current concepts in the diagnosis and management of type 1 gastric neuroendocrine neoplasms

R E V I E W A R T I C L E

Current concepts in the diagnosis and management of type 1gastric neuroendocrine neoplasms

Gregory Kaltsas*, Simona Grozinsky-Glasberg†, Krystallenia I. Alexandraki*, Dimitrios Thomas*, Apostolos V.

Tsolakis‡, David Gross† and Ashley B. Grossman§

*Department of Pathophysiology, National University of Athens, Athens, Greece, †Neuroendocrine Tumor Unit, Endocrinology and

Metabolism Service, Department of Medicine, Hadassah-Hebrew University Hospital, Jerusalem, Israel, ‡Department of Medical

Sciences, Section of Endocrine Oncology, Uppsala, Sweden and §Oxford Centre for Diabetes, Endocrinology and Metabolism,

University of Oxford, Oxford, UK

Summary

The vast majority of gastrin-related gastrointestinal neuroendo-

crine neoplasms (GI-NENs) develop in the context of chronic

atrophic gastritis (type 1), a condition closely related to autoim-

mune thyroid diseases. These neoplasms are defined as gastric

NENs type 1 (GNEN1) and have recently been shown to consti-

tute the commonest GI-NENs in a prospective study. GNEN1s

are usually multiple and follow a relative indolent course, raising

questions regarding the extent that such patients should be

investigated and the appropriate therapeutic interventions

needed. Recently, a number of consensus statements and guide-

lines have been published from various societies dealing with the

diagnosis and management of GI-NENs. Endocrinologists are

among the many different medical specialties involved in

GNEN1s diagnosis and management. However, despite recent

advances, few randomized trials are available, and thus existing

evidence remains relatively weak compared to other malignan-

cies. The purpose of this review is to provide recent evidence

along with currently employed modalities addressing the diagno-

sis, management, long-term follow-up and potential comorbidi-

ties of GNEN1s.

(Received 11 March 2014; returned for revision 7 April 2014;

finally revised 14 April 2014; accepted 15 April 2014)

Introduction

Gastrointestinal neuroendocrine neoplasms (GI-NENs) arise

from cells of the diffuse endocrine system. These tumours can

synthesize, store and secrete amines and peptides that are used

to identify them; in addition, when bioactive, these compounds

can cause distinct clinical syndromes.1 GI-NENs may be

diagnosed on the basis of the presence of symptoms attributable

to clinical syndromes (functioning tumours), but the majority

present with local symptoms and/or mass effects (nonfunction-

ing tumours).1 GI-NENs were originally considered to be rare,

but recent data have suggested that they are increasingly being

diagnosed with an estimated incidence of 2�5–5 cases/100 000/

year.2,3 Although this might be attributed to the increased num-

ber of screening procedures employed, autopsy data have shown

that GI-NENs are probably more common than previously

believed.1,4

The majority of GI-NENs are regarded as well-differentiated

tumours that follow a prolonged course even in the presence of

metastases.1,5–7 In contrast, poorly differentiated GI-NENs, con-

stituting a minority of GI-NENs, follow an aggressive course

similar to small- and large-cell lung carcinomas (SCLC/LCLC),

albeit with a more prolonged survival.8 Since 2006 and after the

implementation of specific classification systems, it has become

apparent that primary site of tumour origin, degree of tumour

cell proliferation based on Ki-67 labelling index (LI) defining

tumour grade and extent of disease based on TNM staging iden-

tify different tumour subtypes and have an impact on progno-

sis9,10 (Tables 1 and 2). Following the diagnosis of GI-NENs, a

meticulous work-up employing biochemical, radiological, radio-

nuclide and histological assessments is required to identify indi-

ces used to predict prognosis and select appropriate treatment

(s).1,11 It is therefore vital for the clinicians to familiarize them-

selves with all recent developments involving diagnostic and

therapeutic approaches to provide evidence-based and cost-effec-

tive patient care.

A recent prospective study has indicated that gastric NENs

(GNENs) are the most common GI-NENs and constitute up to

23% of all GI-NENs recorded over a year.12 Gastric NENs are

further subdivided into types 1–3 on the basis of their pathogen-

esis; types 1 and 2 are usually multiple and related to gastrin hy-

persecretion, in contrast to type 3, which is mostly single and

not gastrin related13 (Table 3). Type 1 GNENs are the result of

excessive gastrin secretion secondary to atrophic gastritis,

whereas type 2 GNENs develop secondary to a gastrin-secretingCorrespondence: Dr. Gregory Kaltsas, Department of Pathophysiology,Medical School of Athens, Mikras Asias 75, 11527, Athens, Greece.Tel.: +30 210 7462513; Fax: +30 210 7462664; E-mail: [email protected]

© 2014 John Wiley & Sons Ltd 157

Clinical Endocrinology (2014) 81, 157–168 doi: 10.1111/cen.12476

tumour of either the duodenum or pancreas, often in the con-

text of multiple endocrine neoplasia type 1 (MEN1).13 While

GNEN type 3 is usually highly malignant resembling gastric car-

cinomas, the vast majority of GNENs are type 1 (GNEN1),

which usually follow an indolent course, although a subset may

become relatively aggressive.7,14,15 Selection of the most appro-

priate treatment modality and follow-up strategy of GNEN1

depends on the associated or underlying disease process, deter-

mined by endoscopic and histological techniques. It is therefore

important to be able to identify GNEN1 at high risk for a more

aggressive course and to utilize targeted diagnostic and

therapeutic approaches in a cost-effective and efficient manner

for the great majority, which have an indolent and essentially

benign course.

