Digestive and Liver Disease 53 (2021) 171–182

Contents lists available at ScienceDirect

Digestive and Liver Disease

journal homepage: www.elsevier.com/locate/dld

Review Article

Update on gastroenteropancreatic neuroendocrine tumors

Valentina Andreasi a,b, Stefano Partelli a,b, Francesca Muffatti a, Marco F. Manzoni c,
Gabriele Capurso d, Massimo Falconi a,b,∗
a
Pancreatic Surgery Unit, Pancreas Translational & Clinical Research Center, OSR ENETS Center of Excellence, IRCCS San Raffaele Scientific Institute, Via
Olgettina 60, 20132 Milan, Italy
b
Vita-Salute San Raffaele University, Milan, Italy
c
Endocrinology Unit, OSR ENETS Center of Excellence, IRCCS San Raffaele Scientific Institute, Milan, Italy
d
Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational & Clinical Research Centre, OSR ENETS Center of Excellence IRCCS San
Raffaele Scientific Institute, Milan, Italy

a r t i c l e i n f o a b s t r a c t

Article history: The incidence gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) has dramatically risen over
Received 11 June 2020 the last three decades, probably due to the increased detection of asymptomatic lesions. The diagnostic
Accepted 21 August 2020
work-up for patients with suspected GEP-NENs is based on conventional imaging, endoscopy, pathology,
Available online 8 September 2020
and functional imaging, including 68 Gallium-DOTATATE PET and 18 F-FDG PET. The choice of the best treat-
Keywords: ment strategy should be based on the evaluation of tumor-related features and patient’s characteristics.
Gastroenteropancreatic neuroendocrine A conservative management, consisting of active surveillance or endoscopic resection, has been advo-
neoplasms cated for patients with small, incidentally discovered, nonfunctioning tumors without features of aggres-
Active surveillance siveness. On the other hand, surgery with lymphadenectomy, also with a minimally invasive approach,
Endoscopic resection represents the gold standard for the curative treatment of localized disease. Moreover, surgical resection
Surgery plays an important role also in the context of a multimodal treatment strategy for patients with advanced
GEP-NENs. Finally, a wide range of medical therapies, comprising somatostatin analogues, peptide recep-
tor radionuclide therapy, target therapies and several chemotherapy regimens, can be offered to patients
with advanced GEP-NENs not amenable of surgical resection, according to the biological and molecular
features of their disease.
© 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

1. Background
Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs)
are a heterogeneous group of malignancies arising from the diffuse
neuroendocrine system.
These neoplasms are generally considered less aggressive than
their exocrine counterpart, although they exhibit a wide range of
aggressiveness depending on several factors, such as site of origin,
stage, grade, and functionality [1].
The management of GEP-NENs is always based on a multidisci-
plinary approach that is inspired by guidelines, but always tailored
on each single patient. In this context, the referral to specialized
centers with dedicated multidisciplinary teams is essential in or-
der to offer the most adequate treatment [2]. A wide variety of
treatment options is currently available, including active surveil-
lance or endoscopic resection for small and asymptomatic lesions,
∗
Corresponding author at: Pancreatic Surgery Unit, Pancreas Translational & Clin-
ical Research Center, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132
Milan, Italy.
E-mail address: falconi.massimo@hsr.it (M. Falconi).
surgical resection, and a broad range of medical treatments for pa-
tients with advanced disease. However, some issues related to GEP-
NENs management are still debated.
The present review critically analyses the recent literature, pro-
viding an updated summary of epidemiology, diagnosis, and treat-
ment of GEP-NENs.
2. Epidemiology
GEP-NENs have been historically regarded as rare, but their in-
cidence has risen dramatically over the last three decades [3,4].
A recent population-based study from the Surveillance, Epidemiol-
ogy, and End Results program evaluated 64,971 patients with NENs
reporting a 6.4-fold age-adjusted incidence increase from 1973 to
2012 [5]. This growth occurred across all sites, disease stages and
tumor grades, but it was particularly pronounced for localized,
low-grade tumors [5]. Consistently with this finding, a Canadian
study showed that, despite a marked overall incidence increase,
the percentage of patients with distant metastases remained sta-
ble over the course of 15 years [6]. These data support the hypoth-
esis that the increased incidence of NENs may be related to the

https://doi.org/10.1016/j.dld.2020.08.031
1590-8658/© 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
172 V. Andreasi, S. Partelli and F. Muffatti et al. / Digestive and Liver Disease 53 (2021) 171–182
increased detection of small and asymptomatic lesions [5,6]. Fur-
thermore, well-defined histological criteria able to allow a reliable
identification of NENs have been defined only in recent years. In
particular, the 20 0 0 World Health Organization (WHO) classifica-
tion for NENs of the gastrointestinal tract [7] and the 2004 WHO
classification for NENs of the pancreas [8] represent basic tools
that have replaced all previous NENs classifications and terms (e.g.
APUDoma, carcinoid), leading to a more precise definition of NENs
and to a consequently increased recognition of these tumors [9].
The gastroenteropancreatic region represents the most common
localization of NENs, with small intestine (31%) and rectum (26%)
being the most frequent primary sites [10]. The incidence of GEP-
NENs in the US has reached 3.65 cases per 10 0,0 0 0 inhabitants
in 2012 [5] and data from Europe and Asia have confirmed the
same trend [9,11]. Among GEP-NENs, the greatest incidence in-
crease has occurred for gastric (G-NENs) and rectal NENs (R-NENs)
[12,13], whereas the incidence of small bowel NENs (SB-NENs) has
changed to a lesser extent [9]. This difference may be related to
the fact that the majority of SB-NENs are not detectable with endo-
scopic techniques, differently from G-NENs and R-NENs [9]. Pancre-
atic and appendiceal NENs as well have become increasingly rec-
ognized starting from the early ‘00s [5,14,15].
It is likely that the real prevalence of GEP-NENs is much higher
than that reported by population-based studies. This hypothesis
is suggested by the high prevalence of small pancreatic neuroen-
docrine tumors (PanNETs) observed in autoptic studies [16]. More-
over, a recent series reported an incidental histological diagnosis
of small PanNETs or microadenomas in 4% of patients submitted
to pancreatic resection for diagnoses other than PanNET [17]. It is
then likely that many individuals are affected by small and asymp-
tomatic PanNETs that will remain unchanged for their entire life.
On the other hand, high-grade neoplasms represent a small
percentage of GEP-NENs [5] and few data are currently avail-
able regarding the epidemiological distribution between well-
differentiated and poorly-differentiated NENs G3. A recent prospec-
tive one-year survey among French pathologists (PRONET study)
included 778 patients with GEP-NENs, of which 14% had a G3 neo-
plasm [18]. Of these patients, 21 (20%) had a well-differentiated
NET G3 [18]. A similar rate of GEP-NETs G3 (18%) had been re-
ported also by a previous experience including 204 patients with
high-grade GEP-NENs [19]. Regarding primary tumor site distribu-
tion, several studies have suggested that well-differentiated GEP-
NETs G3 are more often found in the pancreas. In this regard, Heet-
feld et al. [19] observed that 65% of GEP-NETs G3 were of pancre-
atic origin. Consistently, patients with PanNENs G3 included in the
NORDIC study displayed lower Ki67 values, higher rates of somato-
statin receptors positivity and longer overall survival as compared
to patients with GEP-NENs G3 from other primary sites, suggesting
that well-differentiated tumors are more represented among Pan-
NENs [20].
3. Diagnosis
The diagnostic work-up for GEP-NENs is based on five pillars:
morphological imaging, endoscopic procedures, pathology, func-
tional imaging, and circulating biomarkers.
3.1. Morphological imaging
Cross-sectional radiological examinations, including computed
tomography (CT) and magnetic resonance imaging (MRI), are of
paramount importance for the assessment of location and extent
of GEP-NENs. Therefore, at least one high-quality imaging exam-
ination with contrast enhancement is mandatory for the initial
staging of these neoplasms. However, morphological imaging may
not recognize small tumors, especially those located in the stom-
ach, duodenum or small bowel [21]. In this regard, Pasquer et al.
[22] found that CT was able to preoperatively identify only 21% of
SB-NETs. Furthermore, a recent study including patients with dis-
tant metastases from unresected GEP-NETs reported that CT de-
tected only 150 out of 197 primary tumors [23]. CT and MRI show
a similar sensitivity in terms of initial staging, although CT seems
to be more accurate in defining vascular involvement [24]. On the
other hand, MRI with liver-specific contrast enhancement is more
effective in the identification of liver and bone metastases [25,26].
In this regard, a recent experience reported that the addition of
diffusion-weighted sequences to standard MRI revealed additional
neuroendocrine metastases in 71% of patients [27].
3.2. Endoscopic procedures
Endoscopic procedures with biopsy are the gold standard for
the diagnosis of gastric, duodenal and colorectal NENs [21,26,28].
In particular, total colonoscopy is mandatory for all the patients
with R-NENs, in order to rule out a concomitant colon cancer and
other colorectal NENs, which can occur in up to 8% of cases [26].
Endoscopic ultrasound (EUS) is also important as it represents the
modality of choice for a better assessment of PanNENs and for
achieving a pathological diagnosis [29]. Furthermore, it represents
a key tool for the loco-regional staging of other gastrointestinal
NENs [30,31].
Video-capsule endoscopy and double-balloon enteroscopy are
additional endoscopic procedures that may be indicated when con-
ventional imaging fails to identify the primary tumor, especially in
the case of SB-NENs [24]. However, although these procedures in-
crease the detection of SB-NENs [32], their routine use is not jus-
tified [26] and the intraoperative bi-digital palpation of the whole
small intestine remains the mainstay for the identification of mul-
tifocal lesions [24].
3.3. Pathology
Pathological examination plays a pivotal role for determining
an adequate management. A proper histological evaluation has the
role to confirm the neuroendocrine nature of the tumor and in-
dicate its grade and differentiation. Moreover, the analysis of sur-
gical specimens should always report the depth of invasion, the
presence of lymphovascular and/or perineural invasion, the status
of resection margins and the nodal status. The latest WHO classi-
fication (Table 2) defines GEP-NENs as G1 (Ki67 < 3%), G2 (Ki67
3-20%) and G3 (Ki67 >20%), according to Ki67 proliferative index
[33,34]. GEP-NENs G3 are further classified into two categories:
well-differentiated (GEP-NETs) or poorly-differentiated (GEP neu-
roendocrine carcinomas, GEP-NECs), according to cell morphology.
3.4. Functional imaging
Functional imaging studies are based on the expression of so-
matostatin receptors (SSTRs) by GEP-NETs. Historically, somato-
statin receptor imaging included 111 Indium pentetreotide scintig-
raphy (Octreoscan®), but 68 Gallium(Ga)-DOTATATE PET/CT resulted
to be more accurate and it has now become the preferred modality
[1]. More recently, 68 Ga PET/MRI has been proposed as an alterna-
tive to PET/CT [35].
The execution of 68 Ga-DOTATATE PET is reccomended for a
whole-body staging, but it can be useful also for the localization
of an occult primary tumor [21,24,28,36,37]. 68 Ga PET/CT is able
to detect a higher percentage of neuroendocrine lesions as com-
pared to conventional imaging [38,39]. Recently, a series including
101 patients with NETs reported that 68 Ga PET findings drove the
management in one third of cases, changing the management in
 V. Andreasi, S. Partelli and F. Muffatti et al. / Digestive and Liver Disease 53 (2021) 171–182
Fig. 1. 68 Gallium-DOTATOC PET/CT showing a neuroendocrine bone metastasis (L1
left transverse process, indicated by the red arrow) in a patient previously submit-
ted to distal pancreatectomy and peptide receptor radionuclide therapy (PRRT) for
a pancreatic neuroendocrine tumor (PanNET) G2.
half of patients previously referred to surgery [40]. Furthermore,
the introduction of 68 Gallium-DOTATATE PET/CT in clinical practice
has considerably increased the detection of bone metastases from
GEP-NENs [38,41] (Fig. 1).
68 Ga-PET is also critical for the determination of radiotracer
uptake that correlates with response to peptide receptor radionu-
clide therapy (PRRT) [42]. Differential diagnosis with other patho-
logical conditions associated with SSTRs overexpression should be
taken into account. In particular, false positive 68 Ga PET uptakes
have been observed in patients with non-neuroendocrine neo-
plasms (e.g. meningiomas, metastases from renal cancer and solid
serous cystadenoma) as well as in several non-neoplastic condi-
tions (e.g. pancreatic uncinate process activity, fractures, vertebral
hemangiomas, splenosis) [43].
On the other hand, SSTR imaging is frequently negative in pa-
tients with insulinomas, due to a lower expression of SSTRs as
compared with other GEP-NETs [44]. Hence, a different molecular
target has been investigated for the successful localization of these
tumors. In this setting, the glucagon-like peptide-1 receptor (GLP-
1R) was identified as a promising candidate, due to its overexpres-
sion in nearly 100% of benign insulinomas [45], and exendin-4, a
stable analogue of GLP-1, was used for the development of radiola-
belled GLP-1R ligands. In this regard, a prospective series reported
a 94% accuracy of 68 Ga-DOTA-Exendin-4 PET/CT in the localization
of benign insulinomas, as compared to 68% for MRI [46]. Therefore,
this functional imaging technique might be considered when pre-
operative localization of insulinomas fails with conventional imag-
ing. On the other hand, FDOPA-PET can be useful for the initial
and postoperative evaluation of SB-NENs, as a high FDOPA uptake
is specific to NENs with high amino-acid metabolism, especially
SB-NENs [26]. This functional imaging technique is more sensitive
than morphological imaging and somatostatin receptor scintigra-
phy, but it has been poorly compared with 68 Gallium-DOTATATE
PET.
Finally, the role 18 F-FDG PET/CT in the diagnostic algorithm of
GEP-NENs is still unclear, as conflicting results have been reported
[47]. This functional examination is not routinely performed, as
GEP-NETs are generally slow-growing tumors with low glycolytic
activity. However, 18 F-FDG PET might be useful for detecting ag-
gressive neoplasms with high Ki67 proliferative index and low
SSTRs expression [48]. Furthermore, 18 F-FDG uptake seems to be
173
negatively correlated with prognosis [49,50]. 68 Ga-DOTATOC and
18 F-FDG PET/CT of a patient diagnosed with a locally advanced
PanNET with a single liver metastasis are shown in Fig. 2.
3.5. Biomarkers
Chromogranin A (CgA) represents the most used neuroen-
docrine biomarker, although its value is affected by several condi-
tions that significantly limit its accuracy [51]. In order to overcome
these limitations, a variety of alternative blood markers have been
investigated, although none of them has been already adopted in
the clinical practice [52,53]. One of the most promising biomarkers
is represented by a blood test panel of NET marker genes, derived
from the transcript profile of NET cells (NETest). Several series re-
ported that NETest had a good diagnostic accuracy [54]. Further-
more, NETest was identified as a valuable marker of treatment re-
sponse [55,56].
4. Management of small and asymptomatic well differentiated
GEP-NETs
A conservative management consisting of endoscopic resec-
tion (ER) or active surveillance can be advocated for patients
with small, non-functioning (NF), well-differentiated, asymp-
tomatic GEP-NETs [21,24,28,36,37]. The management of these en-
tities varies according to the site of primary tumor, as shown in
Table 1.
4.1. Gastric NETs (G-NETs)
G-NETs are classified into three categories according to the
background gastric pathology [21].
Type I G-NETs are associated with atrophic body gastritis and
usually present as small, multiple, low-grade tumors limited to the
mucosal/submucosal layer of the gastric body-fundus [57]. The risk
of metastases is low (2-5%) and the prognosis is excellent [21,57].
The management of type I G-NETs is mainly defined by tumor
size and depth of invasion, which have been identified as strong
prognostic factors [21,58,59]. On the other hand, the role of tumor
grade in this setting is still unclear, as conflicting results have been
reported [59,60]. Therefore, according to current guidelines [21,26],
a conservative management should be preferred over surgical re-
section for patients with type I G-NETs limited to the submucosal
layer. Specifically, endoscopic surveillance on a yearly basis can be
considered for lesions ≤ 1 cm [26], whereas ER by endoscopic
mucosal resection (EMR) with cap aspiration or ligation-assisted
or endoscopic submucosal dissection (ESD) is reccomended for le-
sions 1-2 cm without muscular invasion nor suspicious perigastric
lymph nodes [26,57,61]. Several experiences confirmed the safety
of ER, in terms of development of metastases and disease-related
death during follow-up [62–64], despite a higher rate of local re-
currence as compared to surgical resection [62,64].
Type II G-NETs develop in the context of Multiple Endocrine
Neoplasia type 1 (MEN-1) syndrome and their management de-
pends on the simultaneous presence of duodenal or pancreatic
NETs requiring surgical resection [21].
Finally, patients with type III G-NENs are generally not candi-
dates to ER, as they usually present with advanced lesions. How-
ever, the management of type III G-NETs < 2 cm is not defined
and a conservative strategy might be considered as initial treat-
ment in highly selected patients [26,65,66]. In this regard, Min
et al. [66] analysed the outcomes of 22 patients submitted to ER
or wedge resection for type III G-NETs G1 limited to the submu-
cosal layer, without lymphovascular invasion, reporting no disease
recurrence in patients with tumors ≤ 1.5 cm.
174 V. Andreasi, S. Partelli and F. Muffatti et al. / Digestive and Liver Disease 53 (2021) 171–182

