Neuroendocrine Neoplasms (NENs) in Complex Genetic Disorders

  • Wouter W. de HerderEmail author
Living reference work entry
Part of the Endocrinology book series (ENDOCR)


Neuroendocrine neoplasms (NENs) represent a group of neoplasms arising from the neuroendocrine cells of the diffuse endocrine system. The majority of gastrointestinal, pancreatic, lung, and thymic carcinoids are sporadic. However, some of the NEN may occur as part of multisystem autosomal-dominant inherited genetic disorders, such as the multiple endocrine neoplasia type 1 (MEN1) syndrome, von Hippel-Lindau disease (VHL), neurofibromatosis type 1 (NF-1), tuberous sclerosis complex (TSC), Mahvash syndrome, and the Pacak-Zhuang syndrome. Over the last three decades, the genetic basis of tumorigenesis in the context of these familial syndromes has been unraveled, thus providing clinicians with useful screening tools for affected families.


MEN1 von Hippel-Lindau (VHL) Neurofibromatosis Pancreas/pancreatic Duodenum Insulinoma Gastrinoma Neuroendocrine neoplasm (NEN) 


Neuroendocrine neoplasms (NENs) can occur either sporadically or in association with multisystem inherited genetic disorders (Table 1) (de Herder and Lamberts 2004; Modlin et al. 2008). The four most common endocrine tumor syndromes are multiple endocrine neoplasia type 1 (MEN1), multiple endocrine neoplasia type 2 (MEN2a and MEN2b), von Hippel-Lindau disease (VHL), and Carney complex (CC). Less commonly, endocrine tumors of the pancreas have been observed in neurofibromatosis type 1 (NF-1), tuberous sclerosis complex (TSC), Mahvash syndrome, and the Pacak-Zhuang syndrome (Table 1) (Carney 1995; Stratakis 2001; Hes et al. 2005; Marini et al. 2006b; Larizza et al. 2009; Orlova and Crino 2010; Thakker et al. 2012; Chou et al. 2013; Darr et al. 2016; Gild et al. 2018; Yu 2018). Recently, reclassification of neoplasms of the anterior pituitary consistent with that used for other NENs into pituitary neuroendocrine tumors (PitNETs) has been proposed (Asa et al. 2017). This review will only focus on tumor syndromes associated with NEN of the digestive tract, pancreas, and carcinoids of the lung and thymus.
Table 1

Hereditary tumor syndromes associated with neuroendocrine neoplasms (NENs)


Neuroendocrine neoplasm (NEN) (frequency)

MEN1 syndrome (MEN1) (MIM 131100) (Wermer syndrome)

Pituitary adenoma (5–65%)

Thymic carcinoid (mostly ♂) (<10%)

Lung carcinoid (20–25%)

Gastric, type 2, NEN (gastrinoma-related) (5–35%)

MEN2a syndrome (MEN2a) (MIM 171400) (Sipple syndrome)

Medullary thyroid carcinoma


MEN2b syndrome (MEN2b) (MIM 162300)

Medullary thyroid carcinoma


Familiarly medullary thyroid carcinoma (FMTC) (MIM 155240)

Medullary thyroid carcinoma

von Hippel-Lindau (VHL) syndrome (MIM 193300)

Pancreatic NEN (5–10%)

Pheochromocytoma (10–20%)

Neurofibromatosis I (NF 1, MIM 162200)

Peri-ampullary NEN (somatostatinoma)


Tuberous sclerosis (TSC, MIM 191100) (Bourneville’s disease)

Pituitary adenoma?

Pancreatic NEN?

Carney complex I (CNC1, MIM 160980)

Pituitary adenoma

Aryl hydrocarbon receptor-interacting protein (AIP) mutations (MIM 605555)

Pituitary adenoma

Chromosome Xq26.3 duplication syndrome (X-LAG)

Acrogigantism (pituitary adenoma)

Carney-Stratakis syndrome (MIM 606864)


MEN-4 (MEN-X) syndrome (MIM 610755)

Pituitary adenoma

Familial paraganglioma syndromes (MIM 115310, MIM 168000, MIM 601650, MIM 605373, MIM 614165)



MAX deletions (MIM 154950)

Pituitary adenoma


Thyroid tumour

Mahvash disease/mutant P86S glucagon receptor (GCGR)

Pancreatic NEN

Pancreatic α-cell hyperplasia

MAFA mutation (MIM 147630)


Pacak-Zhuang syndrome



References: Stratakis (2001), Marini et al. (2006a, b), Vandeva et al. (2010), Chou et al. (2013), Thakker (2014), Darr et al. (2016), Toledo et al. (2017), Daly et al. (2018), Iacovazzo et al. (2018), and Gild et al. (2018)