Epidemiology

The incidence of GI-NENs is rising as several European and

Asian databases have reported an incidence of 2–3 per 100 000

persons per year.14,16 These findings were also reproduced from

the US data analysis that reported an incidence of 4�4/100 000/

year in Caucasians and much higher in Afro-Americans.2,3,14

Data from the same sources revealed that the incidence of

GI-NENs from some primaries such as stomach and rectum has

increased, whereas those arising from others such as the appen-

dix have decreased.2,3,14 Although it is not clear whether this

high prevalence highlights a true increase in the incidence of GI-

NENs, it is probable that this may be the result of increased

awareness and the number of endoscopic procedures performed

and standardization of pathological reporting.17 Recent studies

have shown that the incidence of GNENs has increased from

0�3% to 1�8% of all gastric tumours,2 whereas a more recent

prospective study has indicated that GNENs represent the most

common GI-NENs identified in up to 23% of cases.12 Type 1

GNENs account for approximately 80% of all GNENs and are

exclusively encountered in patients with atrophic gastritis in the

context of an autoimmune and/or infective process leading to

chronic inflammation and alteration in the normal gastric

mucosa.13,18,19 Chronic atrophic gastritis (CAG) is characterized

by the loss of gastric glandular structures that are replaced by

connective tissue (nonmetaplastic atrophy) and subsequent neu-

roendocrine-cell hyperplasia, or by glandular structures inappro-

priate for this location (metaplastic atrophy).20 The diagnosis of

CAG includes either patients with an exclusively corpus atrophic

involvement, virtually synonymous with autoimmune atrophic

gastritis, or a multifocal atrophic gastritis (patchy areas of atro-

phic-metaplastic changes in the antral and corpus mucosa),

which is almost always a consequence of long-standing Helicob-

acter pylori (H. Pylori) infection.18,21

Although the argument as to whether there is a true increase

in the incidence of GNEN1 is still not settled, there is no doubt

that there will be an increasing number of endoscopic biopsies

revealing neuroendocrine-cell hyperplasia and GNEN1; there is

therefore a need not only to make the correct diagnosis, but also

to provide appropriate management strategies.

Pathogenesis

In response to food and to other stimulants, antral G-cells

secrete gastrin that binds to cholecystokinin (CCK)-2 receptors

located on the membrane of entero-chromaffin-like (ECL) cells,

leading to histamine (H) release; this in turn binds to the H2

receptors on the parietal cells, stimulating gastric acid secre-

tion.22,23 In CAG, the loss of glands in the gastric body and sub-

sequent hypochlorhydria leads to gastrin hypersecretion from

the G-cells of the antrum and enhanced histamine release.

Gastrin exerts trophic effects upon the ECL-cells, leading to

Table 1. ENETS grading system for GI-NENs

Grade Mitotic count (10 HPF)* Ki-67 index (%)†

G1 <2 ≤3G2 2–20 3–20G3 >20 >20

ENETS, European Neuroendocrine Tumour Society; GI-NENs, gastroin-

testinal neuroendocrine neoplasms.

*10 HPF: high-power field = 2 mm2, at least 40 fields (at 9 40 magnifi-

cation) evaluated in areas of highest mitotic density.

†MIB1 antibody: % of 2000 tumour cells in areas of highest nuclear

labelling.

Table 2. TNM staging for GNEN1 proposed by European

Neuroendocrine Tumour Society and AJCC Cancer Staging Manual, 7th

edition

T primary tumour

Tx Primary tumour cannot be assessed

T0 No evidence of primary tumour

Tis Carcinoma in situ/dysplasia (tumour size

<0�5 mm)

