiated lesions usually show a benign clinical course [38].

Periodic screening for tumor manifestations and subsequent treatment of asymptomatic MEN-1 mutation carriers can prevent complications and may lead to a more favorable course of the disease. Therefore, according to the recently published Clinical Practice Guidelines for MEN-1, periodic radiological (and biochemical) screening for pancreatic, thymic, and lung NET is recommended every 1–2 years using thoracic and abdominal CT or MRI [15]. According to these guidelines, MEN-1 germline mutation testing should be offered to index patients with MEN-1 and to their – many times asymptomatic – first-degree relatives from the age of 5 years [13].

von Hippel-Lindau (VHL; MIM 193300) disease is a multisystem autosomal dominant inherited genetic disorder that may manifest with retinal angiomas, Central Nervous System (CNS) hemangioblastomas (involving the cerebellum, spinal cord, or brainstem), clear cell renal carcinoma, uni- or bilateral pheochromocytoma(s), pancreatic lesions (see later), endolymphatic sac tumors of the middle ear, and papillary cystadenomas of the epididymis and broad ligament [8, 39]. The prevalence of the VHL syndrome is approximately 1 in 36,000 newborns [8].

Patients with VHL may be divided into two groups: type 1 and type 2, both leading to a specific phenotype. Patients with type 1 VHL do not develop pheochromocytoma(s), whereas those from type 2 disease are at high risk for developing pheochromocytoma(s). Type 2 VHL is further divided into type 2A, 2B, and 2C. Patients with type 2A VHL have a low risk for renal clear cell carcinoma in contrast with type 2B VHL, and patients with type 2C VHL develop pheochromocytomas only [8, 40].

In 1904, the ophthalmologist Eugen von Hippel first described retinal angiomas [41]. Arvid Vilhelm Lindau described the hemangiomas of the CNS in 1927 [42].

In a recent review of patients affected by VHL, 60 % of VHL patients had pancreatic involvement including true cysts, serous cystadenomas, and NET (in 15 %) [27, 28, 43]. Studies also suggest that VHL-related pancreatic NET are mostly nonfunctional [44]. VHL-related pancreatic NET might be distinguished from MEN-1-related NET based on the (1) absence of duodenal tumors, (2) frequent clinically nonfunctional tumors, and (3) frequent occurrence of cystic adenomas around the pancreatic NET. Libutti and colleagues have formulated guidelines for the follow-up of pancreatic NET in patients with VHL [45]. For pancreatic NET ≤1 cm, they recommend follow-up with CT or MRI every 12 months; for NET between 1 and 3 cm, a case-by-case assessment is recommended; and NET >3 cm that are symptomatic or functional or lesions that are increasing in size are considered for resection [45].