Fig. 2. 68 Gallium-DOTATOC PET/CT (A-C) and 18 F-FDG PET/CT (B-D) of a patient diagnosed with a locally advanced pancreatic neuroendocrine tumor (PanNET) with a single
liver metastasis (indicated by the red arrow). Both primary tumor (A) and liver metastasis (C) display a high 68 Gallium uptake. The primary tumor has also a high 18 F-FDG
uptake (B), whereas the liver metastasis is negative at the metabolic imaging (D).

Table 1
Management of small well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs).

Primary Tumor Site Criteria to be fulfilled for a conservative management Type of management

Stomach • Type I-II G-NETs

a
Endoscopic surveillance (G-NETs ≤ 1 cm)
• Tumor limited to the submucosal layer Endoscopic resection (G-NETs 1-2 cm)
Duodenum • Not ampullary/periampullary location Endoscopic resection
• Nonfunctioning tumor
• Tumor size ≤ 1 cm
• Tumor limited to the submucosal layer
• G1
Pancreas • Nonfunctioning tumor Active surveillance
• Tumor size ≤ 2 cm
• No symptoms
• No dilation of the main pancreatic duct/bile duct
Small bowel Surgical resection with lymphadenectomy is always
recommended
Appendix • Tumor size ≤ 1 cm Appendectomy
R0 resection
• Mesoappendix infiltration < 3 mm
• Location at middle/tip of appendix
• G1
• No lymphovascular invasion
Colon Surgical resection with lymphadenectomy is always
recommended
Rectum • Tumor size ≤ 15 mm Endoscopic resection (R-NETs ≤ 1 cm)
• Tumor limited to the submucosal layer
• G1 Transanal endoscopic microsurgery (R-NETs 10-15 mm with
submucosal invasion)
• No lymphovascular invasion
• No atypical endoscopic aspect

G-NET, gastric neuroendocrine tumor; R-NET, rectal neuroendocrine tumor.

