Gastric and duodenal neuroendocrine tumours

Best Practice & Research Clinical Gastroenterology 26 (2012) 719–735

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Best Practice & Research Clinical Gastroenterology

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Gastric and duodenal neuroendocrine tumours Dermot O’Toole, MD, FRCPI, Associate Professor of Gastroenterology & Clinical Medicine a, *, Gianfranco Delle Fave, MD, PhD, Professor of Medicine b, Robert T. Jensen, MD, Chief, Cell Biology Section c a Department of Gastroenterology and Clinical Medicine, St James’s Hospital and Trinity College, Dublin, Ireland b Department of Digestive and Liver Disease, Ospedale Sant’Andrea, Rome, Italy c Digestive Diseases Branch, NIDDK, NIH, Bethesda, MD, USA

a b s t r a c t Keywords: Neuroendocrine tumours Gastrin Stomach Gastric neuroendocrine tumours Duodenal neuroendocrine tumours

Gastric neuroendocrine neoplasms (NENs) are increasing in frequency and have a varied spectrum with regard to histology, clinicopathologic background, stage, and prognosis. They are usually discovered incidentally, are for the most part benign and are associated with hypergastrinaemia (secondary either to chronic atrophic gastritis or rarely Zollinger–Ellison syndrome; types 1 and 2, respectively) or more rarely sporadic type 3. Applications of recent staging and grading systems – namely using Ki-67 proliferative indices – (from ENETS and WHO 2010) can be particularly helpful in further categorising these tumours. The natural history of Type 1 gastric carcinoids is generally (>95%) favourable and simple surveillance is usually recommended for small (<1 cm) T1 tumours, with local (endoscopic or surgical) resection for larger lesions. Other potential therapies such as somatostatin analogues and gastrin receptor antagonists may offer newer therapeutic possibilities. Rarely, gastric NENs have a malignant course and this is usually confined to Type 2 and especially Type 3 tumours; the latter mimic the biological course of gastric adenocarcinoma and require radical oncological therapies. Most duodenal NENs, apart from gastrinomas (that are not dealt with here) are sporadic and non functional. They are also increasing in frequency probably due to incidental discovery at endoscopy or

* Corresponding author. Tel.: þ353 863728832. E-mail address: [email protected] (D. O’Toole). 1521-6918/$ – see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.bpg.2013.01.002

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imaging for other reasons and this may account for their overall good prognosis. Peri-ampullary and ampullary NENs may have a more aggressive outcome and should be carefully appraised and treated (often with surgical resection). Ó 2013 Elsevier Ltd. All rights reserved.

Introduction Neuroendocrine-derived tumours, originally termed carcinoid tumours, are derived from enterochromaffin or Kulchitsky cells. The term carcinoid was first used by Oberdorfer in 1907 to describe a carcinoma-like tumour, which was considered to have less malignant potential than adenocarcinomas and which may have a broad spectrum of biological behaviours [1,2]. The term neuroendocrine tumour (NET) or neuroendocrine neoplasm (NEN) has supplanted carcinoid in the current nomenclature, although carcinoid tumours may be considered a specific subtype of functioning neuroendocrine tumours that produces serotonin. Gastric and duodenal NENs account for a relatively small and heterogeneous population that differ considerably in clinicopathological, histologic differentiation, stage and prognosis. There have been important additions to the literature on gastric and duodenal NENs, largely on epidemiological and pathological aspects. However, clinical trials are rare and creating large registries will be an important step to further our understanding of these tumours. This review seeks to present an overview of recent developments in understanding of the biology of gastric and duodenal NENs and the current approach to their classification, staging and management. Classification, epidemiology and clinical features (Table 1) Gastric NENs Gastric NENs can be broadly categorised into well and poorly differentiated gastric NETS [3]. These tumours are subdivided into those arising from enterochromaffin cell hyperplasia due to excess gastrin stimulation (Types 1 and 2) and sporadic tumours (that may be well or poorly differentiated tumours) [4] (Table 1). Since the 1950s, there has been a marked increase in the reported incidence of gastric NENs, accounting currently for approximately 1.8% of gastric malignancies compared to 0.3% previously [5]. Age-adjusted incidence rates have shown an 800% increase in incidence in Caucasian females [5]. This may reflect the increased incidence of chronic atrophic gastritis amongst females, increased rates of PPI use or better detection and reporting. While acid suppression with PPIs has been shown to increase gastric NEN formation in rodents [6] this has not been borne out in humans. There has been an 8–9-fold increase in the incidence of gastric NENs reported in two large databases (Florida Cancer data System and SEER registries) over twenty years (1981–2000) [7]. This represents an increase in the ageadjusted incidence from <0.03 per 100,000 population to 0.2. Of these tumours, the majority were localised (94%), with distant metastases in just 1%. The mean age of the patient population was 65 years (21–96 years) [7]. The most frequent gastric NENs is Type I comprising 70–80% of the total, and occur more frequently in women (64.5%), with a mean age of presentation of 63 [2]. Yearly age-adjusted incidence is approximately 0.2 per population of 100,000 [2]. These tumours arise in patients with chronic atrophic gastritis (CAG) – that may be immune or non-immune-related – where the decrease in gastric pH results in compensatory hypergastrinaemia and via binding to CCK-2 receptors, ECL cell hyperplasia [8]. Gastrin signals via the CCK-2 receptor activate protein kinase C and MAP kinase to stimulate an anti-apoptotic effect in AGS-G gastric carcinoma cells stably transfected with the CCK-2 receptor by inducing expression of the anti-apoptotic protein, mcl-1, and mcl-1 expression is also increased in human hypergastrinaemia-associated type I gastric NETs [9]. The relationship between CAG and type I gastric carcinoids was recently examined in a cohort of 367 patients with CAG [10]. Tumours were present at index endoscopy in nine (2.4%) patients and after 1463 person/years, six patients developed type I tumours (annual incidence rate, person-year of 0.4%) [10]. Hypergastrinaemia alone is probably insufficient for tumour development; since chronic PPI use or vagotomy, do not appear to be associated with gastric NETs, and proposed co-factors include genetic,