MEN1 Syndrome

The MEN1 syndrome (MIM 131100) is an autosomal-dominant inherited genetic disorder characterized by hyperplasia and/or multiple adenomas of the parathyroid glands, single or multiple functional/nonfunctional NEN of the pancreas and/or duodenum and stomach, adenomas of the anterior pituitary, carcinoids of the thymus and lung and functioning and nonfunctioning hyperplasia, or adenomas of the adrenal cortex (Figs. 1 and 2). Less common lesions associated with MEN1 include cutaneous lesions like angiofibroma, collagenoma, lipoma and melanoma, and peripheral or central nervous system (CNS) tumors such as ependymoma and meningioma and breast cancer (in female patients) (Leotlela et al. 2003; Marini et al. 2006a; Thakker et al. 2012; Dreijerink et al. 2014; Thakker 2014; van Leeuwaarde et al. 2017; Fig. 3).
Fig. 1

A 67-year-old male with the MEN1 syndrome and duodenal gastrinomas and multiple pancreatic neuroendocrine neoplasms (NENs) – including insulinomas presenting with recurrent hypoglycemias for which he uses frequent meals. In the past he underwent pancreatic body-tail surgeries. 68Ga-NODAGA-exendin PET-CT showed at least five PET-positive lesions in the remaining pancreas, suggestive of multiple insulinomas (images not shown). (a) 68Ga-DOTATATE PET-CT transverse CT image showing a pancreatic NEN/insulinoma (arrow) and multiple scan-positive NEN liver metastases. (bd) Transverse CTs showing a pancreatic NEN (arrow) and multiple hypervascular NEN liver metastases

Fig. 2

A 66-year-old male with the MEN1 syndrome and thymic carcinoid causing compression of the trachea. (a) Transverse and (b) coronal CT showing the thymic carcinoid (box) compressing the trachea

Fig. 3

Upper gastrointestinal endoscopy of the stomach showing thickened gastric folds in a 62-year-old female patient with duodenal gastrinomas and the MEN1 syndrome

The prevalence of the MEN1 syndrome is approximately 0.002–0.02%. MEN1 should be suspected in patients with characteristic endocrine pathology in two out of the three characteristic affected organs or with a characteristic endocrine disorder in one of these organs plus a first-degree relative affected by the MEN1 syndrome (Leotlela et al. 2003; Marini et al. 2006a; Thakker et al. 2012; Thakker 2014; de Laat et al. 2016; van Leeuwaarde et al. 2016).

The MEN1 syndrome is the result of an inactivating mutation of the MEN1 tumor suppressor localized on chromosome 11q13. The MEN1 gene encodes for the 67-kd tumor suppressor protein menin, consisting of 610 amino acids (Chandrasekharappa et al. 1997). More than 300 MEN1 germline mutations have been identified thus far (Lemos and Thakker 2008; Concolino et al. 2016). There is yet no clearly recognizable genotype/phenotype relation among germline MEN1 mutations. Somatic MEN1 mutations have also been reported in sporadic forms of endocrine tumors with variable incidence of 20–40% in pancreatic NEN and lung carcinoids (Leotlela et al. 2003; Jiao et al. 2011). MEN1 patients carrying the p27 rs2066827 variant of the p27 tumor suppressor gene are more likely to have tumors in more endocrine glands (in two to three glands) than those who are not gene carriers (in one to two glands) (Longuini et al. 2014). Missense mutations involving loss of interaction with checkpoint suppressor 1 (FOXN3/CHES1) (associated with DNA repair) correlate with a more aggressive disease course of pancreatic NEN and, therefore, increased NEN-related mortality in MEN1 patients (Bartsch et al. 2014). Similarly, it has been shown that MEN1 patients with mutations in the JunD interacting domain have a higher risk of MEN1-related death (Thevenon et al. 2013).

Clinical screening of patients remains a prerequisite of genetic analysis (Leotlela et al. 2003; Marini et al. 2006a; Thakker et al. 2012; Thakker 2014; de Laat et al. 2016). Patients with MEN1 have a shorter life expectancy than the general population. Nowadays this is mainly caused by MEN1-related NEN (Conemans et al. 2017). The estimated 20-year survival of MEN1 patients is 64% (Leotlela et al. 2003; Marini et al. 2006a; Thakker et al. 2012; de Laat et al. 2014; Thakker 2014; Conemans et al. 2017).

