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24 NEUROENDOCRINE NEOPLASMS OF THE DIGESTIVE SYSTEM 477
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Figure 2 Different type of gastric NETs (asterisks) arising in the oxyntic mucosa. Since they show overlapping morphological features, the morphological
aspect of the peritumoral mucosa is an important diagnostic criterion. In type 1 ECL-cell NETs the mucosa is atrophic showing intestinal and pseudopyloric
metaplasia. In type 2 ECL-cell NETs the mucosa is hypertrophic-hypersecretory, while in Type 3 NETs the mucosa is normal. Peritumoral mucosa observed in
Type 4 ECL-cell NETs shows dilated oxyntic glands containing inspissated secretory material with parietal cells presenting abundant eosinophilic cytoplasm.
In Type 5 ECL-cell NETs peritumoral mucosa shows dilation of oxyntic glands in which parietal cells present apocrine-like swelling. (The figure regarding
type 4 ECL-cell NET is reprinted with permission from the book chapter: La Rosa S, Uccella S, Rindi G. Neuroendocrine neoplasms of the gut. In: Asa SL, La
Rosa S, Mete O. The spectrum of neuroendocrine neoplasia: a practical approach to diagnosis, classification, and therapy. Springer Cam, 2021).
epigenetic, and predisposing genetic factors are likely to be
involved in the development of ECL-cell NETs.
Type 2 ECL-cell NETs are multiple and below <2 cm in size
arising in a hypertrophic-hypersecretory oxyntic mucosa that
shows linear and micronodular ECL-cell proliferations. Most
cases are G1 NETs confined to mucosa-submucosa, but G2
cases infiltrating the gastric wall have been described.
Only MEN1-patients with (usually duodenal) gastrinomas
develop ECL-cell NETs, while patients with sporadic gastrinomas do not, which indicates that the MEN1 gene abnormalities
are essential for type 2 ECL-cell tumorigenesis.
Type 3 NETs are solitary and generally large (>2 cm) tumors
deeply infiltrating the gastric wall. They arise in a normal
mucosa without ECL-cell hyperplasia. Most cases are G1 or G2,
but G3 NETs have also been described (La Rosa et al. 2011;
Vanoli etal. 2018). The pathogenesis of type 3 ECL-cell NETs is
not well known, but loss of heterozygosity for MEN1 gene locus
and/or MEN1 mutations have been identified in 25–50% of
type 3 NETs (Bordi 2014). When distinguishing a G3 NET
from a NEC, the absence of a p53 overexpression or total loss
(corresponding to TP53 wild type status) and/or Rb1 loss is
helpful (Kasajima etal. 2022).
Type 4 ECL-cell NETs are small and multiple tumors arising
in a mucosa showing dilated oxyntic glands with parietal cells
presenting vacuolated abundant eosinophilic cytoplasm with
apical projections into the glandular lumens. The gland lumens
contain inspissated secretory material (Abraham et al. 2005;
Rindi etal. 1993). Molecular mechanisms involved in the pathogenesis of type 4 ECL-cells NETs are not known so far.
Type 5 ECL-cell NETs present as solitary and small tumors
usually confined to mucosa or submucosa. Most tumors are G1
or G2, but rare G3 NETs have been described. The peritumoral
mucosa shows PPI effects including dilation of oxyntic glands in
which parietal cells show apocrine-like swelling and cytoplasmic
snouts. ECL-cell hyperplasia has been observed in about 30% of
cases (Trinh etal. 2020). Molecular mechanisms involved in the
pathogenesis of type 5 ECL-cells NETs are not known so far.
Gastric NECs and MiNENs
Gastric NECs and MiNENs can occur anywhere in the stomach
and present as large, polypoid, ulcerating, or stenotic lesions
resembling gastric adenocarcinoma. MiNENs are composed of
two morphologically recognizable components, each representing at least 30% of the tumor cell population, although this cutoff has been arbitrarily defined and is now matter of debate (La
Rosa and Uccella 2021; Uccella and La Rosa 2020). The neuroendocrine component is often a NEC and only rarely a NET
(Klimstra etal. 2019). The non-neuroendocrine component is
histologically and immunohistochemically that of a gastric adenocarcinoma (Rindi etal. 2022). Gastric NECs have a high mutational burden characterized by multiple alterations involving
TP53, RB1, PIK3CA, KRAS, FHIT, DCC, and SMAD4 (Makuuchi
et al. 2017). Available data on gastric MiNENs indicate the
monoclonal origin of the two tumor components and molecular
similarities with NECs (Scardoni etal. 2014; Volante etal. 2015).