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Table 1 Characteristics of gastric neuroendocrine tumours. Type 1

Type 2

Type 3

Proportion, % Gastric localisation Endoscopic and morphological characteristics Associated disorders Histology

70–80 Corpus, fundus Single/multiple (60%), small (<1 cm); polyploid or submucosal CAG; achlorhydria Well differentiated

5–6 Body, fundus, antrum Often multiple, small (<1–2 cm); polyploid (sessile) Gastrinoma/MEN-1 Well differentiated

Gastrin Gastric pH Risk of metastases, % Management

[ [ 2–5 - <5 mm: biopsies of the tumour and gastric epithelium (antral and body/fundus) to look for associated CAG and ECL cell hyperplasia; - <10 mm surveillance; - 1–2 cm (uT1 on EUS) – endoscopic resection - >2 cm, uT2 or þ margin following incomplete endoscopic resection discuss surgery (wedge resection) Annual or every two years; biopsies from tumours and looks for associated field defects associated with atrophy-metaplasia-dysplasia sequence

[ Y 10–30 Treatment dictated often by associated gastrinomas or non functioning pancreatic tumours; if treatment of gastric tumour required consider endoscopic resection/surgery

14–25 Antrum Single, large size (>2 cm); occasionally ulcerated Sporadic Well differentiated, poorly differentiated or mixed endo/exocrine Normal Normal 50–100 Oncological surgical resection (partial of total gastrectomy)

Surveillance

Surveillance specific to associated gastrinomas and MEN-1; annual OGD

According to subtype of tumour (at least six months initially)

CAG: chronic atrophic gastritis. ECL: enterochromaffin-like. OGD: oesophagogastroduodenoscopy. MEN-1: multiple endocrine neoplasia type 1.

dietary/environmental, hormones and growth factors and bacteria. The Reg (regenerating gene product) 1a gene, a proliferative suppressor in response to gastrin, may be dysregulated in Type 1 gastric NEN [11]. Gastric NENs are typically found during upper GI endoscopy, often incidentally (explorations for non-specific symptoms or dyspepsia) or during investigations for macrocytic or iron deficiency anaemia [12–16]. The majority of Type I NENs are benign (>95%), often multiple (>60%), usually <2 cm (median diameter 5 mm) and are exclusively localised to the gastric body or fundus [17– 19]. They may present in a wide variety of endoscopic/morphological aspects (Figs. 1 and 2) – sessile, firm, papules, rarely polypoid and may also be detected at biopsies (microcarcinoids, 22%) [3]. Most type 1 gastric NENs are WHO group G1 or G2. Their natural course remains poorly defined but overall survival rates are excellent; disease-specific survival approaches 100% [3]. Presence of metastases, a rare event (<5%) [3,20,21] was the only factor which influenced long-term prognosis in a series of 51 cases [22]. The metastatic potential is proportional to tumour size and more deeply infiltrating tumours, but there is no correlation between the degree of multicentricity and metastases [22–24]. Outcome even in the presence of metastases is reasonable – a 75% 5-year survival compared to 98% for non-metastatic disease was reported [22]. Despite a relatively high frequency of these tumours the published experience on metastases remains relatively limited [22,25–29]. Type II gastric NENs account for 5–8% of gastric NENs, are associated with Multiple Endocrine Neoplasia type 1 (MEN-1) and Zollinger–Ellison syndrome (ZES), and have intermediate malignant potential [30,31]. The synergy of the presence of the tumour-suppressor gene mutation on chromosome 11 and the hypergastrinaemia of ZES associated with MEN-1 promotes the development of gastric NENs in 23% of MEN-1 patients [32,33]. The menin tumour suppressor gene interacts with