T1 Tumour invades muscularis propria or

submucosa

T2 Tumour invades the muscularis propria or

>1 cm in size

T3 Tumour penetrates subserosa

T4 Tumour invades visceral peritoneum or other

organs or adjacent structures

For any T add (m) for multiple tumours

N – regional lymph nodes

Nx Cannot be assessed

N0 None involved

N1 Regional lymph node metastasis

M – distant metastasis

Mx Cannot be assessed

M0 No distant metastasis

M1 Distant metastasis

Disease stage

0 Tis N0 M0

I T1 N0 M0

IIa T2 N0 M0

IIb T3 N0 M0

IIIa T4 N0 M0

IIIb Any T N1 M0

IV Any T Any N M1

© 2014 John Wiley & Sons Ltd

Clinical Endocrinology (2014), 81, 157–168

158 G. Kaltsas et al.

ECL-cell hyperplasia and/or dysplasia, which may result in the

development of GNEN1; GNEN1 along with type 2 GNENs

(GNEN2) are referred to as ECL-omas21–23 (Fig. 1). These

tumours tend to be small, multiple and limited to the mucosa

or submucosa.7 In CAG, complete oxyntic mucosal atrophy also

results in achlorhydria and subsequent intrinsic factor defi-

ciency.24 In addition, due to ECL-cell hyperplasia, their main

secretory product chromogranin A (CgA) is also grossly ele-

vated.25–27 It is of interest that a recent observational study eval-

uating the incidence and prevalence of GNEN1 revealed that

pernicious anaemia was present in 50% of patients.28 This is in

contrast to previous studies that reported that GNEN1 only

developed in patients with pernicious anaemia, suggesting that

other causes of CAG such as chronic inflammatory/infective

states may also lead to GNEN1.29

In autoimmune CAG, high gastrin levels exert trophic effects

on ECL-cells that undergo hyperplasia: in a subset, this may

progress to GNEN1.22 In infective CAG, a multistep process that

starts from H. pylori-related chronic inflammation of the gastric

mucosa progresses to CAG and secondary gastrin hypersecretion,

and ECL-cell hyperplasia, and then this may lead to the develop-

ment of GNEN1.30,31 The severity of inflammation depends on

H. pylori aggressiveness (mediated by CD4+ T cells) and the

patient’s immune response, as patients with H. pylori-related

gastritis can develop parietal cell antibodies, probably due to

molecular mimicry between common epitopes for H. pylori and

the H+/K+ ATPase.32 However, the exact relationship of

H. pylori infection to GNEN1 development is still not clearly

defined. In favour of an aetiological relation are findings from

the Mastomys murine model: these rodents have a polymor-

phism in the CCK-2 receptor gene and hypergastrinaemia,

leading to constitutive activation and a 50–80% probability of

GNEN1 developing within 2 years5,33 that is accelerated in the

presence of H. Pylori-induced hypergastrinaemia.34 However, in

patients with Zollinger–Ellison syndrome (ZES), superimposed

infection with H. Pylori and its treatment had no effect on ECL-

cell hyperplasia or dysplasia.35 In a recent meta-analysis, it was

noted that CAG was more prevalent in H. pylori-positive

patients than in H-pylori-negative ones18 and that the incidence

of CAG in H. pylori-infected patients had a rate ratio of 5%

(95% CI: 3�1–8�3).36The prevalence of GNEN1 in patients with CAG has been

described to range between 1�5% and 12�5%; this wide range

could be the result of patient selection and referral bias.24,37–41

An initial study that evaluated 196 patients with pernicious

anaemia, in which only a minority of patients had gastroscopy,

revealed an incidence of 0�1%.42 A later study reported an inci-

dence of 2%, having evaluated 71 patients with CAG over 416

patient-years.39 Further studies suggested that approximately 5%

of patients with autoimmune CAG tend to develop GNEN1.43,44

However, a recent study reported an incidence of only 0�4%after careful evaluation of a cohort of 367 GNEN1 patients for

1463 patient-years.19 These data indicate that the overall inci-

dence of GNEN1 in patients with CAG varies, but is relatively

small, suggesting that factors other than hypergastrinaemia oper-

ate for hyperplastic ECL-cells to transform to GNEN1. However,

when ECL-cell dysplasia develops, the risk of developing GNEN1

is substantially increased. There also seems to be a relation with

the duration and the age of diagnosis of autoimmune CAG.39,45

Genetics

Gastrin binds to CCK-2 receptors on ECL-cells. Upon binding,

gastrin acts via protein kinase C and MAP kinase to induce

Table 3. Distinctive features of the different types of GNENs (type 1–3)

Type 1 Type 2 Type 3

Prevalence (%) among

gastric NENs

70–80% 5–6% 14–25%

Tumour characteristics Multiple lesions (1–2 cm) Multiple lesions Single

Related to Chronic atrophic gastritis Gastrinomas in the context MEN1 –Grading NEN G1 NEN G1/2 NEN/NEC G2/G3

Serum gastrin levels ↑ to ↑↑ ↑ to ↑↑↑ Normal

Gastric pH ↑ ↓ Normal

Associations ECL hyperplasia ECL hyperplasia

Hyperplastic gastric folds

Normal gastric mucosa

Depth of invasion Muscularis mucosa or submucosa Muscularis mucosa or submucosa Any depth

Histopathology Regular, monomorphic nuclei,

inconspicuous nuclei

Regular, monomorphic nuclei,

inconspicuous nuclei

Large vesicular prominent nuclei, irregular

chromatin, focal necrosis

Mitotic count

Grade

<2/10 HPF

<2% Ki67 LI (G1)

<2/10 HPF

<2% Ki67 LI (G1)

2–20/10 HPF

3–20% Ki67 LI (G2)

Metastases

LMN 5–10% 10–20% (* Duodenal lesions) 50–100%

Liver 2–5% 10% 22–75%Prognosis Excellent Very good Similar to gastric adenocarcinoma

NEN, neuroendocrine neoplasm; G, grade; ECL, entero-chromaffin-like; HPF, high-power field; LI, labelling index; MEN, multiple endocrine neoplasia;

LI, labelling index; LMN, lymph node.