Gastroenteropancreatic (GEP) NENs occur in about 30–80% of MEN1 patients and are the second most frequent clinical manifestation of MEN1 (Leotlela et al. 2003; Alexakis et al. 2004; Marini et al. 2006a; Thakker et al. 2012; Philips et al. 2012; Thakker 2014). Unlike sporadic GEP NEN, they are frequently characterized by multiple tumors that are usually diagnosed a decade earlier than sporadic GEP NEN. About two thirds of these tumors are clinically active (= functional), producing one or more peptides/hormones, which can result in distinct clinical syndromes. The most common functional pancreatic NENs are insulinomas (15%) (Leotlela et al. 2003; Marini et al. 2006a; Thakker et al. 2012; Thakker 2014). (Multiple) insulinomas in MEN1 patients are usually diagnosed before the age of 40 – many times in association with gastrinomas – which is generally earlier than the diagnosis of sporadic insulinomas (de Herder et al. 2006). Gastrinomas represent more than half of all functional GEP NENs in MEN1. The great majority of (multiple) gastrinomas (>90%) in MEN1 patients are located in the duodenum. In MEN1 patients, these tumors can manifest with the typical symptoms of the Zollinger-Ellison syndrome usually also before the age of 40 and are generally diagnosed when metastases have occurred (Jensen 1998; Alexakis et al. 2004; Philips et al. 2012). Gastrinomas represent one of the major causes of morbidity and mortality in MEN1 patients and are associated with a poor prognosis (Jensen 1998; Doherty and Thompson 2003; Ito et al. 2013). Variants of the MEN1 syndrome have been described. One of these, MEN1 Burin, is characterized by a low incidence of gastrinomas (10%) (Hao et al. 2004). Glucagonomas have also been reported in only a few MEN1 cases. Thymic carcinoids almost exclusively occur in male patients with MEN1. Their prevalence is between 3% and 4%, and the 10-year survival of patients with these tumors is approximately 25%.

Lung carcinoids occur in 20–25% of MEN1 patients. MEN1 patients with a lung carcinoid, as compared to those with a thymic carcinoid, have a much better 10-year survival (>70%) (de Laat et al. 2012, 2014; Ito et al. 2013; Pieterman et al. 2014).

The therapy of NEN and NEN syndromes in MEN1 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 MEN1 patients (Thompson et al. 1983; MacFarlane et al. 1995; Jensen 1998; Norton et al. 2001). Gastric NENs in MEN1 patients almost exclusively develop in the presence of the Zollinger-Ellison syndrome (O’Toole et al. 2012). They are generally characterized as type 2 ECL-omas or gastric carcinoids/NEN. These generally well-differentiated lesions usually show a benign clinical course (O’Toole et al. 2012). Surgery for nonfunctioning pancreatic NEN in MEN1 patients is associated with relatively high rates (up to 33%) of major short- and long-term complications (Nell et al. 2018a). It is generally recommended that MEN1 patients with nonfunctioning pancreatic NEN with a diameter <2  cm can be managed by watchful waiting, hereby avoiding major surgery without loss of oncological safety. The beneficial effect of a surgery in nonfunctioning pancreatic NEN with a diameter between 2 and 3  cm in MEN1 requires further research. In MEN1 patients with nonfunctioning pancreatic NEN with a diameter >3  cm, or those increasing in size, surgery is generally recommended (Triponez et al. 2006; Nell et al. 2018b).

Periodic screening for tumor manifestations and subsequent treatment of asymptomatic MEN1 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 MEN1, periodic (biochemical) and radiological screening for pancreatic, thymic, and lung carcinoids is recommended every 1–2 years using thoracic and abdominal CT or MRI (Thakker et al. 2012). There might also be a role for 68Ga-DOTATOC or DOTATATE PET-CT in the follow-up of MEN1 patients (Froeling et al. 2012; Morgat et al. 2016; Albers et al. 2017). In experienced hands, endoscopic ultrasonography (EUS) appears to be the most sensitive localization technique for pancreatic NEN in MEN1 (van Asselt et al. 2015). According to the current guidelines, MEN1 germline mutation testing should be offered to index patients with MEN1 and to their – many times asymptomatic – first-degree relatives from the age of 5 years (Thakker 2014; van Leeuwaarde et al. 2018).

von Hippel-Lindau Disease

von Hippel-Lindau (VHL, MIM 193300) disease is a multisystem autosomal-dominant inherited genetic disorder that may manifest with retinal angiomas, central nervous system 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 (Lonser et al. 2003; Hes et al. 2005; Maher et al. 2011; Gossage et al. 2015; Nielsen et al. 2016). The prevalence of the VHL syndrome is approximately 0.003% (Hes et al. 2005).