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Fig. 1. a: Typical endoscopic appearance of a type 1 gastric neuroendocrine neoplasm (NEN); note the smooth adjacent mucosa in a patient with chronic atrophic gastritis.; b: A type 1 gastrin NEN with a more polypoid appearance; c: this type 1 gastric NEN has a more intra- or submucosal aspect and is well defined on EUS (d) as a well defined hypoechoic 8 mm lesion lying within the submocosal layer and at a distance form the deeper layers (uT1). e: Biopsies (40  magnification) reveal (H&E) features consistent with a well differentiated appearance with polygonal cells with abundant pale cytoplasm; the nuclei are round/oval regular in size and have a granular chromatin pattern with micronucleoli. Diffuse strongly staining for chromogranin A is seen (f). The proliferative index (MIB-1 immunostain for Ki-67) is <2% (G1).

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Fig. 2. Type 1 gastric neuroendocrine tumour that measures 12 mm in the gastric body and was a uT1 on EUS. This lesion was resected using an EMR technique (Duette kit, Cook) following injection of a small amount of methylene blue to lift the lesion from the deep muscle layer. The blue deep submucosa/muscularis propria is seen in the clean base following resection (b). C: Histology (H & E) and immunohistochemistry for chromogranin A is diffusely positive (d) with a low Ki-67 proliferative indeed of 2% (insert, e).

a member of the AP-1/JunD pathway which may be co-stimulated by gastrin [34]. Type II gastric carcinoids are estimated to be >70-fold more frequent in MEN1/ZES patients than those with sporadic ZES (No MEN1), because gastric carcinoids occur in the latter group in <1% of patients [33,35]. Loss of heterozygosity of the MEN-I gene locus on 11q13 has also been described in the other types of gastric NENs – in 17–73% of Type I tumours and 25–50% in Type III tumours [36,37]. Type II NENs display a relatively indolent behaviour but do have a greater metastatic potential than Type I tumours, with approximately 10–30% metastasising [30,31,38]. Where Type I tumours are limited to the mucosa of the body and fundus (Figs. 1 and 2), Type II may also occur in the gastric antrum (Fig. 3). Type III tumours represent approximately 15–20% of gastric NENs, arise sporadically and are the most aggressive gastric NEN subtype; between 50 and 100% metastasise [4,20] (Table 1). Their development and biology is unrelated to gastrin concentration. They are frequently large (>2 cm) and localised in the gastric antrum (Fig. 4). They typically produce 5-hydroxytryptophan (5-HT) rather than serotonin. Carcinoid syndrome is a rare presentation of gastric NENs (<1%) and almost exclusively associated with Type III tumours with associated liver metastases. Some advocate the subdivision of Type III tumours into two groups (Type III and IV), where Type III tumours are sporadic nonfunctioning gastric NETs and Type IV tumours are those that are poorly differentiated or arise from ACTH or serotonin-cells or are of mixed endocrine–exocrine aetiology [22]. The clinical behaviour of all of these tumour types is similar and distinguishing them as separate types, of entities has little clinical utility, at least from a management viewpoint. Mutation of the tumour suppressor gene p53 has been reported to be strongly correlated with Type III tumours and functionally may play a role in stimulating proliferation [39]. Differential gene expression signatures specific to Type III compared with Type I and II gastric NENs has also been found [40]. Of 270 genes differentially altered, CgA [41], MAGE-D2 (adhesin), MTA1 (histone deacetlyase regulator) [42] b and CCN2 (growth factor) [40] can differentiate between Type III and I tumours. Duodenal NENs Duodenal NENs comprises up to 3% of all duodenal tumours [43] and almost 3% of all NEN tumours in the pan SEER Registry (1973–1999) [44–46]. Their incidence is 0.19 in the latest SEER data set [47]. In some studies, duodenal NENs were classified generally into five different tumour types [46,48]. Duodenal NENs comprise largely gastrinomas (not dealth with here), somatostatinomas, non-

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Fig. 3. Example of a Type 2 gastric neuroendocrine neoplasm (NENs) with multiple tumours of various size in the gastric body and proximal antrum (a) and in the 2nd part of the duodenum (b). At EUS of the gastric lesions, the NENs are seen (c, *) as well defined homogeneous hypoechoic uT1 lesions. However, while a 9 mm duodenal tumour is see to be well within the T1 limits (d, *) EUS clearly demonstrates a lymph node adjacent to the duodenal wall (d, arrows).