a
The management of type II G-NETs depends on the simultaneous presence of duodenal or pancreatic NETs requiring surgical resection.
 V. Andreasi, S. Partelli and F. Muffatti et al. / Digestive and Liver Disease 53 (2021) 171–182
Table 2
World Health Organization (WHO) classification for neuroendocrine neoplasms of the gastrointestinal tract and hepatopancreatobiliary organs [33].
Definition Cell morphology
NET G1 Well-differentiated
NET G2
NET G3
NEC G3 Poorly-differentiated
Small-cell type
Large-cell type
MiNEN Well- or poorly-differentiated
NET, neuroendocrine tumor; NEC, neuroendocrine carcinoma; MiNEN, mixed neuroendocrine-non-neuroendocrine neoplasm.
Mitotic rates are expressed as the number of mitoses/2 mm2 determined in 50 fields of 0.2 mm2 ; Ki-67 proliferative index is determined by counting ≥ 500 cells in the
regions of highest labelling; the final grade is based on the proliferation index that places the neoplasm in the higher-grade category.
4.2. Duodenal NETs (D-NETs)
The management of incidentally discovered D-NETs mainly de-
pends on tumor location, functionality, size, grade, depth of inva-
sion, and evidence of nodal or distant metastases [21,57].
Lesions located in the ampullary/periampullary region have to
be considered as a separate entity, due to their more aggressive
behaviour and poorer prognosis as compared to other D-NETs [67].
Therefore, surgical resection is always recommended, irrespective
of tumor size, for patients with ampullary/periampullary D-NETs
[21,26]. Similarly, functioning D-NETs, including gastrinomas and
ampullary-type somatostatin producing NETs, always require sur-
gical treatment, due to high rates of local infiltration and nodal
metastases [68,69].
However, also other tumor-related features should be consid-
ered [26,70]. A recent series including 44 D-NETs submitted to ER
or surgical resection identified tumor size >10 mm, invasion be-
yond the submucosa, tumor grade G2 and lymphovascular inva-
sion, as risk factors for nodal metastases [71]. Consistently, cur-
rent guidelines suggest that a conservative management based on
ER can be proposed safely only to patients diagnosed with asymp-
tomatic D-NETs G1 ≤ 1 cm, limited to the submucosal layer, when
the presence of nodal metastases has been ruled out [21,26]. In
contrast to these indications, a recent review by Neißen et al.
[72] reported that D-NETs < 1 cm are associated to nodal metas-
tases in 20% of cases. However, this high rate of nodal involve-
ment may be related to a selection bias due to the presence of
more aggressive tumors in surgical series and to the fact that also
ampullary D-NETs were considered in this analysis [72]. Regard-
ing post-procedural outcomes, ER of D-NETs is associated with a
significant risk of complications and difficulty to achieve a radical
resection. Cap aspiration or ligation-assisted EMR should be pre-
ferred over standard polipectomy or simple EMR due to the higher
rates of R0 resection, whereas ESD should be avoided due to the
high risk of duodenal perforation [26].
The management of D-NETs measuring 1-2 cm is still not stan-
dardized, although the risk of malignancy is significantly higher as
compared to lesions < 1 cm [26,70,72].
4.3. Pancreatic NETs
An active surveillance (AS) strategy has been advocated for pa-
tients with asymptomatic, NF-PanNETs ≤ 2 cm [36,37] and several
studies [73] have demonstrated safety and feasibility of this ap-
proach. Consistently, two recent series [74,75] reported that no pa-
tients submitted to AS developed distant or nodal metastases and
that relevant tumor growth occurred only in a small percentage
(2-7%) of cases during follow-up. On the contrary, Assi et al. found
that a conservative management was safe only for patients with
tumors < 1 cm and surgical resection was associated with an over-
all survival (OS) benefit in patients with tumors measuring 1-2 cm
[76]. However, these results are probably biased by a better perfor-
175
Ki67 proliferative index Mitotic count
< 3% <2
3 – 20% 2 – 20
> 20% > 20
> 20% > 20
Variable Variable
mance status in patients undergoing surgical management. Consis-
tently, no differences in terms of disease-specific survival between
AS and surgery were demonstrated in another study [77].
Nevertheless, a “watch and wait” management for small, asymp-
tomatic NF-PanNETs is still not widely accepted [78]. The physi-
cian’s attitude is still influenced by several factors such as patients’
age and tumor grading. Young age is one of the main determi-
nants of the surgical choice [74,75], due to the lack of long-term
data on the natural history of these small lesions. However, since
no clear correlation between age and risk of NF-PanNETs malig-
nancy has been demonstrated, the indication for surgery in young
patients is not always justified [79]. Another factor that may lead
to surgical treatment of small NF-PanNETs is the finding of a G2-
tumor on preoperative fine needle aspirate (FNA) samples. Con-
flicting results have been reported regarding the reliability of cy-
tological grading [74,75]. For sure, the value of Ki67 determined on
FNA samples of small PanNETs should be taken with extreme cau-
tion and the treatment of preoperatively determined G2, asymp-
tomatic, NF-PanNET ≤ 2 cm should be weighted with the risk
related to surgery and with patient’s expectations. On the other
hand, surgery is always mandatory in the presence of bile duct or
main pancreatic duct (MPD) dilation, that represent additional risk
factors for malignant behaviour [75,80]. Preoperative CT and MRI
of a patient with a small NF-PanNET with dilation of the MPD are
shown in Fig. 3.
4.4. Small bowel NETs
The incidental diagnosis of SB-NETs is rare and generally made
during exploratory laparotomies performed in an emergency set-
ting for intestinal obstruction. The majority of SB-NETs display fea-
tures of aggressiveness (e.g. nodal metastases) even when < 1 cm
[81] and therefore these neoplasms should be always treated with
intestinal resection associated to lymphadenectomy [24].
4.5. Appendiceal NETs (A-NETs)
A-NETs are frequently diagnosed incidentally at final patho-
logical examination after appendectomy performed for acute ap-
pendicitis [82]. A preoperative incidental diagnosis is extremely
rare, as differential diagnosis with acute appendicitis is difficult
[61]. Appendectomy usually represents the definitive treatment for
small A-NETs (≤ 1 cm) with a limited mesoappendix infiltration
(< 3 mm), located at the middle/tip of the appendix, graded as G1
and without lymphovascular invasion after a R0 resection [26,83].
On the other hand, there is no recommendation on whether sim-
ple appendectomy or additional right hemicolectomy (RHC) is the
most appropriate treatment for A-NETs G2 ≤ 1 cm [26].
4.6. Colorectal NETs
Colonic (C-NETs) and rectal NETs (R-NETs) should be regarded
as two distinct clinical entities, since C-NETs have more aggressive
176 V. Andreasi, S. Partelli and F. Muffatti et al. / Digestive and Liver Disease 53 (2021) 171–182
Fig. 3. CT scan (A) and MRI (T1 phase) (B) with contrast enhancement showing a 6 mm PanNET of the pancreatic body associated to a dilation of the main pancreatic duct
(up to 7 mm).
features and worse survival outcomes, as compared to R-NETs [84].
Since C-NETs are generally high-grade, poorly-differentiated neo-
plasms, surgical resection followed by a strict surveillance is rec-
ommended whenever feasible [28]. On the other hand, R-NETs
are usually small, low-grade tumors with low risk of metastases.
In particular, incidentally discovered R-NETs ≤ 1 cm, limited to
mucosal or submucosal layers, without features of aggressiveness
(atypical endoscopic aspect, tumor grade G2 and lymphovascular
invasion) can be safely managed by ER [28,31,85,86]. According to
the French Intergroup guidelines, advanced ER techniques should
be preferred to standard polipectomy or EMR due to the high
rate of positive margins [26]. For lesions < 10 mm, cap aspiration
or ligation-assisted EMR are suggested, whereas ESD is more fre-
quently performed for lesions measuring 10-15 mm [26]. Transanal
endoscopic microsurgery (TEM) is another available option: the ad-
vantage of this technique compared to ER is represented by the
possibility to perform a full-thickness resection of the lesion, thus
avoiding segmental resection surgery [31]. Chen et al. considered
59 patients submitted to TEM for R-NETs reporting a complete
clearance of surgical margins and no disease recurrence in all the
cases [87]. TEM represents nowadays the reference resection tech-
nique for T1 R-NETs measuring 10-15 mm and invading the sub-
mucosa, especially when located in the low-intermediate rectum
[31]. Salvage resection by ESD or TEM can be performed for R-
NETs at low metastatic risk with an initial R1 ER. No follow-up
is required for completely resected R-NETs < 10 mm with no risk
features [26].
5. Surgical treatment of localized GEP-NETs
Surgery represents the backbone for the curative treatment of
well-differentiated GEP-NETs. Different surgical strategies are rec-
ommended according to the site of the primary tumor.
5.1. Gastric NETs
Tumor type is the main determinant for surgical indications in
patients with G-NETs [60,88]. Current guidelines recommend local
excision or partial gastrectomy with lymph node picking for stage
T2 (or above) type I G-NETs or in the presence of positive margins
after ER [21,26]. The management of type II G-NETs should be al-
ways discussed in a multidisciplinary setting, as it strictly depends
on the presence or absence of other GEP-NETs such as gastrinomas
[21]. Regarding type III G-NENs, it is crucial to evaluate their dif-
ferentiation [60]. According to the localization of the lesion and its
extension, total or partial gastrectomy with lymphadenectomy are
generally recommended in the presence of poorly-differentiated G-
NECs [21]. On the other hand limited resections may be considered
for patients with well-differentiated forms [60].
5.2. Duodenal NETs
Radical surgery with lymphadenectomy is recommended for pa-
tients with D-NETs ≥ 2 cm and/or extending beyond the submu-
cosal layer and/or with an ampullary-periampullary location [21].
Pancreaticoduodenectomy (PD) is the procedure of choice as it al-
lows performing a proper staging of lymph nodes (LN) that are in-
volved in the 40-60% of cases [69,89]. A recent series found that
a regional lymphadenectomy with ≥ 8 resected LN is needed in
order to guarantee an accurate staging in D-NETs [90]. The role of
parenchyma-sparing surgery in this setting is still not well-defined,
although an ampullary resection might be considered for small (<
10-15 mm) periampullary D-NETs without nodal metastases, espe-
cially in patients with comorbidities who are unfit for PD [26].
5.3. Pancreatic NETs
A formal pancreatic resection with a standard lymphadenec-
tomy is reccomended for all the patients with NF-PanNETs > 2
cm as well as for those with symptoms or radiological features
of aggressiveness [24,37]. The presence of nodal involvement is
one of the most powerful prognostic factors after curative surgery
[91–93] and the prognostic significance of the number of PLN has
been recently demonstrated [94,95]. There is still no consensus
about the minimum number of LN to be harvested in order to en-