*There is no sufficient data as to whether duodenal lymph node involvement affects survival



Diagnosis and treatment of gastric NEN type 1 159

expression of anti-apoptotic mcl-1 signals leading to ECL-cell

hyperplasia.23 However, hypergastrinaemia alone is not sufficient

to lead to tumour development as chronic use of proton pump

inhibitors (PPIs) or vagotomy that is associated with hypergas-

trinaemia does not seem to cause GNEN1.17,46 This implies that

genetic, nutritional, hormonal and/or infective factors are also

needed for such a tumoral evolution to develop. Animal models,

such as the African rodent Mastomys and Cotton rats, show a

genetic predisposition to GNEN1 development that is acceler-

ated by the administration of acid-suppressive drugs.22 By the

8th week of life, ECL-cell hyperplasia is evident in Mastomys

that progress to neoplasia by 12–16 weeks after PPI therapy.22 It

is therefore plausible to consider that gastrin plays a permissive

role in genetically predisposed individuals. It has also been sug-

gested that mutations of the regenerating gene product (Reg

gene 1a), which counteracts the gastrin-stimulating effect on the

ECL-cells, may be responsible,47 as well as alterations in the

expression of the BCL-2 oncogene.17 Although germline muta-

tions in the MEN-1 locus have not been found in GNEN1, there

is loss of heterozygosity within the 11q13-14 region suggesting a

potential involvement of the MEN-1 gene and/or telomeric

region in their pathogenesis1.15

Clinical presentation

The great majority of GNEN1 are found following upper gastro-

intestinal (GI) endoscopy performed for non-specific symptoms

such as dyspepsia (70%) and/or anaemia (>70%); however,

many patients with CAG may be completely asymptom-

atic.17,31,46 GNEN1 presents as polyps in the gastric body or fun-

dus that are usually multiple with a mean diameter of 5 mm;

however, a significant number are identified only at biopsy25

(Fig. 2). These tumours are not usually associated with a

functional syndrome; an atypical carcinoid syndrome (CS) due

to histamine production is extremely rare.7 GNEN1 has a low

malignant potential, and only a few (<5%) develop metastases;

however, cases where the diagnosis was made from a metastatic

site have been described.7,46,48,49 Although their natural history

is not completely defined, it appears that disease-specific survival

is almost 100%, and even patients with metastatic disease seem

to have a better survival compared with other metastatic

GI-NENs.7,17,50

Diagnostic approach

Most GNEN1s are incidentally diagnosed during upper endo-

scopic GI tract procedures, either for surveillance reasons or

secondary to non-specific symptoms.7,17,46 In addition, the diag-

nosis may be suspected in patients with low vitamin B12 levels,

particularly in the context of endocrine autoimmune disorders –

mainly autoimmune thyroiditis – as approximately 30% of such

patients have serological markers of an underlying autoimmune

CAG.7,45

Biochemical

Gastrin and CgA levels are raised in patients with GNEN1, and

their levels may correlate with the mass of ECL-cells; it has been

shown that serum gastrin in particular also correlates with maxi-

mal tumour diameter.21,26,27 A recent study showed that higher

gastrin and CgA levels were found in patients with CAG and

GNEN1 compared to patients with CAG without GNEN1.19

However, their routine use to identify GNEN1 is not recom-

mended as there are no data to define a cut-off value suggestive

Fig. 1 Pathophysiology of type 1 gastric

neuroendocrine neoplasms (GNEN1s): in chronic

atrophic gastritis, the loss of glands in the gastric

body and subsequent hypochlorydria leads to

gastrin hypersecretion from the G-cells of the

antrum and enhanced histamine release. Gastrin

exerts trophic effects upon the ECL-cells leading to

ECL-cell hyperplasia and/or dysplasia, which may

result in the development of GNEN1. APCA,

antiparietal cell antibodies; ECL, entero-

chromaffin-like cell.




of the presence of a GNEN1 and/or identify a relapse following

removal of such tumours.27 Although the specificity and

sensitivity of CgA in identifying NENs, and thus GNEN1, are

high, there are many causes of false positives. Conditions such

as CAG per se with underlying ECL-cell hyperplasia without

ECL-omas, untreated hypertension, Parkinson’s disease, cardiac,

hepatic and renal impairment, the presence of heterophilic anti-

bodies, pregnancy and particularly PPIs are associated with

increased CgA levels, and thus, its measurement for routine

screening is not recommended.17,46 All GNENs are derived from

the formerly designated ‘foregut’ tumours and have a low

activity of aromatic L-amino acid decarboxylase, which forms

serotonin from the precursor 5-HTP (5-hydroxytryptamine).