functional tumours (that may stain for calcitonin and serotonin), duodenal gangliocytic paragangliomas, and high-grade poorly differentiated NECs [48,49] (Table 5). Ampullary or peri-ampullary tumours may have a more aggressive behaviour and pathological expression [50–55]. The latter are frequently associated with von Recklinghausen’s disease [49,53,56–60]. A recent review cites duodenal gastrinomas to be the most frequent (48%) followed by somatostatinomas (44%), non-functional serotonin-containing tumours (28%), non-functional calcitonin-containing NETs (9%) and finally rare gangliocytic paragangliomas or NE carcinomas [46]. Many series include gastrinomas when considering duodenal NENs and this almost certainly skews data with respect to many factors such as size, location and metastatic potential. More than 90% of all duodenal NENs arise in the first and second part of the duodenum [49,61–64] and approximately 20% occur in the periampullary region [49]. They are characteristically small (mean, 1.2–1.5 cm) and [49] and >75% are <2 cm [49,53,63,65,66] (Fig. 5). Most duodenal NENs are T1 but regional lymph node metastases has been reported to occur in 40–60% of cases [48,49,67–69]; this contrasts with a 10% regional metastatic rate in latest SEER data [47]; again, inclusion of gastrinomas may account for these discrepancies. Liver metastases generally occur in <10% of all patients with duodenal NENs [47,49]. Multiple tumours should lead to a suspicion of MEN-1 (the latter is far more frequent occurring in up to 30% of tumours associated with ZES) [46,69,70]. Duodenal NENs present in the 6th decade and there is a slight male predominance (1.5/1 in latest SEER data set) [47]. These tumours are discovered incidentally (up to a third) or due to pain, bleeding or anaemia, jaundice or duodenal obstruction or diarrhoea [46]. Obviously in duodenal NEN associated with gastrinoma symptoms of ZES occur and frank carcinoid syndrome can occur however it is rare (<4%). Other rare presentations include Cushing’s syndrome, acromegaly due to a GRF-secreting tumour, somatostatinoma syndrome, insulinoma, glucagonoma or due to the development of polycythaemia

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Fig. 4. Macroscopic appearance of a Type 3 gastric neuroendocrine tumour found incidentally at upper GI endoscopy. a: Endoscopy reveals a polypoid mucosal/submucosal lesion with poor lifting following saline injection; b: Endoscopic ultrasound demonstrates a hypoechoic submucosal lesion in the distal stomach 1.1 cm extending to involve the deep muscle layer (muscularis propria); c: Gross appearance following partial gastrectomy: 1.3 cm polypoid lesion; d: Transverse section shows a firm, white tumour predominantly submucosal. Na this was found at histology to be a well differentiated tumour with a Ki-67 of 6% (G2) with two positive lymph nodes.

rubra vera [49,57,59,60,71–73]. Periampullary NENs more frequently present with jaundice and are more often associated with von Recklinghausen’s disease (18%) and the presence of somatostatin immunoreactivity (25–100%); however, a clinical somatostatinoma syndrome is very rare with these tumours [49,52,53,58,74,75]. Pathology, staging systems and prognosis Gastric and duodenal NENs typically have a solid, yellow-tan or white gross morphology. As with other NENs, histologically, the tumour cells, with faint pink granular cytoplasm and round nuclei with few mitoses, form trabecular, glandular or rosette-shaped patterns [76]. In a series of 205 gastric NENs, 191 of 193 well differentiated tumours were mainly composed of enterochromaffin-like cells, with two tumours derived from G-cells [27]. There have been case reports of enterochromaffin cell and ghrelinproducing NENs [77]. Type III gastric NETs are occasionally functional and can secrete kinins, prostaglandins, substance P, somatostatin, insulin, corticotrophin and neuron-specific enolase. Sampling gastric and duodenal lesions is usually simple and often biopsies suffice to obtain histological proof. For gastric NENs, biopsies of fundic non-polypoid regions should also be performed to search for atrophic

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Fig. 5. a. Example of a small (<10 mm) non functioning duodenal neuroendocrine neoplasm that was confined to the mucosa and submucosa (b), uT1 and without regional nodes at EUS and was fully excised using an EMR technique. The final histology confirmed a well differentiated NEN (G1) with a Ki-67 <1%.