sure a proper nodal staging, but it seems that 13 and 7 LN repre-
sent an adequate number of nodes to be examined after PD and
distal pancreatectomy, respectively [94,96].
Parenchyma-sparing resections, including enucleation, mid-
dle pancreatectomy and middle-preserving pancreatectomy [97],
represent an alternative option for the treatment of functioning
PanNETs and small NF-PanNETs [24]. The main advantage of
conservative resections consists in a reduced risk of developing
pancreatic insufficiency, as compared to formal resections [98,99].
On the other hand, the main concern is related to inadequate
clearance of surgical margins during enucleation and to the
absence of a standard lymphadenectomy.
5.4. Small bowel NETs
A radical resection of the primary tumor(s) associated to a lym-
phadenectomy along the superior mesenteric root and around the
mesentery is recommended in all the patients with localized SB-
NETs, whenever feasible [24,26,100]. A standard lymphadenectomy
should be always performed [24] as nodal metastases are found
in 80-90% of patients with SB-NETs [101]. Retractile mesenteritis,
large mesenteric LN and/or resectable peritoneal carcinomatosis
should not contraindicate surgery [26]. The proper number of LN
to be resected is still undefined, but it seems that ≥ 8 LN should
 V. Andreasi, S. Partelli and F. Muffatti et al. / Digestive and Liver Disease 53 (2021) 171–182
be examined in order to accurately stage these patients [102,103].
Lymphadenectomy along the superior mesenteric artery trunk up
to the retropancreatic area has been suggested, but its usefulness
requires further confirmation [26]. An adequate lymphadenectomy
does not require an extended small bowel resection, as no corre-
lation between the number of resected LN and the length of small
bowel specimen has been found [101]. The surgical approach of
SB-NETs should follow two precise criteria. First, an intraoperative
bi-digital palpation of the whole small intestine should always be
performed in order to detect multifocal lesions [24]. Second, the
so-called “pizza-pie” resection rule should be abandoned, in favour
of a small intestinal-sparing strategy [22,26,101].
5.5. Appendiceal NETs
The appropriate management of A-NETs is still controversial
[82]. As a rule of thumb, appendectomy is considered curative for
A-NETs < 1 cm, whereas RHC is recommended for tumors > 2
cm [83] or in the presence of atypical histology (e.g. goblet cell
adenocarcinoma) [26]. The management of A-NETs measuring 1-
2 cm should be tailored according to the presence of other risk
features (mesoappendix invasion, location in the appendiceal base,
tumor grade, lymphovascular invasion and R1 resection) [26,83].
According to a recent retrospective experience including 435 pa-
tients submitted to surgery for A-NETs, tumor size >15 mm and/or
grading G2 and/or lymphovascular invasion represent indications
for oncological radicalization [104]. On the other hand, the prog-
nostic significance of mesoappendix invasion and tumor location
in the appendix has been questioned by several recent series
[82,104–106]. No postoperative follow-up is required for patients
considered cured after simple appendectomy as well as for those
submitted to RHC with lymphadenectomy for A-NETs < 2 cm, with
low Ki67 and without nodal metastases [26].
5.6. Colonic NETs
Current guidelines recommend localized colectomy with lym-
phadenectomy for the treatment of localized C-NETs [107]. Nodal
dissection should be always performed, as the presence of
nodal metastases is one of the most powerful prognostic factors
[108] and the prognostic significance of the number of PLN has
been recognized as well [109]. However, no consensus exists for
a minimal number of LN to be sampled, but it seems that the op-
timal number is close to 12 [109].
5.7. Rectal NETs
The management of R-NETs should be guided by the presence
of predictors of nodal involvement, including tumor size ≥ 15 mm,
atypical endoscopic aspect, invasion of the muscular layer, tumor
grade G2-G3 and lymphovascular invasion [28,31,85,86]. When one
or more of these features are present, a formal oncologic low ante-
rior resection with total mesorectal excision should be performed
[26,28]. Also in this setting, the number of PLN has been iden-
tified as an independent prognostic factor [110], but the optimal
extent of lymphadenectomy is not yet defined. A nodal dissection
extended to pelvic and/or obturator canal regions should be per-
formed whenever suspicious LN are identified [31,111]. Postopera-
tive follow-up should be based on regular endoscopic examinations
and abdominal/pelvic MRI [26].
5.8. Minimally invasive surgery
Minimally invasive surgery (MIS) has gained wide acceptance
over the last few decades for the treatment of GEP-NETs [112,113],
especially PanNETs. Several retrospective studies demonstrated the
177
advantages of MIS in terms of short-term postoperative outcomes
[113,114]. Furthermore, similar recurrence and survival rates were
reported between patients submitted to laparoscopic/robotic and
open resections for PanNENs [115]. Regarding the comparison be-
tween different minimally invasive approaches, some retrospective
experiences compared laparoscopic and robotic DP performed for
PanNENs, reporting lower conversion rates after robotic DP [116].
On the other hand, a relevant advantage for the laparoscopic ap-
proach was found in terms of total costs [117].
6. Surgical management of high-grade and metastatic
GEP-NENs
6.1. Surgery for GEP-NENs G3
The role of surgery for GEP-NENs G3 is still debated. Accord-
ing to some retrospective series, radical surgical resection is asso-
ciated with a survival benefit as compared to systemic therapies or
palliative resection alone in patients with localized GEP-NENs G3
[118–121], especially when well-differentiated [120,121]. Further-
more, a possible survival benefit has been recently reported also
for highly selected patients with metastatic well-differentiated
PanNETs G3 submitted to radical surgery [121,122]. Therefore, sur-
gical resection represents a valuable option for patients with GEP-
NETs G3, whereas it should be carefully considered for patients
with localized GEP-NECs G3 and completely avoided for metastatic
GEP-NECs G3. Concerning the role of adjuvant therapy in this set-
ting, no additional survival benefit from this treatment was re-
cently reported in patients submitted to surgery with curative in-
tent for GEP-NENs G3 [122]. On the other hand, current French In-
tergroup guidelines report that adjuvant chemotherapy with etopo-
side + cisplatin should be considered after surgical resection per-
formed with curative intent for poorly-differentiated GEP-NECs G3
[26].
6.2. Surgery for metastatic disease
Surgical resection plays an important role also in the multi-
modal management of patients with metastatic disease [24]. Ac-
cording to current guidelines, surgery with curative intent should
be considered in the presence of GEP-NETs G1-G2 with resectable
or potentially resectable liver metastases, when extra-abdominal
disease has been ruled out [24,26,37,123]. On the other hand, pal-
liative resection of the primary tumor is generally recommended to
relieve symptoms related to hormonal hypersecretion and mass ef-
fect [24]. More recently, several retrospective experiences reported
a survival advantage for patients undergoing palliative resection
of the primary tumor in the presence of unresectable metastases
[124,125]. This benefit was particularly pronounced for young pa-
tients with GEP-NETs G1-G2 [125]. In the context of PanNENs, the
most appropriate candidates for palliative resection of the primary
tumor are those patients with G1-low G2 PanNETs located in the
pancreatic body/tail, with no or low disease progression after sev-
eral months of surveillance or medical treatment. On the other
hand, indications for palliative PD are exceptional, due to the high
morbidity and to the presence of a bilio-enteric anastomosis that
will strongly limit future locoregional treatments [26]. It has been
observed that the resection of the primary tumor enhances the ef-
ficacy of other treatments by reducing the disease burden [126].
Hepatic cytoreduction represents another surgical option, that may
ameliorate symptoms and prolong survival [127], also controlling
oligometastatic disease progression [128]. Finally, liver transplanta-
tion (LT) can be considered for highly selected patients with neu-
roendocrine liver metastases fulfilling strict inclusion criteria [129].
Patients who undergo LT have a greater survival benefit as com-
pared with those undergoing alternative treatments [129] although
178 V. Andreasi, S. Partelli and F. Muffatti et al. / Digestive and Liver Disease 53 (2021) 171–182
it has been estimated that only 1% of patients with metastatic GEP-
NENs can be candidates for LT [123].
7. Medical treatment of advanced GEP-NENs
Several options are available for the management of advanced
GEP-NENs.
7.1. Somatostatin analogues (SSAs)
SSAs (octreotide LAR and lanreotide) are generally indicated
for patients with well-differentiated GEP-NETs with two aims: 1)
symptoms control in patients with functioning tumors; 2) antineo-
plastic treatment in patients with locally advanced or metastatic
G1-G2 GEP-NETs expressing SSTRs and with a low burden of dis-
ease [26,123]. Two phase 3 randomized controlled trials, reported
a significantly better progression-free survival (PFS) in the SSA
treatment group, compared to the placebo group, in patients with
metastatic midgut NETs [147] and advanced NF enteropancreatic
NETs G1-G2 [148]. More recently, the CLARINET open-label exten-
sion study suggested that long-term treatment with lanreotide is
safe and well-tolerated [130]. Concerning the long-term outcomes
of patients enrolled in the PROMID trial, OS was similar in patients
receiving octreotide or placebo [131]. However, the crossover of the
majority of patients in the placebo group to octreotide may have
confounded these data.
7.2. Peptide receptor radionuclide therapy (PRRT)
PRRT is another antineoplastic treatment for patients with un-
resectable or metastatic well-differentiated GEP-NETs G1-G2 ex-
pressing SSTRs [132].
The value of PRRT was demonstrated by several sing-arm stud-
ies [133,134] and by a recent phase 3 trial (NETTER-1) that re-
ported a markedly longer PFS in patients affected by advanced
midgut NETs treated with 177 Lu-DOTATATE PRRT + octreotide, as
compared to those who underwent octreotide alone [135]. In the
experimental group, an OS benefit was reported after interim anal-
ysis [135].
PRRT could represent a valuable option also in a salvage set-
ting, as patients who respond to PRRT but subsequently progress
can be retreated with PRRT [136]. PRRT may also be considered
as a potential neoadjuvant treatment in patients with borderline
resectable tumors to downsize the neoplasm [137]. A PFS benefit
has been observed in patients with PanNETs undergoing curative
surgery after neoadjuvant PRRT, as compared to those submitted
to upfront surgery [137].
Finally, a liver selective internal radiation therapy (SIRT) using
90 Yttrium microspheres can be considered in very selected patients
with military hepatic metastases, impaired liver function and/or
contraindications to (chemo)-embolization [26].
7.3. Targeted therapies