Measurement of 5-hydroxyindoloacetic acid (5-HIAA) is there-

fore not useful for GNEN1 diagnosis and is only reserved for

the minority that may be associated with a functional syn-

drome.7 In the extremely rare case of atypical CS, measurement

of histamine metabolites may be useful.25

Due to their aetiological relation to autoimmune endocrine

diseases and/or an underlying inflammatory infective process,

the search for the presence of related disorders should be under-

taken. Antiparietal cell and anti-intrinsic factor autoantibodies

should be performed to identify the cases of autoimmune CAG

along with vitamin B12 levels, thyroid function tests and thyroid

autoantibodies.25 In addition, the H. pylori status should be

assessed.45

As GNEN1 is associated with hypochlorhydria (gastric juice

pH in excess of 4) and atrophic gastritis, some authorities sug-

gest that initial investigation for GNEN1 should include assess-

ment of gastric juice pH.27

Endoscopy

Gastric NEN1 presents mostly as multiple polyps in the gastric

fundus in approximately 65% of cases, with a median diameter

of 5 mm, and exhibiting white macroscopic appearance25,46

(Fig. 3). In approximately 22% of cases, lesions can only be

identified when blind biopsies are taken from the body/fundus

(microcarcinoids) as their size does not allow visual recogni-

tion17,25,46 (Fig. 2). When the size of the lesions is less than

Fig. 2 Layers of gastric wall and schematic representation of gastric wall involvement in GNEN1 according to TNM.




1 cm, no further imaging modality is required; however, in the

case of lesions greater than 1 cm, endoscopic ultrasonography

(EUS) is employed to determine the depth of gastric wall inva-

sion.17,25 EUS permits visualization of tumoral extension beyond

the muscularis propria as well as locoregional lymph invasion

before proceeding to resection7,17,25 (Fig. 3). In a recent multi-

centre study, the mean number of lesions identified at diagnosis

in 111 patients was 3�6 � 3�8 with a maximum diameter of

8 � 12�1 mm.27

Histopathology

Pathological diagnosis is essential and should be performed after

biopsy at initial endoscopic inspection or following tumour

removal. When more than one lesion is present, biopsy should

be performed of all visible tumours along with areas of nonpoly-

poid lesions to verify the presence of CAG and ECL-cell hyper-

plasia.7 The typical appearance of GNEN1 is easily verified on

routine haematoxylin and eosin stains, with cells showing faint

pink granular cytoplasm and round nuclei with very few mitoses

forming trabecular, glandular or rosette-shaped patterns17,21

(Fig. 3). Invasive GNEN1 involves the mucosa and penetrates

the muscularis mucosa to infiltrate the submucosa.21 All

tumours should be stained for the neuroendocrine markers CgA

and synaptophysin and have estimation of their proliferative rate

by assessment of Ki-67 LI immunohistochemically (IHC) to

ensure grading.25,28 The great majority of GNEN1 are G1

tumours with a mean Ki-67 LI of 1�9 � 2�4%.2 Although overt

malignancy is identified by the presence of metastases, GNEN1

designated to have an aggressive course may exhibit nuclear aty-

(a) (b)

(c)

(d)

Fig. 3 (a) Endoscopic appearance of multiple GNEN1 in the context of chronic atrophic gastritis, (b1) endoscopic ultrasonography (EUS) appearance

of the layers of the stomach (b2), EUS revealing a GNEN1 with extension into submucosa, (c) endoscopic mucosal resection of GNEN1, (d) histology

of GNEN1.




pia, increased mitotic index (>10 mitoses per HPF), angioinva-

sion, high Ki-67 LI (>2%) and/or necrosis.7,49,51

Entero-chromaffin-like cell hyperplasia can be diffuse, linear,

nodular and adenomatoid; the latter two can be detected by

simple microscopy,21 whereas the diffuse and linear forms

require proper IHC with neuroendocrine markers.21,28 Alterna-

tively, vesicular monoamine transporter-2, a component of the

vesicular membrane, can be used to identify ECL-cells with

high accuracy.52,53 ECL-cell linear hyperplasia is defined by

the presence of linear groups of five consecutive neuroendo-

crine cells lining a gland per millimetre, or linear groups in 1

HPF, whereas micronodular hyperplasia consists of clusters of

5 or more neuroendocrine cells bounded by a basement mem-

brane <150 lm in diameter.21 Even in the absence of a

tumour, the presence of ECL-cell hyperplasia is important as

it confers a 26-fold increase in the risk of developing ECL-

omas, particularly in dysplastic (150–500 lm with enlarged

nuclei) lesions24; diffusely hyperplastic lesions show at least a

doubling ECL-cell numbers.21 With severe hypergastrinaemia,

ECL-cells form adenomatoid lesions with multiple membrane-

bound micronodules within strands of lamina propria. Such

lesions can either be intramucosal GNEN1 and/or infiltrate

the submucosa; however, such lesions still do not indicate

malignancy17,21 (Fig. 2).