The VHL gene is a tumor suppressor gene located on chromosome 3p25-26. The VHL protein binds to elongin C and elongin B, thereby inhibiting transcription elongation, Cul2, and Rbx1 and degrades the α-subunits of hypoxia-inducible factors (HIF). This mechanism is influenced by oxygen. In the absence of the VHL protein, lack of degradation of HIF results in uncontrolled production of factors, like vascular endothelial growth factor (VEGF), that promote formation of new blood vessels and tumor development (Hes et al. 2005; Chou et al. 2013). Germline mutations in the VHL gene are now identifiable in virtually all VHL families (Hes et al. 2005). VHL gene sequencing has been useful in VHL disease for presymptomatic diagnosis (Hes et al. 2005). The exact molecular mechanism of development of NEN in VHL is yet unknown.

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 types 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 (Hes et al. 2005; Chou et al. 2013).

Approximately 60% of VHL patients can develop pancreatic disease including true cysts, serous cystadenomas, metastases (from renal carcinoma), and NEN (in 15%), which can also be cystic (Alexakis et al. 2004; Philips et al. 2012; Charlesworth et al. 2012; van Asselt et al. 2013). Studies also suggest that VHL-related pancreatic NENs are mostly nonfunctional (Hammel et al. 2000; de Mestier and Hammel 2015). VHL-related pancreatic NEN might be distinguished from MEN1-related NEN based on (1) the absence of duodenal tumors, (2) frequent clinically nonfunctional tumors, and (3) frequent occurrence of cystic adenomas around the pancreatic NEN. In VHL patients, for pancreatic NEN with a diameter ≤1 cm in VHL patients, annual follow-up with CT or MRI is recommended. For pancreatic NEN between 1 and 3 cm in VHL, a personalized approach is recommended. NENs >3 cm that are symptomatic or functional or lesions that are increasing in size should be considered for resection (Libutti et al. 1998; Blansfield et al. 2007; Keutgen et al. 2016). For the imaging of pancreatic NEN in VHL patients, not only CT or MRI can be used, but both 68Ga-DOTATOC/DOTATATE PET-CT and EUS also show high detection rates (van Asselt et al. 2016; Prasad et al. 2016).

Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF-1) (von Recklinghausen disease, MIM 162200) is a multisystem autosomal-dominant inherited genetic disorder characterized by neurofibromas, multiple cafe au lait spots, axillary and inguinal freckling, iris hematomas (Lisch nodules), skeletal abnormalities, CNS gliomas, pheochromocytomas and paragangliomas, and occasionally with peri-ampullary somatostatinomas (Relles et al. 2010). The prevalence of NF-1 is about 0.03%.

The NF-1 gene is located on chromosome 17q11.2. It encodes for the protein neurofibromin, which inhibits the intracellular phosphoinositide 3-kinase-protein kinase B-mammalian target of rapamycin (PI3K-AKT-mTOR) pathway, which is important in apoptosis. Loss of function of the NF-1 gene results in mTOR upregulation and tumor development (Larizza et al. 2009; Franz and Weiss 2012).

Approximately 40% of the peri-ampullary somatostatinomas are associated with NF-1 (Relles et al. 2010).

Tuberous Sclerosis Complex

Tuberous sclerosis complex (TSC) (OMIM 191100) is a multisystem autosomal-dominant inherited genetic disorder, which is characterized by hamartomas in several organs, including the brain, heart, skin, eyes, kidneys, lungs, and liver. Prevalence of the TSC is approximately 0.015%.

TSC is caused by inactivating mutations in either of the two genes TSC1 (located on chromosome 9q34 and encoding for the protein hamartin) or TSC2 (located on chromosome 16p13.3 and encoding for the gene product tuberin). Mutations of the TSC1 and TSC2 genes result in an impaired function of the hamartin-tuberin complex, which results in the upregulation of the PI3K-AKT-mTOR pathway (Orlova and Crino 2010; Franz and Weiss 2012).

Pancreatic NENs, mostly insulinomas or nonfunctioning tumors, appear to be more frequent in TSC patients than in the general population. However, it is still unclear whether pancreatic NEN should be considered as a feature of TSC. Current clinical recommendations for TSC do not include routine investigation for pancreatic NEN (Alexakis et al. 2004; Yates 2006; Yates et al. 2011; Philips et al. 2012).



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Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Department of Internal Medicine, Sector of Endocrinology, ENETS Center of Excellence for Neuroendocrine TumoursErasmus MC & Erasmus MC Cancer CenterRotterdamThe Netherlands

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