Targeted therapies for NETs include everolimus and sunitinib.
Everolimus, an oral inhibitor of the mammalian target of ra-
pamycin, is registered for treatment of advanced, progressive Pan-
NETs and G1-G2 NF-NETs of gastrointestinal and lung origin [138].
These indications are based on two phase 3 randomized controlled
trials (RADIANT-3 and RADIANT-4) that demonstrated a PFS advan-
tage in patients treated with everolimus as compared to placebo
[139,140].
Sunitinib is an oral multi-targeted antiangiogenic agent in-
hibiting endothelial growth factor receptors and platelet-derived
growth factor receptors. Sunitinib is registered for the treatment
of patients with progressive, locally advanced or metastatic, well-
differentiated PanNETs [138]. This indication is based on the results
of a phase 3 study that demonstrated a statistically significant im-
provement in PFS on the sunitinib arm as compared to the placebo
arm in patients with low-intermediate grade progressive PanNETs
[141].
7.4. Chemotherapy
Systemic chemotherapy is generally reccomended for pa-
tients with progressive or bulky GEP-NETs and in those with
high-grade GEP-NENs. Platinum-based chemotherapy with cis-
platin/carboplatin and etoposide/irinotecan is recommended
for patients with poorly-differentiated NECs G3 [142]. On the
other hand, well-differentiated PanNETs are particularly sen-
sitive to streptozocin (STZ) or temozolomide (TEM), typically
combined with 5-fluorouracile or capecitabine. European Neuroen-
docrine Tumor Society (ENETS) guidelines recommend STZ-based
chemotherapy for patients with PanNETs G1-G2 with high tumor
burden and/or when a significant tumor progression occurs in <
6-12 months [26,123]. When the disease is predominantly located
in the liver, a transarterial embolization or chemoembolization
using STZ can be performed, unless a biliary anastomosis or a
stent or a complete portal thrombosis are present [26]. However,
the capecitabine-temozolomide (CAP/TEM) regimen is nowadays
gaining popularity and replacing STZ-based chemotherapy. Several
studies evaluating TEM-based chemotherapy reported response
rates up to 70%, with the highest ones for CAP/TEM in patients
with PanNETs [143,144]. Other recent data from an ongoing phase
2 randomized trial showed a PFS and OS improvement in the
CAP/TEM group, as compared to TEM alone, among 144 patients
with progressive PanNETs G1-G2 [145]. The best duration of
CAP/TEM treatment is still controversial although Chatzellis et al.
recently reported that this regimen is effective and safe even after
prolonged (> 12 months) administration [146].
7.5. Medical management of PanNETs G3
Well-differentiated GEP-NETs G3 represent a new diagnostic
and clinical entity, and their optimal management is still not stan-
dardized. Being the pancreas the most frequent primary tumor site
[19,20], PanNETs G3 deserve a separate mention. As previously re-
ported, current guidelines recommend surgical resection for local-
ized well-differentiated PanNETs G3 [37,147] and no data suggest
a benefit from adjuvant treatment [120,148]. On the other hand,
chemotherapy represents the gold standard in patients with ad-
vanced or metastatic PanNETs G3 [123]. In this setting, several
chemotherapy regimens have been investigated: PanNETs G3 with
Ki67 below 55% should be managed similarly to PanNETs G1-G2,
whereas PanNETs G3 with Ki67 higher than 55% require a man-
agement in line with that of PanNECs G3 [148]. Based on current
evidence, the CAP/TEM regimen seems to represent a reasonable
first-line therapy for patients with well-differentiated PanNETs G3
with Ki67 < 55% [37,148], with objective response rates ranging
between 33% and 70% [1]. In this regard, Strosberg et al. reported
high and durable response rates in patients with metastatic Pan-
NENs G3 treated with a combination of capecitabine (from day
1 to 14) and temozolomide (from day 10 to 14) [143]. Further-
more, a recent multicenter retrospective review including 118 pa-
tients with metastatic/unresectable GEP-NENs G3 (75% pancreatic)
showed that NETs G3 had better clinical and oncological outcomes
as compared to poorly-differentiated neoplasms. Therefore, TEM-
based regimens should be regarded as a valuable treatment option
in this setting [149]. As a second-line strategy for treating these
patients, irinotecan in addition to 5-fluorouracil (FOLFIRI) can be
considered [150]. On the other hand, when PanNETs G3 display a
 V. Andreasi, S. Partelli and F. Muffatti et al. / Digestive and Liver Disease 53 (2021) 171–182
Ki67 ≥ 55% a platinum-based chemotherapy (cisplatin-etoposide)
represents the first choice [123,148].
7.6. Management of particular metastatic sites
Bone metastases are present in 10–20% of patients with
metastatic GEP-NENs and can be associated with a poor prognosis.
In the presence of symptoms, such as pain and compression, ra-
diotherapy, surgery, radiofrequency ablation and cryotherapy might
be considered [26]. Peritoneal carcinomatosis (PC) affects 10-30%
of patients with GEP-NENs [100]. According to current guidelines,
complete resection of PC seems to be beneficial in terms of survival
[26]. The addition of hyperthermic intraperitoneal chemotherapy
(HIPEC) carries a high morbidity without being associated with a
further survival improvement [26]. Therefore, HIPEC is not recom-
mended in the management of GEP-NENs with PC.
8. Conclusions
The management of GEP-NENs spans a wide variety of options
that can be integrated in the context of a multimodal strategy. A
conservative treatment can be considered for patients with small
and asymptomatic lesions without features of aggressiveness. On
the other hand, surgical resection is the backbone for the cura-
tive treatment of localized disease, but it might play a role also
in selected patients with high-grade or metastatic GEP-NENs. Fi-
nally, several medical therapies are available for the management
of advanced and unresectable neoplasms, alone or combined with
other medical or locoregional treatments.
Declaration of Competing Interest
The Authors declare that there are no conflicts of interest asso-
ciated with this publication and there has been no financial sup-
port for this work that could have influenced its outcome.
Acknowledgements
The authors are grateful to Gioja Bianca Costanza Fund for sup-
porting the PhD Scholarship of Dr. Valentina Andreasi and the Re-
search Fellowship of Dr. Francesca Muffatti. Authors thank the ERN
EURACAN initiative.
References
[1] Cives M, Strosberg JR. Gastroenteropancreatic Neuroendocrine Tumors. CA
Cancer J Clin 2018;68:471–87. doi:10.3322/caac.21493.
[2] Singh S, Law C. Multidisciplinary reference centers: the care of neuroen-
docrine tumors. J Oncol Pract 2010;6:e11–16. doi:10.120 0/JOP.2010.0 0 0 098.
[3] Boyar Cetinkaya R, Aagnes B, Thiis-Evensen E, Tretli S, Bergestuen DS,
Hansen S. Trends in incidence of neuroendocrine neoplasms in norway:
a report of 16,075 cases from 1993 through 2010. Neuroendocrinology
2017;104:1–10. doi:10.1159/0 0 0442207.
[4] Wyld D, Wan MH, Moore J, Dunn N, Youl P. Epidemiological trends of neu-
roendocrine tumours over three decades in Queensland, Australia. Cancer Epi-
demiol 2019;63:101598. doi:10.1016/j.canep.2019.101598.
[5] Dasari A, Shen C, Halperin D, Zhao B, Zhou S, Xu Y, et al. Trends in
the incidence, prevalence, and survival outcomes in patients with neuroen-
docrine tumors in the United States. JAMA Oncol 2017;3:1335–42. doi:10.
1001/jamaoncol.2017.0589.
[6] Hallet J, Law CHL, Cukier M, Saskin R, Liu N, Singh S. Exploring the ris-
ing incidence of neuroendocrine tumors: a population-based analysis of epi-
demiology, metastatic presentation, and outcomes. Cancer 2015;121:589–97.
doi:10.1002/cncr.29099.
[7] Solcia E, Kloppel G SL. Histological typing of endocrine tumors. WHO inter-
national histological classification of tumors. 2nd ed. Berlin: Springer; 20 0 0.
[8] Heitz PU, Komminoth P, Perren A, Klimstra DS DY. Pancreatic endocrine tu-
mors: introduction. In: DeLellis RA, Lloyd RV, Heitz PU EC, editors. Pathol.
Genet. tumors Endocr. organs. Lyon: WHO Classif. tumors.; 2004. p. 177–82.
[9] Fraenkel M, Kim M, Faggiano A, de Herder WW, Valk GD. Incidence of gas-
troenteropancreatic neuroendocrine tumours: a systematic review of the lit-
erature. Endocr Relat Cancer 2014;21:R153–63. doi:10.1530/ERC- 13- 0125.
179
[10] Frilling A, Akerstrom G, Falconi M, Pavel M, Ramos J, Kidd M, et al. Neu-
roendocrine tumor disease: an evolving landscape. Endocr Relat Cancer
2012;19:R163–85. doi:10.1530/ERC- 12- 0024.
[11] Lawrence B, Gustafsson BI, Chan A, Svejda B, Kidd M, Modlin IM. The
epidemiology of gastroenteropancreatic neuroendocrine tumors. Endocrinol
Metab Clin North Am 2011;40:1–18 vii. doi:10.1016/j.ecl.2010.12.005.
[12] Cao L-L, Lu J, Lin J-X, Zheng C-H, Li P, Xie J-W, et al. Incidence and survival
trends for gastric neuroendocrine neoplasms: An analysis of 3523 patients in
the SEER database. Eur J Surg Oncol 2018;44:1628–33. doi:10.1016/j.ejso.2018.
01.082.
[13] Kooyker AI, Verbeek WH, van den Berg JG, Tesselaar ME, van Leerdam ME.
Change in incidence, characteristics and management of colorectal neuroen-
docrine tumours in the Netherlands in the last decade. United Eur Gastroen-
terol J 2020;8:59–67. doi:10.1177/2050640619865113.
[14] Kuo EJ, Salem RR. Population-level analysis of pancreatic neuroendocrine tu-
mors 2 cm or less in size. Ann Surg Oncol 2013;20:2815–21. doi:10.1245/
s10434- 013- 3005- 7.
[15] Singh H, Koomson AS, Decker KM, Park J, Demers AA. Continued increasing
incidence of malignant appendiceal tumors in Canada and the United States:
A population-based study. Cancer 2020;126:2206–16. doi:10.1002/cncr.32793.
[16] Kishi S, Sakamoto K, Mori M, Isogawa A, Shiba T. Asymptomatic insulinoma:
a case report and autopsy series. Diabetes Res Clin Pract 2012;98:445–51.
doi:10.1016/j.diabres.2012.08.007.
[17] Partelli S, Giannone F, Schiavo Lena M, Muffatti F, Andreasi V, Crippa S, et al.
Is the real prevalence of pancreatic neuroendocrine tumors underestimated?
A retrospective study on a large series of pancreatic specimens. Neuroen-
docrinology 2019. doi:10.1159/0 0 0499606.
[18] Scoazec J-Y, Couvelard A, Monges G, Guyétant S, Bisot-Locard S, Parot X,
et al. Professional practices and diagnostic issues in neuroendocrine tumour
pathology: results of a prospective one-year survey among French patholo-
gists (the PRONET Study). Neuroendocrinology 2017;105:67–76. doi:10.1159/
0 0 0448431.
[19] Heetfeld M, Chougnet CN, Olsen IH, Rinke A, Borbath I, Crespo G, et al. Char-
acteristics and treatment of patients with G3 gastroenteropancreatic neu-
roendocrine neoplasms. Endocr Relat Cancer 2015;22:657–64. doi:10.1530/
ERC- 15- 0119.
[20] Sorbye H, Welin S, Langer SW, Vestermark LW, Holt N, Osterlund P, et al.
Predictive and prognostic factors for treatment and survival in 305 patients
with advanced gastrointestinal neuroendocrine carcinoma (WHO G3): the
NORDIC NEC study. Ann Oncol Off J Eur Soc Med Oncol 2013;24:152–60.
doi:10.1093/annonc/mds276.
[21] Delle Fave G, O’Toole D, Sundin A, Taal B, Ferolla P, Ramage JK, et al. ENETS
consensus guidelines update for gastroduodenal neuroendocrine neoplasms.
Neuroendocrinology 2016;103:119–24. doi:10.1159/0 0 0443168.
[22] Pasquer A, Walter T, Hervieu V, Forestier J, Scoazec J-Y, Lombard-Bohas C,