Radiology – nuclear medicine

Imaging of the abdomen and pelvis [with either computerized

tomography (CT) of magnetic resonance imaging (MRI)] has

been the standard means to assess local and distant spread, and

along with somatostatin receptor imaging (SRI), it is used as

staging imaging modality for GI-NENs.7 However, their use has

been questioned for GNEN1 staging as the great majority of

these tumours are confined to the mucosa or submucosa of the

stomach.7 A recent multicentre study evaluating 111 patients

revealed that abdominal imaging and SRI studies showed pathol-

ogy in 8% and 10%, respectively, without, however, revealing

previously unidentified lesions.27 Therefore, imaging modalities

should be restricted to large tumours or those at high risk of an

aggressive course.

Prognosis

Type 1 GNENs are well-differentiated, mostly grade 1 (Ki-67

<2%), tumours that in general have an excellent prognosis as

lesions (T1) confined to the mucosa/submucosa can be safely

removed endoscopically, achieving a near 100% survival.7,16,17,46

However, the great majority of cases will relapse, with a med-

ian recurrence-free survival of 24 months, but only a minority

will develop metastatic disease.7,16,17,46 However, even in the

presence of metastases, prognosis is relatively good, with 75�5%of 5-year survival compared with 98% for nonmetastatic

GNEN1.31 Metastatic potential is related to tumour size and

depth of infiltration, but not multicentricity.1,17,34,46 Size is cru-

cial and stage independent in predicting metastatic potential, as

in patients with a tumour size of ≥3 cm virtually all develop

metastases compared with only 3/94 <1 cm during follow-up.28

Deep mucosal invasion or angiolymphatic invasion can also be

a poor prognostic factor; invasion of deep submucosa seems to

confer increased malignant potential compared to superficial

submucosa invasion.21,28 In a recent study of 984 patients with

localized GNEN1, tumour size and depth of invasion predicted

lymph node metastasis.54 However, despite the increasing fre-

quency of GNEN1, published experience on metastases has

been relatively limited.13,31,43,55 In a recent multicentre study of

254 patients with GNEN1, 20 (7�9%) were found to have

metastases (12 lymph node and eight hepatic metastases); these

patients had a mean primary tumour diameter of

20�12 � 10�83 mm (mean � SD) and a mean Ki-67 LI of

6�8 � 11�2%, supporting the significance of these parameters

as important risk factors for a more aggressive course.49 In

addition, patients with metastases were younger and had higher

gastrin levels, but all remained alive after a mean follow-up

period of 83 months.49

Treatment

Management approaches have evolved along with advances in

endoscopic staging and information that have been acquired

regarding the biology and natural history of GNEN1. Their

treatment depends on the number, size and degree of extension

of the lesion(s) with endoscopic [biopsy forceps or endoscopic

mucosal resection (EMR)/endoscopic submucosa dissection

(ESD)] and laparoscopic approaches being the main curative

procedures used, and open surgery reserved for a minority of

cases.7,17

Localized disease

The great majority of patients with GNEN1 have localized

disease. The TNM staging system uses 1 cm in size as a cut-

off to define T1/2 tumours.7,16,17,46,56 Lesions less than 1 cm

should be endoscopically resected with interval follow-up

ranging from 6 to 12 months depending on the number of

the lesions and the recurrence rate.7,16,17 Lesions greater than

1 cm can be removed via EMR with repeated procedures in

the absence of invasion to the muscularis propria56,57 (Fig. 3).

Recurrence of GNEN1 following apparently successful treat-

ment is not unusual, as antral G-cell hyperplasia and resultant

hypergastrinaemia, which constitute the background of tumor-

al formation, persist.17,27 The recurrence rate in one series of

patients who were treated endoscopically was 63�6% at a

median of 8 months, and 66�6% of these had a second recur-

rence.25 There is currently inconsistency as to whether

tumours 1–2 cm in size should be managed with local resec-

tion.17,46 For such sized lesions and where there is suspicion

of tumour extension beyond the submucosa, EUS is used to

precisely estimate the depth of invasion7 (Fig. 3).

Surgery should be considered when there is involvement beyond

the submucosa or in the presence of positive margins following ini-

tial resection. Other features of concern such as tumour size

>2 cm, extended multiplicity and atypical pathology (particularly




if Ki-67 > 2%) constitute further indications for a surgical

approach.7,16,17,46 Although antrectomy has been widely utilized in

the past, simple wedge resection or localized excision is currently

employed for single or lesions adjacent to each other.7,17,46 In cases

of multiple tumours (>6) or frequent recurrence, more extensive

surgery can be utilized to decrease the gastrin-producing cell mass

of the stomach.43 In most cases, approximately 80%, antrectomy

results in regression of neoplastic and ECL-cell hyperplastic

areas47,58,59 although in some60,61 there is persisting disease. This is

probably due to established and evolving changes in the genome of

ECL-cells that undergo autonomous proliferation in the absence of

gastrin stimulation.49,51 Although an octreotide suppression test

has been used as a mean to predict response to antrectomy, this is

not widely accepted.47,62 Partial or total gastrectomy is only rarely

performed, mostly in highly recurrent high-risk patients and when

other modalities have failed.63 A recent small study evaluating

whether partial gastrectomy with lymph node resection and thus

proper TNM staging might be of value in high-risk patients

revealed that, even in this group of patients, there was no lymph

node involvement, confirming the relative indolent course of

GNEN1.63 These findings provide further evidence that as the risk

of a truly malignant behaviour is extremely low, a conservative

approach should generally be followed. However, more detailed

studies on large and/or invasive GNEN1 are required to define the

optimal surgical approach17,57 (Fig. 3).