gastritis [78] and also ECL cell hyperplasia (the predisposing condition leading to Type 1 gastric NENs). In addition, a careful exploration of the stomach in cases of gastric atrophy should be made to examine for field defects and early adenomatous changes (associated with CAG) according to guidelines [3,46,79]. In addition to standard histology with haematoxylin and eosin, staining for chromogranin A and synaptophysin [4,80–83] should be performed. Grading is also mandated with mitotic index/10 HPF and Ki-67 proliferation index calculations [84,85]. Use of the WHO classification to distinguish NEN from NEC, and G1-G3 should also be performed. Duodenal NENs share much homology with their gastric counterparts frequently (80%) showing argyrophilic (silver staining) [58,63,66,86] and being argentaffin-negative (0–12% positive) [58,66,86]. A large proportion synthesise peptides/amines that may be biologically active. Their relative frequency is: gastrinomas (48%), somatostatinomas (43%), non-functioning serotonin-containing tumours (27%), non-functioning calcitonin-containing tumours (9%), NEC G3, and gangliocytic paragangliomas [49]. Duodenal somatostatinomas localise to the periampullary region and approximately half contain psammoma bodies [49,50,58,64–66,87]. Duodenal paragangliomas contain epithelial (PP and somatostatin cells), ganglia, and spindle cells [49,64,88]. They characteristically contain gangliocytic differentiation and S-100 protein-immunoreactive Schwann cells [64,88]. Prognosis and outcome ENETS and World Health Organization 2010 grade and stage classifications (Tables 2–4) were recently tested together with additional clinicopathologic and histologic parameters in a series of 209 gastric NENs (51 G3 NECs and 15 mixed endocrine/exocrine carcinomas or poor outcome separated from 143 G1 or G2 NENs) with a median follow-up of 89 months [89]. Most G1 cases had excellent prognosis, even when metastatic, whereas G2 and G3 neoplasms had worse or very severe prognosis, respectively. ENETs and WHO 2010 proliferative grading system correlated well with patient survival. Standard staging using ENETS system was not effective for well differentiated gastric NENs but modifications and use of a novel T (T1a and T1b or deep submucosal) and N categories (N1, b3 nodes metastases; N2, 3) allowed a simplified, equally informative 3-stage TNM system. Data from the SEER registry reveals that 76% of gastric NENs are localised at time of diagnosis [47]. Survival trends have also improved as an overall five-year survival of 63% was shown compared with previous data which estimated 51% [5]. Clearly, prognosis of gastric NENs varies according to tumour

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Table 2 ENETS TNM staging for gastric neuroendocrine neoplasms [115]. TNM Tdprimary tumour TX T0 Tis T1 T2 T3 T4 Ndregional lymph nodes NX N0 N1 Mddistant metastasis MX M0 M1a Stage Disease stages Stage 0 Stage I Stage IIa Stage IIb Stage IIIa Stage IIIb Stage IV a

Primary tumour cannot be assessed No evidence of primary tumour In situ tumour/dysplasia (<0.5 mm) Tumour invades lamina propria or submucosa and 1 cm Tumour invades muscularis propria or subserosa or >1 cm Tumour penetrates serosa Tumour invades adjacent structures For any T, add (m) for multiple tumours Regional lymph nodes cannot be assessed No regional lymph node metastasis Regional lymph node metastasis Distant metastasis cannot be assessed No distant metastasis Distant metastasis

Tis T1 T2 T3 T4 Any T Any T

N0 N0 N0 N0 N0 N1 Any N

M0 M0 M0 M0 M0 M0 M1

M1 specific sites defined according to Sobin and Wittekind [116].

type. Type 1 tumours, being usually well differentiated and with low Ki-67 (NET G1), generally have an excellent prognosis and early T1 lesions managed endoscopically can achieve close to 100% survival. Size plays an important role in metastatic potential and was recently found to be a stage-independent prognostic factor (3 cm) where only three of 94 tumours 1 cm and only one (a NEC) of 59 tumours <0.5 cm were metastatic at diagnosis or during follow-up [89]. Deep submucosal invasion or angiolymphinvasion have also been proposed as a poorer prognostic indicator [89–92]. Liver metastases are rare. Disease recurrence is infrequent with a recent median recurrence-free survival of 24 months [93]; interestingly in a small proportion of patients 3% developed more aggressive tumour behaviour becoming high grade NECs [93]. Type 2 gastric NENs, displaying intermediate grading (G1 or G2) have a metastatic rate of 10–30%; although given their association with duodenal and pancreatic NENs as part of MEN-1-related ZES, it may be difficult to accurately identify the ‘primary’ lesion responsible for metastases. Outcome in sporadic type 3 tumours is poor with a 25–30% five-year survival rate and a metastatic rate of 50–100% [4,23,94]. Subtypes I and II of gastric NENs are associated with an approximate 80% five-year overall survival and Type III is associated with approximately 33% five-year survival. Diagnostic tests – biological, endoscopy and imaging tests General markers for both gastric and duodenal NENs include serum chromogranin A with or without neuron specific enolase (especially if a G3 NEC is suspected). In addition, functional tumours may also require specific relevant assay estimations (e.g., gastrin, somatostatin, PP) [3,46]. Patients with Type 1 gastric NENs present with elevated serum gastrin (important in making the diagnosis in conjunction with achlorhydria) and serum chromogranin A and levels may be hard to correlate with disease status and generally are not useful as part of follow-up. A diagnosis of auto-immune related CAG is made in the presence of anti-parietal cell or anti-intrinsic factor antibodies (present in 50% of