et al. Surgical management of small bowel neuroendocrine tumors: specific
requirements and their impact on staging and prognosis. Ann Surg Oncol
2015;22(Suppl 3):S742–9. doi:10.1245/s10434- 015- 4620- 2.
[23] Keck KJ, Maxwell JE, Menda Y, Bellizzi A, Dillon J, O’Dorisio TM, et al. Iden-
tification of primary tumors in patients presenting with metastatic gastroen-
teropancreatic neuroendocrine tumors. Surgery 2017;161:272–9. doi:10.1016/
j.surg.2016.05.055.
[24] Partelli S, Bartsch DK, Capdevila J, Chen J, Knigge U, Niederle B, et al.
ENETS consensus guidelines for standard of care in neuroendocrine tumours:
surgery for small intestinal and pancreatic neuroendocrine tumours. Neu-
roendocrinology 2017;105:255–65. doi:10.1159/0 0 0464292.
[25] Dromain C, de Baere T, Lumbroso J, Caillet H, Laplanche A, Boige V, et al.
Detection of liver metastases from endocrine tumors: a prospective compari-
son of somatostatin receptor scintigraphy, computed tomography, and mag-
netic resonance imaging. J Clin Oncol 2005;23:70–8. doi:10.1200/JCO.2005.
01.013.
[26] de Mestier L, Lepage C, Baudin E, Coriat R, Courbon F, Couvelard A, et al.
Digestive neuroendocrine neoplasms (NEN): French Intergroup clinical prac-
tice guidelines for diagnosis, treatment and follow-up (SNFGE, GTE, RENATEN,
TENPATH, FFCD, GERCOR, UNICANCER, SFCD, SFED, SFRO, SFR). Dig Liver Dis
Off J Ital Soc Gastroenterol Ital Assoc Study Liver 2020;52:473–92. doi:10.
1016/j.dld.2020.02.011.
[27] Moryoussef F, de Mestier L, Belkebir M, Deguelte-Lardiere S, Brixi H, Kian-
manesh R, et al. Impact of liver and whole-body diffusion-weighted MRI
for neuroendocrine tumors on patient management: a pilot study. Neuroen-
docrinology 2017;104:264–72. doi:10.1159/0 0 0446369.
[28] Ramage JK, De Herder WW, Delle Fave G, Ferolla P, Ferone D, Ito T, et al.
ENETS consensus guidelines update for colorectal neuroendocrine neoplasms.
Neuroendocrinology 2016. doi:10.1159/0 0 0443166.
[29] Di Leo M, Poliani L, Rahal D, Auriemma F, Anderloni A, Ridolfi C, et al. Pan-
creatic neuroendocrine tumours: the role of endoscopic ultrasound biopsy
in diagnosis and grading based on the WHO 2017 classification. Dig Dis
2019;37:325–33. doi:10.1159/0 0 0499172.
[30] O’Toole D, Palazzo L. Endoscopy and endoscopic ultrasound in assessing
and managing neuroendocrine neoplasms. Front Horm Res 2015;44:88–103.
doi:10.1159/0 0 0382062.
[31] de Mestier L, Lorenzo D, Fine C, Cros J, Hentic O, Walter T, et al. Endoscopic,
transanal, laparoscopic, and transabdominal management of rectal neuroen-
docrine tumors. Best Pract Res Clin Endocrinol Metab 2019;33:101293. doi:10.
1016/j.beem.2019.101293.
180 V. Andreasi, S. Partelli and F. Muffatti et al. / Digestive and Liver Disease 53 (2021) 171–182
[32] Noujaim MG, Green J, Min M, Schlieve CR, Patel K, Cahan M, et al. Carci-
noids and capsules: a case series highlighting the utility of capsule endoscopy
in patients with small bowel carcinoids. Gastroenterol Res 2017;10:347–51.
doi:10.14740/gr937w.
[33] Board WC of TE WHO classification of tumours. digestive system tumours.
5th ed editor. Lyon: IARC Press; 2019.
[34] Lloyd RV, Osamura RY, Klopper G, Rosai J, editors. WHO classification of tu-
mours of endocrine organs. 4th ed.. Lyon: IARC; 2017.
[35] Sawicki LM, Deuschl C, Beiderwellen K, Ruhlmann V, Poeppel TD, Heusch P,
et al. Evaluation of (68)Ga-DOTATOC PET/MRI for whole-body staging of neu-
roendocrine tumours in comparison with (68)Ga-DOTATOC PET/CT. Eur Radiol
2017;27:4091–9. doi:10.10 07/s0 0330- 017- 4803- 2.
[36] Falconi M, Eriksson B, Kaltsas G, Bartsch DK, Capdevila J, Caplin M, et al.
ENETS consensus guidelines update for the management of patients with
functional pancreatic neuroendocrine tumors and non-functional pancreatic
neuroendocrine tumors. Neuroendocrinology 2016;103:153–71. doi:10.1159/
0 0 0443171.
[37] Howe JR, Merchant NB, Conrad C, Keutgen XM, Hallet J, Drebin JA, et al. The
North American neuroendocrine tumor society consensus paper on the surgi-
cal management of pancreatic neuroendocrine tumors. Pancreas 2020;49:1–
33. doi:10.1097/MPA.0 0 0 0 0 0 0 0 0 0 0 01454.
[38] Sadowski SM, Neychev V, Millo C, Shih J, Nilubol N, Herscovitch P,
et al. Prospective Study of 68Ga-DOTATATE positron emission tomogra-
phy/computed tomography for detecting gastro-entero-pancreatic neuroen-
docrine tumors and unknown primary sites. J Clin Oncol 2016;34:588–96.
doi:10.1200/JCO.2015.64.0987.
[39] Skoura E, Michopoulou S, Mohmaduvesh M, Panagiotidis E, Al Harbi M,
Toumpanakis C, et al. The impact of 68Ga-DOTATATE PET/CT imaging on
management of patients with neuroendocrine tumors: experience from a
national referral center in the United Kingdom. J Nucl Med 2016;57:34–40.
doi:10.2967/jnumed.115.166017.
[40] Crown A, Rocha FG, Raghu P, Lin B, Funk G, Alseidi A, et al. Impact of initial
imaging with gallium-68 dotatate PET/CT on diagnosis and management of
patients with neuroendocrine tumors. J Surg Oncol 2020;121:480–5. doi:10.
1002/jso.25812.
[41] Altieri B, Di Dato C, Martini C, Sciammarella C, Di Sarno A, Colao A, et al.
Bone metastases in neuroendocrine neoplasms: from pathogenesis to clinical
management. Cancers (Basel) 2019;11. doi:10.3390/cancers11091332.
[42] van Adrichem RCS, Kamp K, van Deurzen CHM, Biermann K, Feelders RA,
Franssen GJH, et al. Is there an additional value of using somatostatin re-
ceptor subtype 2a immunohistochemistry compared to somatostatin receptor
scintigraphy uptake in predicting gastroenteropancreatic neuroendocrine tu-
mor response? Neuroendocrinology 2016;103:560–6. doi:10.1159/0 0 0441604.
[43] Hofman MS, Lau WFE, Hicks RJ. Somatostatin receptor imaging with 68Ga
DOTATATE PET/CT: clinical utility, normal patterns, pearls, and pitfalls in in-
terpretation. Radiographics 2015;35:500–16. doi:10.1148/rg.352140164.
[44] Christ E, Antwi K, Fani M, Wild D. Innovative imaging of insulinoma: the end
of sampling? A review. Endocr Relat Cancer 2020. doi:10.1530/ERC- 19- 0476.
[45] Reubi JC, Waser B. Concomitant expression of several peptide receptors
in neuroendocrine tumours: molecular basis for in vivo multireceptor tu-
mour targeting. Eur J Nucl Med Mol Imaging 2003;30:781–93. doi:10.1007/
s0 0259-0 03-1184-3.
[46] Antwi K, Fani M, Heye T, Nicolas G, Rottenburger C, Kaul F, et al. Compar-
ison of glucagon-like peptide-1 receptor (GLP-1R) PET/CT, SPECT/CT and 3T
MRI for the localisation of occult insulinomas: evaluation of diagnostic accu-
racy in a prospective crossover imaging study. Eur J Nucl Med Mol Imaging
2018;45:2318–27. doi:10.10 07/s0 0259- 018- 4101- 5.
[47] Partelli S, Rinzivillo M, Maurizi A, Panzuto F, Salgarello M, Polenta V, et al.
The role of combined Ga-DOTANOC and (18)FDG PET/CT in the manage-
ment of patients with pancreatic neuroendocrine tumors. Neuroendocrinol-
ogy 2014;100:293–9. doi:10.1159/0 0 0368609.
[48] Zhang P, Yu J, Li J, Shen L, Li N, Zhu H, et al. Clinical and Prognostic Value
of PET/CT Imaging with Combination of (68)Ga-DOTATATE and (18)F-FDG
in Gastroenteropancreatic Neuroendocrine Neoplasms. Contrast Media Mol
Imaging 2018;2018:2340389. doi:10.1155/2018/2340389.
[49] Matsumoto T, Okabe H, Yamashita Y-I, Yusa T, Itoyama R, Nakao Y, et al. Clini-
cal role of fludeoxyglucose (18F) positron emission tomography/computed to-
mography ((18)F-FDG PET/CT) in patients with pancreatic neuroendocrine tu-
mors. Surg Today 2019;49:21–6. doi:10.10 07/s0 0595- 018- 1703- 2.
[50] Rinzivillo M, Partelli S, Prosperi D, Capurso G, Pizzichini P, Iannicelli E,
et al. Clinical usefulness of (18)F-fluorodeoxyglucose positron emission
tomography in the diagnostic algorithm of advanced entero-pancreatic
neuroendocrine neoplasms. Oncologist 2018;23:186–92. doi:10.1634/
theoncologist.2017-0278.
[51] Marotta V, Zatelli MC, Sciammarella C, Ambrosio MR, Bondanelli M, Colao A,
et al. Chromogranin A as circulating marker for diagnosis and management
of neuroendocrine neoplasms: more flaws than fame. Endocr Relat Cancer
2018;25:R11–29. doi:10.1530/ERC- 17- 0269.
[52] Oberg K, Modlin IM, De Herder W, Pavel M, Klimstra D, Frilling A, et al.
Consensus on biomarkers for neuroendocrine tumour disease. Lancet Oncol
2015;16:e435–46. doi:10.1016/S1470-2045(15)00186-2.
[53] Andreasi V, Partelli S, Manzoni M, Muffatti F, Colombo B, Corti A, et al. Associ-
ation between preoperative Vasostatin-1 and pathological features of aggres-
siveness in localized nonfunctioning pancreatic neuroendocrine tumors (NF-
PanNET). Pancreatology 2019;19:57–63. doi:10.1016/j.pan.2018.11.005.
[54] Malczewska A, Witkowska M, Wojcik-Giertuga M, Kusnierz K, Bocian A, Wal-
ter A, et al. Prospective Evaluation of the NETest as a Liquid Biopsy for
Gastroenteropancreatic and Bronchopulmonary Neuroendocrine Tumours: An
ENETS Centre of Excellence Experience. Neuroendocrinology 2020. doi:10.
1159/0 0 0508106.
[55] Partelli S, Andreasi V, Muffatti F, Schiavo Lena M, Falconi M. Circulating neu-
roendocrine gene transcripts (NETest): a postoperative strategy for early iden-
tification of the efficacy of radical surgery for pancreatic neuroendocrine tu-
mors. Ann Surg Oncol 2020. doi:10.1245/s10434- 020- 08425- 6.
[56] Bodei L, Kidd MS, Singh A, van der Zwan WA, Severi S, Drozdov IA, et al.
PRRT neuroendocrine tumor response monitored using circulating transcript
analysis: the NETest. Eur J Nucl Med Mol Imaging 2020;47:895–906. doi:10.
10 07/s0 0259- 019- 04601- 3.
[57] Sato Y, Hashimoto S, Mizuno K-I, Takeuchi M, Terai S. Management of gastric
and duodenal neuroendocrine tumors. World J Gastroenterol 2016;22:6817–
28. doi:10.3748/wjg.v22.i30.6817.
[58] Grozinsky-Glasberg S, Thomas D, Strosberg JR, Pape U-F, Felder S, Tsolakis A
V, et al. Metastatic type 1 gastric carcinoid: a real threat or just a myth?
World J Gastroenterol 2013;19:8687–95. doi:10.3748/wjg.v19.i46.8687.
[59] Panzuto F, Campana D, Massironi S, Faggiano A, Rinzivillo M, Lamberti G,
et al. Tumour type and size are prognostic factors in gastric neuroendocrine
neoplasia: A multicentre retrospective study. Dig Liver Dis 2019;51:1456–60.
doi:10.1016/j.dld.2019.04.016.
[60] Vanoli A, La Rosa S, Miceli E, Klersy C, Maragliano R, Capuano F, et al.
Prognostic evaluations tailored to specific gastric neuroendocrine neo-
plasms: analysis of 200 cases with extended follow-up. Neuroendocrinology
2018;107:114–26. doi:10.1159/0 0 0489902.
[61] Ariotti R, Partelli S, Muffatti F, Andreasi V, della Sala F, Falconi M. How should
incidental NEN of the pancreas and gastrointestinal tract be followed? Rev
Endocr Metab Disord 2018. doi:10.1007/s11154- 018- 9445- 4.
[62] Merola E, Sbrozzi-Vanni A, Panzuto F, D’Ambra G, Di Giulio E, Pilozzi E,
et al. Type I gastric carcinoids: a prospective study on endoscopic manage-
ment and recurrence rate. Neuroendocrinology 2012;95:207–13. doi:10.1159/
0 0 0329043.
[63] Manfredi S, Walter T, Baudin E, Coriat R, Ruszniewski P, Lecomte T, et al. Man-
agement of gastric neuro-endocrine tumours in a large French national cohort
(GTE). Endocrine 2017;57:504–11. doi:10.1007/s12020- 017- 1355- 9.
[64] Daskalakis K, Tsoli M, Karapanagioti A, Chrysochoou M, Thomas D, Sou-
gioultzis S, et al. Recurrence and metastatic potential in Type 1 gastric neu-
roendocrine neoplasms. Clin Endocrinol (Oxf) 2019;91:534–43. doi:10.1111/
cen.14055.
[65] Kwon YH, Jeon SW, Kim GH, Il Kim J, Chung I-K, Jee SR, et al. Long-term fol-