Advanced disease

For the minority of patients who present with more extensive

disease (stage III, VI), surgery with a curative intent should

always be considered, when possible.7 Locoregional therapies

with embolization and/or radiofrequency ablation could be uti-

lized in patients with predominant hepatic metastases.7 There

are currently a number of systemic therapies available for

patients with disseminated disease.

Medical therapies

Patients with localized disease

Somatostatin analogues: These compounds inhibit gastrin secre-

tion from the G-cells and thus can ameliorate its effect on ECL-

cells. Treatment with somatostatin analogues (SSAs) should

always be administered to the rare patients with functioning

tumours.7 Following successful treatment with subcutaneous

octreotide in a patient with MEN1 and GNEN2, long-acting SSAs

(octreotide and lanreotide) have been shown to be effective in

decreasing the number and size of GNEN1/2.27,51,64 This is

achieved by reducing gastrin levels and thus the effect of gastrin

on GNEN1 and ECL-cell hyperplasia and/or a direct effect on

ECL-cells.51 Using these compounds, tumour disappearance rates

of up to 73% have been described, along with improvement in

the remaining GNEN1 and ECL-cell hyperplastic/dysplastic

lesions.27,51 The combination of octreotide and a-interferon has

also shown activity in a patient with metastatic hepatic disease.21

Treatment with SSAs presents a reasonable alternative for patients

with multiple and highly recurrent tumours not amenable to sur-

gical treatment. However, the precise indications and duration of

such treatment have not been defined, and rebound tumour

growth following treatment cessation usually occurs.21,65 In addi-

tion, this treatment is hampered by the lack of controlled trials

and relatively high cost.7,21

Gastrin (CCK-B) antagonists: Gastrin plays a major role in

ECL-cell proliferation, with gastrin-17 (G17) as its more active

form; gastrin also mediates angiogenesis and may also act in an

autocrine or paracrine manner to promote carcinogenesis.66

Therefore, its inhibition may be of therapeutic significance. Netaz-

epide is an orally administered peripheral CCK-B inhibitor that

has rapid onset and prolonged duration, leading to gastric acid

output suppression.15 In a series of eight patients with multiple

GNEN1 who received netazepide for 12 weeks, CgA levels nor-

malized within 3 weeks and this was associated with a substantial

tumoral reduction, although ECL-cell hyperplasia was not

affected.67 However, similarly to treatment with SSAs, discontinu-

ation of treatment was associated with biochemical relapse.67

G17-diptheria toxin immunogen (G17DT) acts as a B cell epitope

and is an antigastrin vaccination element.68 Administration of

GD17DT in three patients with autoimmune CAG and GNEN1

resulted in a sharp rise in gastrin and GD17 followed by a subse-

quent decrease in and regression of the ECL-cell lesions in two-

thirds of patients; this effect lasted for some years without appear-

ance or exacerbation of an autoimmune process.33 These data sug-

gest that the administration of the vaccine is able to produce

inhibition of the ECL-cell growth and an active generalized

immune response, but needs to be confirmed by larger studies.15

Patients with advanced disease

In rare cases of patients with GNEN1 and advanced disease,

recent findings have suggested that treatment with SSAs is associ-

ated with more prolonged progression-free survival (PFS) com-

pared to placebo.7 As GNEN1 seems to have a better prognosis

than other GI-NENs even in the presence of extensive disease,

treatment with these agents seems an appropriate first-line

approach. For patients with progressive disease despite treatment

with SSAs, further therapeutic modalities such as the administra-

tion of molecular targeted therapies and radiopharmaceuticals

could be employed.7 Although traditionally GI-NENs other than

pancreatic NENs are not considered to be chemosensitive, recent

data have suggested that they may also respond to temozolomide-

based chemotherapy.7 However, as the sequence of application of

these treatments has not as yet been defined and may possibly

apply to only a small minority of GNEN1, further discussion is

beyond the scope of this review.