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D. O’Toole et al. / Best Practice & Research Clinical Gastroenterology 26 (2012) 719–735 Table 3 ENETS TNM staging for duodenal, ampulla and proximal jejunum neuroendocrine neoplasms [115]. TNM Tdprimary tumour TX T0 T1 T2 T3 T4

Primary tumour cannot be assessed No evidence of primary tumour Tumour invades lamina propria or submucosa and size 1 cma Tumour invades muscularis propria or subserosa or size >1 cm Tumour invades pancreas or retroperitoneum Tumour invades peritoneum or other organs For any T, add (m) for multiple tumours

Ndregional lymph nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Regional lymph node metastasis Mddistant metastasis MX Distant metastasis cannot be assessed M0 No distant metastasis Distant metastasis M1b Stage Disease stages Stage I T1 N0 Stage IIa T2 N0 Stage IIb T3 N0 Stage IIIa T4 N0 Stage IIIb Any T N1 Stage IV Any T Any N a b

M0 M0 M0 M0 M0 M1

Tumour limited to ampulla of Vater for ampullary gangliocytic paraganglioma. M1 specific sites defined according to Sobin and Wittekind [116].

cases). Biological assays for associated auto-immune thyroiditis is also useful at baseline. For gastric NENs, genetic testing for hereditary tumour syndrome should only be performed in case of suspected or established diagnosis of ZES. Germline testing for MEN-1 in patients with duodenal tumours is restricted to cases of suspected MEN-1, a family history suggestive of MEN-1 or with multiple duodenal tumours (following genetic counselling). Upper gastrointestinal endoscopy is recommended for all gastric NENs and for small (<1 cm) tumours is usually the only recommended imaging procedure. Here, biopsies from the dominant tumour are required, but in addition it is mandatory to sample the gastric antrum (two biopsies) and body/ fundus (four biopsies) in addition to biopsies of the largest polyps [78]. Endoscopic ultrasound (EUS) enables assessment of the degree of parietal extension (invasion of the muscularis propria) and locoregional lymph node invasion (essential in patients with gastric tumours 1 cm) and is recommended before resection of polyps 1–2 cm in diameter [19] (Figs. 1–4). The same principles hold true for primary duodenal NEN, where axial endoscopy with biopsy is recommended and EUS to confirm the diagnosis and locally stage the disease [46,95]; the latter is especially important as their size is usually small and may be localised to the submucosal and not detected on axial endoscopy. In fact duodenal gastrinomas are hard to detect even with aid of EUS and combination with somatostatin receptor scintigraphy (SRS) or 68-gallium PET-CT can increase detection rates. In cases of sporadic gastric tumours (Type 3), a more extensive imaging protocol should be performed and in addition to Table 4 ENETS Grading system for foregut tumours [115]. Grade

Mitotic count (10 HPF)a

Ki-67 index (%)b

G1 G2 G3

<2 2–20 >20

3 3–20 >20

a 10 HPF: high power field ¼ 2 mm2, at least 40 fields (at 40  magnification) evaluated in areas of highest mitotic density. b MIB1 antibody; % of 2,000 tumour cells in areas of highest nuclear labelling.

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Table 5 Classification duodenal neuroendocirne neoplasms (adapted from [3]). NEN Grade 1

NEN Grade 2

NEC G3

Benign: non-functioning, confined to mucosa-submucosa, non-angioinvasive, <1 cm in size Gastrin-producing tumour (upper part of the duodenum) – Serotonin (5-HT)-producing tumour – Gangliocytic paraganglioma (any size and extension, periampullary) Benign or low-grade malignant (uncertain malignant potential): confined to mucosa-submucosa, with or without angioinvasion, or >1 cm in size – Functioning gastrin-producing tumour (gastrinoma), sporadic or MEN-associated – Non-functioning somatostatin-producing tumour (ampullary region) with or without – Neurofibromatosis type 1 non-functioning serotonin-producing tumour Low-grade malignant: invasion of the muscularis propria and beyond or metastases Functioning gastrin-producing carcinoma (gastrinoma), sporadic or MEN-1-associated – Non-functioning somatostatin-producing carcinoma (ampullary region) with or without neurofibromatosis type 1 – Non-functioning or functioning carcinoma (with carcinoid syndrome) – Malignant gangliocytic paraganglioma High-grade malignant (large cell, small cell carcinoma)