low up of endoscopic resection for type 3 gastric NET. World J Gastroenterol
2013;19:8703–8. doi:10.3748/wjg.v19.i46.8703.
[66] Min B-H, Hong M, Lee JH, Rhee P-L, Sohn TS, Kim S, et al. Clinicopathological
features and outcome of type 3 gastric neuroendocrine tumours. Br J Surg
2018;105:1480–6. doi:10.1002/bjs.10901.
[67] Randle RW, Ahmed S, Newman NA, Clark CJ. Clinical outcomes for neuroen-
docrine tumors of the duodenum and ampulla of Vater: a population-based
study. J Gastrointest Surg 2014;18:354–62. doi:10.1007/s11605- 013- 2365- 4.
[68] Vanoli A, La Rosa S, Klersy C, Grillo F, Albarello L, Inzani F, et al. Four
Neuroendocrine Tumor Types and Neuroendocrine Carcinoma of the Duo-
denum: Analysis of 203 Cases. Neuroendocrinology 2017;104:112–25. doi:10.
1159/0 0 0444803.
[69] Massironi S, Campana D, Partelli S, Panzuto F, Rossi RE, Faggiano A, et al. Het-
erogeneity of duodenal neuroendocrine tumors: an italian multi-center expe-
rience. Ann Surg Oncol 2018;25:3200–6. doi:10.1245/s10434- 018- 6673- 5.
[70] Lee SW, Sung JK, Cho YS, Bang KB, Kang SH, Kim KB, et al. Comparisons
of therapeutic outcomes in patients with nonampullary duodenal neuroen-
docrine tumors (NADNETs): A multicenter retrospective study. Medicine (Bal-
timore) 2019;98:e16154. doi:10.1097/.0 0 0 0 0 0 0 0 0 0 016154.
[71] Park SG, Lee BE, Kim GH, Park JW, Lee MW, Kim SJ, et al. Risk factors for
lymph node metastasis in duodenal neuroendocrine tumors: A retrospective,
single-center study. Medicine (Baltimore) 2019;98:e15885. doi:10.1097/MD.
0 0 0 0 0 0 0 0 0 0 015885.
[72] Niessen A, Bergmann F, Hinz U, Schimmack S, Hackert T, Buchler MW, et al.
Surgical resection for duodenal neuroendocrine neoplasia: Outcome, prognos-
tic factors and risk of metastases. Eur J Surg Oncol 2020. doi:10.1016/j.ejso.
2020.01.030.
[73] Partelli S, Cirocchi R, Crippa S, Cardinali L, Fendrich V, Bartsch DK, et al. Sys-
tematic review of active surveillance versus surgical management of asymp-
tomatic small non-functioning pancreatic neuroendocrine neoplasms. Br J
Surg 2017;104:34–41. doi:10.1002/bjs.10312.
[74] Barenboim A, Lahat G, Nachmany I, Nakache R, Goykhman Y, Geva R,
et al. Resection versus observation of small asymptomatic nonfunctioning
pancreatic neuroendocrine tumors. J Gastrointest Surg 2019. doi:10.1007/
s11605- 019- 04285- y.
[75] Partelli S, Mazza M, Andreasi V, Muffatti F, Crippa S, Tamburrino D, et al.
Management of small asymptomatic nonfunctioning pancreatic neuroen-
docrine tumors: Limitations to apply guidelines into real life. Surg (United
States) 2019. doi:10.1016/j.surg.2019.04.003.
[76] Assi HA, Mukherjee S, Kunz PL, Machiorlatti M, Vesely S, Pareek V, et al.
Surgery versus surveillance for well-differentiated, nonfunctional pancreatic
neuroendocrine tumors: an 11-year analysis of the national cancer database.
Oncologist 2019. doi:10.1634/theoncologist.2019-0466.
 V. Andreasi, S. Partelli and F. Muffatti et al. / Digestive and Liver Disease 53 (2021) 171–182
[77] Powers BD, Rothermel LD, Fleming JB, Strosberg JR, Anaya DA. A survival
analysis of patients with localized, asymptomatic pancreatic neuroendocrine
tumors: no surgical survival benefit when examining appropriately selected
outcomes. J Gastrointest Surg 2019. doi:10.1007/s11605- 019- 04433- 4.
[78] Mintziras I, Keck T, Werner J, Fichtner-Feigl S, Wittel U, Senninger N, et al.
Implementation of current ENETS guidelines for surgery of small (≤2 cm)
pancreatic neuroendocrine neoplasms in the german surgical community: an
analysis of the prospective DGAV StuDoQ|Pancreas registry. World J Surg 2019.
doi:10.10 07/s0 0268- 018- 4751- 2.
[79] Partelli S, Muffatti F, Rancoita PMV, Andreasi V, Balzano G, Crippa S, et al.
The size of well differentiated pancreatic neuroendocrine tumors correlates
with Ki67 proliferative index and is not associated with age. Dig Liver Dis
2019;51:735–40. doi:10.1016/j.dld.2019.01.008.
[80] Massironi S, Partelli S, Petrone MC, Zilli A, Conte D, Falconi M, et al. En-
doscopic ultrasound appearance of pancreatic serotonin-staining neuroen-
docrine neoplasms. Pancreatology 2018;18:792–8. doi:10.1016/j.pan.2018.08.
004.
[81] Walsh JC, Schaeffer DF, Kirsch R, Pollett A, Manzoni M, Riddell RH, et al. Ileal
“carcinoid” tumors-small size belies deadly intent: high rate of nodal metas-
tasis in tumors </=1 cm in size. Hum Pathol 2016;56:123–7. doi:10.1016/j.
humpath.2016.05.023.
[82] Rault-Petit B, Do Cao C, Guyetant S, Guimbaud R, Rohmer V, Julie C, et al.
Current management and predictive factors of lymph node metastasis of
appendix neuroendocrine tumors: a national study from the french group
of endocrine tumors (GTE). Ann Surg 2019;270:165–71. doi:10.1097/SLA.
0 0 0 0 0 0 0 0 0 0 0 02736.
[83] Pape UF, Niederle B, Costa F, Gross D, Kelestimur F, Kianmanesh R, et al.
ENETS consensus guidelines for neuroendocrine neoplasms of the appendix
(excluding goblet cell carcinomas). Neuroendocrinology 2016;103:144–52.
doi:10.1159/0 0 0443165.
[84] Broecker JS, Ethun CG, Postlewait LM, Le N, McInnis M, Russell MC,
et al. Colon and rectal neuroendocrine tumors: are they really one dis-
ease? a single-institution experience over 15 years. Am Surg 2018;84:
717–726.
[85] Folkert IW, Sinnamon AJ, Concors SJ, Bennett BJ, Fraker DL, Mahmoud NN,
et al. Grade is a dominant risk factor for metastasis in patients with rec-
tal neuroendocrine tumors. Ann Surg Oncol 2020;27:855–63. doi:10.1245/
s10434- 019- 07848- 0.
[86] Gamboa AC, Liu Y, Lee RM, Zaidi MY, Staley CA, Russell MC, et al. A novel
preoperative risk score to predict lymph node positivity for rectal neuroen-
docrine tumors: An NCDB analysis to guide operative technique. J Surg Oncol
2019;120:932–9. doi:10.1002/jso.25679.
[87] Chen W-J, Wu N, Zhou J-L, Lin G-L, Qiu H-Z. Full-thickness excision using
transanal endoscopic microsurgery for treatment of rectal neuroendocrine tu-
mors. World J Gastroenterol 2015;21:9142–9. doi:10.3748/wjg.v21.i30.9142.
[88] Crown A, Kennecke H, Kozarek R, Lopez-Aguiar AG, Dillhoff M, Beal EW, et al.
Gastric carcinoids: Does type of surgery or tumor affect survival? Am J Surg
2019;217:937–42. doi:10.1016/j.amjsurg.2018.12.057.
[89] Dogeas E, Cameron JL, Wolfgang CL, Hirose K, Hruban RH, Makary MA,
et al. Duodenal and ampullary carcinoid tumors: size predicts neces-
sity for lymphadenectomy. J Gastrointest Surg 2017;21:1262–9. doi:10.1007/
s11605- 017- 3448- 4.
[90] Zhang X-F, Wu X-N, Tsilimigras DI, Poultsides G, Rocha F, Abbott DE, et al.
Duodenal neuroendocrine tumors: Impact of tumor size and total number
of lymph nodes examined. J Surg Oncol 2019;120:1302–10. doi:10.1002/jso.
25753.
[91] Zaidi MY, Lopez-Aguiar AG, Switchenko JM, Lipscomb J, Andreasi V, Partelli S,
et al. A novel validated recurrence risk score to guide a pragmatic surveillance
strategy after resection of pancreatic neuroendocrine tumors: an international
study of 1006 patients. Ann Surg 2019. doi:10.1097/SLA.0 0 0 0 0 0 0 0 0 0 0 03461.
[92] Genc CG, Jilesen AP, Partelli S, Falconi M, Muffatti F, van Kemenade FJ, et al.
A new scoring system to predict recurrent disease in grade 1 and 2 non-
functional pancreatic neuroendocrine tumors. Ann Surg 2018;267:1148–54.
doi:10.1097/SLA.0 0 0 0 0 0 0 0 0 0 0 02123.
[93] Partelli S, Gaujoux S, Boninsegna L, Cherif R, Crippa S, Couvelard A, et al.
Pattern and clinical predictors of lymph node involvement in nonfunctioning
pancreatic neuroendocrine tumors (NF-PanNETs). JAMA Surg 2013;148:932–9.
doi:10.1001/jamasurg.2013.3376.
[94] Partelli S, Javed AA, Andreasi V, He J, Muffatti F, Weiss MJ, et al. The num-
ber of positive nodes accurately predicts recurrence after pancreaticoduo-
denectomy for nonfunctioning neuroendocrine neoplasms. Eur J Surg Oncol
2018;44. doi:10.1016/j.ejso.2018.03.005.
[95] Zhang X-F, Xue F, Dong D-H, Lopez-Aguiar AG, Poultsides G, Makris E, et al.
New nodal staging for primary pancreatic neuroendocrine tumors: a multi-
institutional and national data analysis. Ann Surg 2019. doi:10.1097/SLA.
0 0 0 0 0 0 0 0 0 0 0 03478.
[96] Lopez-Aguiar AG, Zaidi MY, Beal EW, Dillhoff M, Cannon JGD, Poultsides GA,
et al. Defining the role of lymphadenectomy for pancreatic neuroendocrine
tumors: an eight-institution study of 695 patients from the US neuroen-
docrine tumor study group. Ann Surg Oncol 2019;26:2517–24. doi:10.1245/
s10434- 019- 07367- y.
[97] Partelli S, Boninsegna L, Salvia R, Bassi C, Pederzoli P, Falconi M. Middle-
preserving pancreatectomy for multicentric body-sparing lesions of the pan-
creas. Am J Surg 2009;198:e49–53. doi:10.1016/j.amjsurg.2009.02.017.
[98] Andreasi V, Partelli S, Capurso G, Muffatti F, Balzano G, Crippa S, et al. Long-
term pancreatic functional impairment after surgery for neuroendocrine neo-
plasms. J Clin Med 2019;8. doi:10.3390/jcm8101611.
181
[99] Lim PW, Dinh KH, Sullivan M, Wassef WY, Zivny J, Whalen GF, et al. Thirty-
day outcomes underestimate endocrine and exocrine insufficiency after pan-
creatic resection. HPB 2016. doi:10.1016/j.hpb.2015.11.003.
[100] Howe JR, Cardona K, Fraker DL, Kebebew E, Untch BR, Wang Y-Z, et al.
The surgical management of small bowel neuroendocrine tumors: consen-
sus guidelines of the North American neuroendocrine tumor society. Pancreas
2017;46:715–31. doi:10.1097/MPA.0 0 0 0 0 0 0 0 0 0 0 0 0846.
[101] Lardiere-Deguelte S, de Mestier L, Appere F, Vullierme M-P, Zappa M, Ho-
effel C, et al. Toward a preoperative classification of lymph node metas-
tases in patients with small intestinal neuroendocrine tumors in the era of
intestinal-sparing surgery. Neuroendocrinology 2016;103:552–9. doi:10.1159/
0 0 0441423.
[102] Landry CS, Lin HY, Phan A, Charnsangavej C, Abdalla EK, Aloia T, et al. Re-
section of at-risk mesenteric lymph nodes is associated with improved sur-
vival in patients with small bowel neuroendocrine tumors. World J Surg
2013;37:1695–700. doi:10.10 07/s0 0268- 013- 1918- 8.
[103] Zaidi MY, Lopez-Aguiar AG, Dillhoff M, Beal E, Poultsides G, Makris E,
et al. Prognostic role of lymph node positivity and number of lymph nodes
needed for accurately staging small-bowel neuroendocrine tumors. JAMA
Surg 2019;154:134–40. doi:10.1001/jamasurg.2018.3865.
[104] Brighi N, La Rosa S, Rossi G, Grillo F, Pusceddu S, Rinzivillo M, et al. Mor-
phological factors related to nodal metastases in neuroendocrine tumors of
the appendix: a multicentric retrospective study. Ann Surg 2020;271:527–33.
doi:10.1097/SLA.0 0 0 0 0 0 0 0 0 0 0 02939.
[105] Ricci C, Ingaldi C, Alberici L, Brighi N, Santini D, Mosconi C, et al. Histopatho-
logical diagnosis of appendiceal neuroendocrine neoplasms: when to perform
a right hemicolectomy? A systematic review and meta-analysis. Endocrine
2019:1–7. doi:10.1007/s12020- 019- 01984- z.
[106] Daskalakis K, Alexandraki K, Kassi E, Tsoli M, Angelousi A, Ragkousi A, et al.
The risk of lymph node metastases and their impact on survival in patients
with appendiceal neuroendocrine neoplasms: a systematic review and meta-
analysis of adult and paediatric patients. Endocrine 2020;67:20–34. doi:10.
1007/s12020- 019- 02072- y.
[107] Caplin M, Sundin A, Nillson O, Baum RP, Klose KJ, Kelestimur F, et al.
ENETS Consensus Guidelines for the management of patients with digestive
neuroendocrine neoplasms: colorectal neuroendocrine neoplasms. Neuroen-
docrinology 2012;95:88–97. doi:10.1159/0 0 0335594.
[108] Chagpar R, Chiang Y-J, Xing Y, Cormier JN, Feig BW, Rashid A, et al. Neuroen-