Comorbidities

It has previously been suggested that patients with GΝΕΝ1 are

at increased risk of developing further GI malignancies, thyroid

disease, diabetes mellitus, hyperparathyroidism and hyper-

tension.38,43 In a recent multicentre series of 111 patients,

an increased prevalence of parathyroid adenomas, thyroid




carcinomas and adrenal adenomas was observed, which was 10

times higher compared with the corresponding European popu-

lation.27 However, this figure may be an overestimate, as a sub-

set of these patients has undergone extensive investigations

whereas the population included was of mixed ethnic origin.27

Nevertheless, parathyroid adenomas have consistently been

shown to be prevalent in patients with GNEN1 in several differ-

ent studies.69 Although the precise reason for this association

has not been ascertained, it is plausible to speculate that it could

develop as a result of excessive gastrin secretion acting on the

parathyroid glands or high calcium levels per se.69 When the

underlying aetiology is autoimmune gastritis, other autoimmune

endocrine disorders are encountered with increased frequency,

mainly Hashimoto’s thyroiditis (HT) (80%).27 Furthermore, a

recent prospective study that evaluated whether patients with

autoimmune thyroid diseases are at increased risk for GNEN1

development revealed that 33% of them had autoimmune CAG,

17�5% of whom had ECL-cell hyperplasia that evolved in

GNEN1 in one (2�5%).45 Larger studies with a long follow-up

period are necessary to define the exact prevalence of GNEN1

in patients with ATD and ECL-cell hyperplasia and potential

implications.45

GNEN1

Risk Stratification based ontumour characteristics and

concomitant CAG

SUGGESTED BASELINE EVALUATIONBIOCHEMICAL: gastrin, CgA, FT4, TSH,thyroid Abs, APCA, B12; pH of gastric juiceHISTOLOGICAL: Neuroendocrine markers(CgA, synaptophysin, VMAT-2), mitoticindex, grade (Ki67), ECL-cell hyperplasia

LOW RISKSize < 1 cmSingle or < 5 lesionsGrade 1

Endoscopicpolypectomy

6-12 monthendoscopic follow-

Recurrence

EUS to assess depth ofinvasion if single, not if

> 5 lesions

Non invasive Invasive

Antrectomy andlocal resection

Partial/totalgastrectomy + lymph

node resection

INTERMEDIATE RISKSize > 1 cm and < 2 cmMultiple or > 5 lesionsGrade 1

HIGH RISKSize > 2 cmMuscularis invasionAngioinvasionGrade 2TNM stage > II

6-month endoscopicfollow-up

Recurrence

6-month endoscopicfollow-up

Recurrence

SystemicTreatment*Repeat Risk

stratification

Repeat Riskstratification

* SS analogues

Gastrin antagonists

Fig. 4 Therapeutic and follow-up algorithm for GNEN1.




Follow-up

Type 1 GNENs are a recurring disease as the initiating factor,

hypergastrinaemia, usually persists leading to ECL-cell hyperpla-

sia/dysplasia that constitutes the background for further tumour

development.7,25 In addition, patients with ECL dysplasia are at

also higher risk for GNEN1 development as it is considered a

premalignant state, and such patients may benefit from more

regular follow-up.19,24 As precise risk factors for GNEN1 devel-

opment have not been identified, the European Neuroendocrine

Tumour Society (ENETS) guidelines suggest endoscopic follow-

up every 6–12 months following the diagnosis of GNEN1

according to the presence of risk factors (Fig. 4). This time

interval permits the identification of recurrent or new lesions at

an early stage, thus allowing endoscopic removal at an early

stage.19,31 Although in a prospective study approximately 60% of

GNEN1 had recurred following endoscopic resection, this treat-

ment is considered safe and effective for low-risk tumours.25

Whether a yearly clinical evaluation along with a repeat endos-

copy every 2 years is more cost-effective for the patient for such

indolent lesion needs to be further explored in a clinical trial.

Ongoing clinical trials

Following the initial promising results with netazepide,67 a clinical

trial for its use as a potential treatment for GNEN1 has been initi-

ated (ClinicalTrials.gov NCT01339169). As noted above, a preli-

minary analysis of eight patients with GNEN1 and multiple

tumours treated with netazepide for 12 weeks with a follow-up of

12 weeks later showed a substantial reduction in the number and

size of tumours with concomitant CgA level reduction that

increased post-treatment discontinuation.70

Conclusions

GNEN1 is increasingly being recognized and currently consti-

tutes the most common GI-NENs being a chronic and highly

relapsing condition. These tumours are not associated with spe-

cific symptoms and should always be suspected in the presence

of CAG or its sequelae substantiated by elevated gastrin and

CgA levels. The great majority of GNEN1 exhibit an indolent

course as they are mainly confined to the gastric mucosa/sub-

mucosa and thus do not require the extensive staging imaging

modalities that are employed only in high-risk patients with a

more aggressive course. Endoscopic removal with EUS assess-

ment of the depth of invasion as required is sufficient for the

majority of GNEN1, followed by regular endoscopy to detect

early recurrence. However, it should be emphasized that an

alternative approach of simple observation for GNEN1 without

endoscopic removal cannot be excluded as a therapeutic alterna-

tive as the natural history of small lesions is relatively benign.

Patients with large (>2 cm), deeply infiltrating G2 tumours, or

in the presence of multiple and widespread tumours, are amena-

ble to surgery with local excision, laparoscopic antrectomy or in

refractory cases more extensive surgery. Medical therapy with

SSAs can also reduce the number and size of the tumours and

background ECL-cell hyperplasia and can be used in specific

clinical settings. As more information is obtained from large

prospective databases regarding the natural history of GNEN1, it

may be expected that a balanced therapeutic approach regarding

utilization of conservative or more aggressive treatments to

avoid unnecessary side effects and high costs will evolve.

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PLoS ONE, 8, e76462.




current concepts in the diagnosis and management of type 1 gastric neuroendocrine neoplasms

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