EUS (Fig. 4), axial imaging for loco-regional nodes and liver metastases is recommended along with somatostatin receptor scintigraphy. Axial imaging with triple phase CT scan and/or MRI in conjunction with is recommended for large or suspicious Type 1 tumours and in all Type 2 and Type 3 gastric NENs to stage nodal, liver and bony metastases. Treatment a. Gastric NENs. Surveillance, local resection Management of gastric NENs is determined by subtype, and whether the disease is localised or metastatic. Since the commonest subtype of gastric NEN (Type 1) usually displays a benign and indolent clinical behaviour, simple surveillance or localised endoscopic treatment modalities can be employed for small tumours [26]: tumours <1 cm surveillance can be recommended; tumours between 1 and 2 cm confined to mucosa/submucosa (guided by careful EUS appraisal – uT1) endoscopic resection is recommended with an experienced endoscopist in this field using endoscopic mucosal resection or ESD techniques (Fig. 2) to ensure complete resection. Endoscopic resection can be easily repeated provided tumours do not grow beyond T1 [3,96] and this strategy appears to be universally accepted Nonetheless, recurrences do occur and a recurrence rate in a recent series of patients treated endoscopically was 64% (21/33) at a median of eight months and of these, 67% (14/21) had a second recurrence [19]. The TNM staging system uses 1 cm in size as a cut off to define T1/2 tumours, although there is inconsistency in guidelines as to whether tumours between 1 and 2 cm should be treated with local resection. Surgery should be performed in case of involvement beyond submucosa, or positive margin after endoscopic resection and either a local resection (e.g., wedge resection) and antrectomy or total gastrectomy depending on tumour histological features, invasion and localisation have been recommended. While antrectomy has the theoretical advantage of removing the stimulus for gastrin secretion, this technique have become outdated by many expert groups [25] as the adequacy of antrectomy has been questioned in the past and a simple wedge or localised excision followed by endoscopic surveillance may be more appropriate [3,8,25]. Follow-up for small tumours is annual or every 24-month endoscopies (the latter may be appropriate for stable or non-recurring cases). An octreotide suppression test has been suggested as a means to assess whether type-1 gastric NENs are likely to regress following antrectomy [97] (by assaying serum gastrin concentrations and gastric corpus and tumour histidine decarboxylase mRNA abundances before and 72 h after the administration of 25 mg/h intravenous octreotide and gastric tumour response can be assessed endoscopically

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following subsequent antrectomy). A positive test is not always predictive of tumour response to antrectomy [98]. Other medical therapies Somatostatin analogues (SSA) are known to be potent inhibitors of gastrin secretion [99] from G cells and thus reducing ECL cell hyperplasia. They have been demonstrated to be effective in decreasing the size and number of Type 1 and 2 gastric NENs [21,100,101]. Complete disappearance of the tumours has been reported in up to 70% and with significant reduction in gastrin levels [100]. Use of SSA cannot be universally recommended, for what many believe to be a slow-growing indolent tumours (that are frequently readily controllable using surveillance/endoscopic resection for enlarging tumours); however their use in certain situations needs to be examined (tumours with slightly more aggressive behaviour) [102]. Rebound growth following interruption of SSA therapy has also been suggested at medium term follow-up in a small cohort of patients [103]. SSA cannot be recommended in patients with sporadic Type 3 tumours where full oncological resection (partial or total gastrectomy) with adequate lymph node clearance is the treatment of choice following adequate preoperative staging. For G1 and G2 tumours with advanced but limited disease (e.g., limited liver metastases) amenable to surgery, SSA therapy should be considered following multidisciplinary consultation. Gastrin (CCK-B) antagonist – several gastrin and CCKB receptor antagonists have been tested to try to effect acid-related stimulation over the last 2 decades. Recently netazepide (YF476), a peripheral CCK-B (gastric) inhibitor has been shown to be a potent inhibitor of gastric acid secretion with rapid onset and a prolonged duration. Inhibition of CCK-B receptors with this agent has been found to produce potent ECL-cell inhibition and the development of hypergastrinemia induced G-cell hyperplasia. In Rodents netazepide has anti-tumour effects in various rodent models of gastric carcinogenesis driven by hypergastrinaemia [104–106]. A first report on this agent in patients with Type 1 gastric NENs was recently published [107]. Here eight patients with multiple Type 1 gastric NENs and a background of CAG were treated orally once daily for 12 weeks in an open-label, pilot trial. The therapy was well tolerated and all experience a reduction in the number and size of their largest NEN Serum chromogranin A reduced to normal levels at three weeks and remained so until 12 weeks, but had returned to pre-treatment levels at 24 weeks. ECL hyperplasia and serum gastrin were unchanged by therapy (perhaps related to GAC present in these patients) [107]. Further data are required to substantiate CCKB inhibition as a possible targeted treatment of hypergastrinaemia-induced type 1 gastric NEN but certainly this opens a new potential pathway to target. b. Duodenal NENs Curative resection is possible in the majority of patients with duodenal NENs as only 9% have [47,49] distant metastases at diagnosis [3,6,7,94,98,99,107]. Functional tumours can be treated using SSA to control symptoms prior to considering surgery. Small (<1 cm) T1 tumours can be excised either endoscopically (EMR or ESD) or surgically (formal resections including pancreatico-duodenectomy (PD), duodenectomy and local excision) [46,55,66,108–110]. Therapies for curative resection should be based on the localisation of the tumour and ease at which therapies can be applied as well as staging extent and underlying tumour grade. Tumours close to or involving the ampulla could in theory be cured by local excision and lymph node clearance/sampling but as no correlation between the tumour size and the presence of malignancy [50,54,55,111] has been described an oncological resection (usually pancreaticoduodenectomy) is generally recommended. Treatment of advanced disease Treatment choices and strategies in cases of advanced inoperable stage 3 or 4 disease are similar whether dealing with gastric or duodenal NENs and depend on the following considerations: presence of symptoms, the differentiation and grade of the tumour and the slope or velocity of tumour growth [112,113]. Patients with symptoms due to hormonal hypersecretion often benefit from SSA and these agents should be started early. Moreover, SSA have been shown to exert anti-proliferative effects in