docrine tumors of the colon and rectum: prognostic relevance and compara-
tive performance of current staging systems. Ann Surg Oncol 2013;20:1170–8.
doi:10.1245/s10434- 012- 2746- z.
[109] Fields AC, McCarty JC, Lu P, Vierra BM, Pak LM, Irani J, et al. Colon neuroen-
docrine tumors: a new lymph node staging classification. Ann Surg Oncol
2019;26:2028–36. doi:10.1245/s10434- 019- 07327- 6.
[110] Fields AC, McCarty JC, Ma-Pak L, Lu P, Irani J, Goldberg JE, et al. New lymph
node staging for rectal neuroendocrine tumors. J Surg Oncol 2019;119:156–62.
doi:10.1002/jso.25307.
[111] Wang Y-Z, Beyer DT, Hall M. Obturator canal lymph node metasta-
sis from rectal carcinoid tumors: total mesorectal excision may be
insufficient. J Gastrointest Surg 2016;20:1247–52. doi:10.1007/
s11605-016-3128-9.
[112] Takatsu Y, Fukunaga Y, Nagasaki T, Akiyoshi T, Konishi T, Fujimoto Y, et al.
Short- and long-term outcomes of laparoscopic total mesenteric excision
for neuroendocrine tumors of the rectum. Dis Colon Rectum 2017;60:284–9.
doi:10.1097/DCR.0 0 0 0 0 0 0 0 0 0 0 0 0745.
[113] Partelli S, Andreasi V, Rancoita PMV, Perez-Sanchez E, Muffatti F, Balzano G,
et al. Outcomes after distal pancreatectomy for neuroendocrine neoplasms:
a retrospective comparison between minimally invasive and open ap-
proach using propensity score weighting. Surg Endosc 2020. doi:10.1007/
s00464- 020- 07375- 0.
[114] Tamburrino D, Partelli S, Renzi C, Crippa S, Muffatti F, Perali C, et al.
Systematic review and meta-analysis on laparoscopic pancreatic resections
for neuroendocrine neoplasms (PNENs). Expert Rev Gastroenterol Hepatol
2017;11:65–73. doi:10.1080/17474124.2017.1253473.
[115] Zhang X-F, Lopez-Aguiar AG, Poultsides G, Makris E, Rocha F, Kanji Z, et al.
Minimally invasive versus open distal pancreatectomy for pancreatic neu-
roendocrine tumors: An analysis from the U.S. neuroendocrine tumor study
group. J Surg Oncol 2019;120:231–40. doi:10.1002/jso.25481.
[116] Guerrini GP, Lauretta A, Belluco C, Olivieri M, Forlin M, Basso S, et al. Robotic
versus laparoscopic distal pancreatectomy: an up-to-date meta-analysis. BMC
Surg 2017;17:105. doi:10.1186/s12893- 017- 0301- 3.
[117] Alfieri S, Butturini G, Boggi U, Pietrabissa A, Morelli L, Vistoli F, et al. Short-
term and long-term outcomes after robot-assisted versus laparoscopic distal
pancreatectomy for pancreatic neuroendocrine tumors (pNETs): a multicen-
ter comparative study. Langenbeck’s Arch Surg 2019;404:459–68. doi:10.1007/
s00423- 019- 01786- x.
[118] Crippa S, Partelli S, Bassi C, Berardi R, Capelli P, Scarpa A, et al. Long-
term outcomes and prognostic factors in neuroendocrine carcinomas of the
pancreas: Morphology matters. Surgery 2016;159:862–71. doi:10.1016/j.surg.
2015.09.012.
[119] Haugvik S-P, Marangos IP, Rosok BI, Pomianowska E, Gladhaug IP,
Mathisen O, et al. Long-term outcome of laparoscopic surgery for pan-
creatic neuroendocrine tumors. World J Surg 2013;37:582–90. doi:10.1007/
s00268- 012- 1893- 5.
[120] Merola E, Rinke A, Partelli S, Gress TM, Andreasi V, Kollár A, et al. Surgery
with radical intent: is there an indication for G3 neuroendocrine neoplasms?
Ann Surg Oncol 2019. doi:10.1245/s10434- 019- 08049- 5.
182 V. Andreasi, S. Partelli and F. Muffatti et al. / Digestive and Liver Disease 53 (2021) 171–182
[121] Yoshida T, Hijioka S, Hosoda W, Ueno M, Furukawa M, Kobayashi N,
et al. Surgery for pancreatic neuroendocrine tumor G3 and carcinoma
G3 should be considered separately. Ann Surg Oncol 2019. doi:10.1245/
s10434- 019- 07252- 8.
[122] Merola E, Falconi M, Rinke A, Staettner S, Krendl F, Partelli S, et al. Radical
intended surgery for highly selected stage IV neuroendocrine neoplasms G3.
Am J Surg 2020. doi:10.1016/j.amjsurg.2020.03.009.
[123] Pavel M, O’Toole D, Costa F, Capdevila J, Gross D, Kianmanesh R, et al.
ENETS consensus guidelines update for the management of distant metastatic
disease of intestinal, pancreatic, bronchial neuroendocrine neoplasms (NEN)
and NEN of unknown primary site. Neuroendocrinology 2016;103:172–85.
doi:10.1159/0 0 0443167.
[124] Partelli S, Cirocchi R, Rancoita PMV, Muffatti F, Andreasi V, Crippa S, et al.
A Systematic review and meta-analysis on the role of palliative primary re-
section for pancreatic neuroendocrine neoplasm with liver metastases. HPB
2018;20. doi:10.1016/j.hpb.2017.10.014.
[125] Tierney JF, Chivukula S V, Wang X, Pappas SG, Schadde E, Hertl M, et al.
Resection of primary tumor may prolong survival in metastatic gastroen-
teropancreatic neuroendocrine tumors. Surgery 2019;165:644–51. doi:10.
1016/j.surg.2018.09.006.
[126] Bertani E, Fazio N, Radice D, Zardini C, Grana C, Bodei L, et al. Resection
of the primary tumor followed by peptide receptor radionuclide therapy as
upfront strategy for the treatment of G1–G2 pancreatic neuroendocrine tu-
mors with unresectable liver metastases. Ann Surg Oncol 2016. doi:10.1245/
s10434- 016- 5550- 3.
[127] Maxwell JE, Sherman SK, O’Dorisio TM, Bellizzi AM, Howe JR. Liver-directed
surgery of neuroendocrine metastases: what is the optimal strategy? Surgery
2016;159:320–33. doi:10.1016/j.surg.2015.05.040.
[128] Al-Toubah T, Partelli S, Cives M, Andreasi V, Silvestris F, Falconi M, et al. Local
treatment for focal progression in metastatic neuroendocrine tumors. Endocr
Relat Cancer 2018. doi:10.1530/ERC- 18- 0462.
[129] Mazzaferro V, Sposito C, Coppa J, Miceli R, Bhoori S, Bongini M, et al.
The long-term benefit of liver transplantation for hepatic metastases from
neuroendocrine tumors. Am J Transplant 2016;16:2892–902. doi:10.1111/ajt.
13831.
[130] Caplin ME, Pavel M, Cwikla JB, Phan AT, Raderer M, Sedlackova E, et al. Anti-
tumour effects of lanreotide for pancreatic and intestinal neuroendocrine
tumours: the CLARINET open-label extension study. Endocr Relat Cancer
2016;23:191–9. doi:10.1530/ERC-15-0490.
[131] Rinke A, Wittenberg M, Schade-Brittinger C, Aminossadati B, Ronicke E,
Gress TM, et al. Placebo-controlled, double-blind, prospective, randomized
study on the effect of octreotide LAR in the control of tumor growth
in patients with metastatic neuroendocrine midgut tumors (PROMID): re-
sults of long-term survival. Neuroendocrinology 2017;104:26–32. doi:10.1159/
0 0 0443612.
[132] Hicks RJ, Kwekkeboom DJ, Krenning E, Bodei L, Grozinsky-Glasberg S,
Arnold R, et al. ENETS consensus guidelines for the standards of care in
neuroendocrine neoplasia: peptide receptor radionuclide therapy with ra-
diolabeled somatostatin analogues. Neuroendocrinology 2017;105:295–309.
doi:10.1159/0 0 0475526.
[133] Brabander T, van der Zwan WA, Teunissen JJM, Kam BLR, Feelders RA,
de Herder WW, et al. Long-term efficacy, survival, and safety of
[(177)Lu-DOTA(0),Tyr(3)]octreotate in patients with gastroenteropancreatic
and bronchial neuroendocrine tumors. Clin Cancer Res 2017;23:4617–24.
doi:10.1158/1078- 0432.CCR- 16- 2743.
[134] Kwekkeboom DJ, de Herder WW, Kam BL, van Eijck CH, van Essen M,
Kooij PP, et al. Treatment with the radiolabeled somatostatin analog [177
Lu-DOTA 0,Tyr3]octreotate: toxicity, efficacy, and survival. J Clin Oncol
2008;26:2124–30. doi:10.1200/JCO.2007.15.2553.
[135] Strosberg J, El-Haddad G, Wolin E, Hendifar A, Yao J, Chasen B, et al. Phase
3 trial of 177lu-dotatate for midgut neuroendocrine tumors. N. Engl. J. Med.
2017. doi:10.1056/NEJMoa1607427.
[136] Rudisile S, Gosewisch A, Wenter V, Unterrainer M, Boning G, Gilde-
haus FJ, et al. Salvage PRRT with (177)Lu-DOTA-octreotate in extensively
pretreated patients with metastatic neuroendocrine tumor (NET): dosime-
try, toxicity, efficacy, and survival. BMC Cancer 2019;19:788. doi:10.1186/
s12885- 019- 60 0 0-y.
[137] Partelli S, Bertani E, Bartolomei M, Perali C, Muffatti F, Grana CM, et al.
Peptide receptor radionuclide therapy as neoadjuvant therapy for resectable
or potentially resectable pancreatic neuroendocrine neoplasms. Surg (United
States) 2018. doi:10.1016/j.surg.2017.11.007.
[138] Pavel M, Valle JW, Eriksson B, Rinke A, Caplin M, Chen J, et al. ENETS con-
sensus guidelines for the standards of care in neuroendocrine neoplasms:
systemic therapy-biotherapy and novel targeted agents. Neuroendocrinology
2017. doi:10.1159/0 0 0471880.
[139] Yao JC, Shah MH, Ito T, Bohas CL, Wolin EM, Van Cutsem E, et al. Everolimus
for advanced pancreatic neuroendocrine tumors. N Engl J Med 2011;364:514–
23. doi:10.1056/NEJMoa1009290.
[140] Yao JC, Fazio N, Singh S, Buzzoni R, Carnaghi C, Wolin E, et al. Everolimus
for the treatment of advanced, non-functional neuroendocrine tumours of the
lung or gastrointestinal tract (RADIANT-4): a randomised, placebo-controlled,
phase 3 study. Lancet (London, England) 2016;387:968–77. doi:10.1016/
S0140- 6736(15)00817- X.
[141] Raymond E, Dahan L, Raoul J-L, Bang Y-J, Borbath I, Lombard-Bohas C, et al.
Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N
Engl J Med 2011;364:501–13. doi:10.1056/NEJMoa1003825.
[142] Garcia-Carbonero R, Rinke A, Valle JW, Fazio N, Caplin M, Gorbounova V, et al.
ENETS consensus guidelines for the standards of care in neuroendocrine neo-
plasms: systemic therapy-chemotherapy. Neuroendocrinology 2017. doi:10.
1159/0 0 0473892.
[143] Strosberg JR, Fine RL, Choi J, Nasir A, Coppola D, Chen D-T, et al. First-
line chemotherapy with capecitabine and temozolomide in patients with
metastatic pancreatic endocrine carcinomas. Cancer 2011;117:268–75. doi:10.
1002/cncr.25425.
[144] Thomas K, Voros BA, Meadows-Taylor M, Smeltzer MP, Griffin R,
Boudreaux JP, et al. Outcomes of capecitabine and temozolomide (CAPTEM)
in advanced neuroendocrine neoplasms (NENs). Cancers (Basel) 2020;12.
doi:10.3390/cancers12010206.
[145] Kunz PL, Catalano PJ, Nimeiri H, Fisher GA, Longacre TA, Suarez CJ, et al. A
randomized study of temozolomide or temozolomide and capecitabine in pa-
tients with advanced pancreatic neuroendocrine tumors: A trial of the ECOG-
ACRIN cancer research group (E2211). J Clin Oncol 2018;36:40 04. doi:10.120 0/
JCO.2018.36.15_suppl.4004.
[146] Chatzellis E, Angelousi A, Daskalakis K, Tsoli M, Alexandraki KI,
Wachula E, et al. Activity and safety of standard and prolonged
capecitabine/temozolomide administration in patients with advanced
neuroendocrine neoplasms. Neuroendocrinology 2019;109:333–45.
doi:10.1159/0 0 050 0135.
[147] Falconi M, Bartsch DK, Eriksson B, Kloppel G, Lopes JM, O’Connor JM, et al.
ENETS Consensus Guidelines for the management of patients with digestive
neuroendocrine neoplasms of the digestive system: well-differentiated pan-
creatic non-functioning tumors. Neuroendocrinology 2012;95:120–34. doi:10.
1159/0 0 0335587.
[148] Coriat R, Walter T, Terris B, Couvelard A, Ruszniewski P. Gastroenteropancre-
atic well-differentiated grade 3 neuroendocrine tumors: review and position
statement. Oncologist 2016;21:1191–9. doi:10.1634/theoncologist.2015-0476.
[149] Chan D, Bergsland EK, Chan JA, Gadgil R, Halfdanarson TR, Hornbacker K,
et al. Temozolomide in grade III neuroendocrine neoplasms (G3 NENs): A
multicenter retrospective review. J Clin Oncol 2019;37:321. doi:10.1200/JCO.
2019.37.4_suppl.321.
[150] Brixi-Benmansour H, Jouve J-L, Mitry E, Bonnetain F, Landi B, Hentic O,
et al. Phase II study of first-line FOLFIRI for progressive metastatic well-
differentiated pancreatic endocrine carcinoma. Dig Liver Dis 2011;43:912–16.
doi:10.1016/j.dld.2011.07.001.