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localised gastric NENs [21,100] however, data on therapeutic effects in the presence of advanced disease is not available. However, like in other gastrointestinal NENs, SSA may be of value in subgroups of patients with slowly progressive low proliferative NET (G1) of gastroduodenal origin although specific data are required to corroborate this. As gastro-duodenal NENs often fell into subgroups of trials on other foregut tumours (especially pancreatic) other possible chemotherapeutic options for well differentiated (G1, G2) gastro-duodenal NENs include systemic chemotherapy with streptozotocin-based regimens, perhaps temozolamide, and newer molecular targeted therapies including sunitinib and everolimus. However, data on the efficacy of such therapies is lacking due to the small numbers of patients treated with advanced gastro-duodenal NENs treated. Loco-regional therapies including trans-arterial hepatic (chemo)-embolisation, radiofrequency or microwave ablation or radioembolisation may be used to treat well differentiated hepatic-predominant disease. Peptide receptor radionuclide therapy with lutetium-177- or yttrium-90-labelled SSA [112–114] may be useful in cases of octreotide-positive tumours although again there is not extensive experience specific to gastroduodenal NENs. Conclusion While gastric NENs are increasing in frequency data are needed to support optimal treatment strategies especially for Type 1 tumours. While endoscopic follow-up is generally recommended and appears acceptable for the majority of patients with gastric Type 1 tumours (combined with local resection as tumours get larger) this could carry could some risk and is expensive and leads to repeated examinations and patient inconvenience. Use of SSA (or other agents targeting perhaps the gastrin receptor) may be beneficial in some situations but has to be tested in large prospective studies. Our aim should be to accurately balance between under and over-treatment to avoid unnecessary side effects and high costs. Better stratification of tumour risk should permit a tailored approach to therapy. Type 2 gastric NENs are managed within the context of MEN-1 associated with ZES and oncological resection should be considered for Type 3 tumours. Most duodenal NENs can be resected locally with the exception of ampullary and peri-ampullary lesions that usually require oncological resection due to the more aggressive patterns of behaviour.

Practice points  Type 1 gastric neuroendocrine neoplasms are usually small and often multiple and develop on a background of atrophic gastritis (auto-immune or not) are by far the most frequent gastric NET;  Endoscopic surveillance of type 1 NENs is recommended for small tumours (<1 cm) and endoscopic resection for lesion >1 cm is recommended but requires expertise endoscopic techniques (EMR or ESD);  Duodenal NENs are rare outside of gastrinomas and usually have a good prognosis, being small and limited to the superficial layers (T1), rendering local therapy possible.

Research agenda  Distinction between gastric and duodenal NENs liable to be more agressive and metastasise merits evaluation;  Detailed studies on the mechanism and durability of somatostatin analogue therapy as antiproliferative agents in gastric type 1 NENs are required;  Role and mechanism of CCK/gastrin receptor inhibition in gastric NENs opens exciting research possibilities

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Conflict of interest statement There is no conflict of interest pertaining to this paper.

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