Prognosis
The prognosis of patients with gastric NETs associated with
hypergastrinemia is better than that of patients with normogastrinemia (Table 3). However, among the former NETs some
subtype-specific differences are observed. Patients with type 1
ECL-cell NETs have an excellent prognosis with a 10-year
survival rate of more than 90%, whereby G1 and G2 cases do not
differ significantly from each other in their outcome, suggesting
that tumor grade may not be the most important prognostic predictor in this specific subgroup. Conversely, the risk for lymph
node metastasis is mainly correlated with tumor size and deep
wall invasion (Panzuto etal. 2019; Vanoli etal. 2018) and, for this
reason, an accurate endoscopic evaluation of the wall infiltration
plays a crucial role in determining the best therapeutic approach
rather than the simple evaluation of tumor grade.
Type 2 NETs show lymph node and distant metastases in
30% and 10% of patients, respectively, and the 10-year survival
rate is 60–90% (La Rosa and Vanoli 2014).
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Due to their extreme rarity, the prognosis of patients with
type 4 ECL-cell NETs is not known, although lymph node
metastases have been described (Abraham etal. 2005).
Patients with type 5 ECL-cell NETs develop lymph node metastases in about 15% of cases, but show an excellent prognosis, with
a 10-year survival rate close to 100% (Trinh etal. 2020).
In contrast, type 3 gastric NETs are aggressive tumors, presenting metastases in about 50% of cases and a 10-year diseasespecific survival <50% (La Rosa etal. 2011; Vanoli etal. 2018).
In this specific subtype, tumor grade is associated with prognosis (Vanoli etal. 2018).
The rare antral gastrin- and somatostatin-producing NETs
are indolent and associated with an excellent prognosis, even in
presence of deep wall invasion or lymph node metastasis (La
Rosa and Vanoli 2014).
Gastric NECs and MiNENs are aggressive carcinomas associated with a dismal prognosis and a mean survival time of few
months. The Ki67 proliferative index, using the cut-off of 55%,
is a prognostic factor in NECs, but also in MiNENs, where it
needs to be evaluated in the NEC component (La Rosa 2021;
Milione etal. 2018, 2017).
Clinical Presentation and Diagnosis
Matthias Schott
Type 1 tumors represent 75–80% of all gastric NENs and, as
they involve only patients with atrophic body gastritis (2.4% of
patients with atrophy at time of first diagnosis), occur mostly in
women and are rarely responsible for symptoms. In fact, they usually are nonfunctioning tumors, typically found during upper-GI
endoscopy performed for dyspepsia or for macrocytic or iron
deficiency anemia. This condition is associated with slow gastric
emptying (explaining dyspepsia) and progressive reduction of
acid output, thus impairing iron and vitamin B12 absorption.
They present frequently as polyps in the fundic mucosa but
can be also detected only at biopsies (previously called microcarcinoids, 22.2%). Type 2 tumors are exclusively seen in multiple endocrine neoplasia type 1 (MEN-1) patients, occurring
in 23–29% of such cases (as compared with 1–3% in sporadic
gastrinomas), so that genetic testing should be applied in young
patients affected by these tumors. They appear as small (diameter
1–2 cm) polyps and may involve the entire fundic mucosa. They
are generally asymptomatic. Type 3 tumors may be discovered
incidentally, but are often responsible for pain, weight loss, and
iron deficiency anemia. Atypical carcinoid syndrome due to histamine production is extremely rare (Gluckman and Metz 2019).
Diagnostic Imaging
Clarisse Dromain & Nicolas Villard
Multiphasic CT that includes the arterial phase and the portal
venous phase is the first-line imaging modality.
Imaging features of gastric NENs are depending on the type of
gastric NEN. Type 1 (associated with chronic atrophic gastritis)
and type 2 (associated with hypergastrinemia) usually appear on
CT images as very small (<1 cm) multifocal hypervascular
masses located in the fundus or the body of the stomach
(Ganeshan etal. 2013). Because of the hypergastrinemia, present
in type II, a marked gastric wall thickening may also be present.
Type 3 usually present as large hypervascular solid masses.
Duodenum
Epidemiology and Pathology
Atsuko Kasajima, Günter Klöppel & Stefano La Rosa
Epidemiology
The relative frequency of duodenal NETs under all GEP NETs
is 2–4%. Their incidence has steadily increased in the past 30
years (Klöppel 2011; Yao etal. 2008). They occur mainly in the
sixth decade of life with a similar distribution of male and
female patients (Klöppel 2011; Milione etal. 2018).
Classification
Duodenal NENs are classified according to the 2019 WHO criteria into NET G1, G2, and G3 (Table 1), NECs, and MiNENs
(Klimstra etal. 2019). Duodenal NETs can be subdivided into
three groups based on their histologic, hormonal, and genetic
features (Vanoli etal. 2017). I) nonfunctioning NETs without
special histologic patterns and immunoreactive for gastrin,
somatostatin, and/or serotonin; II) nonfunctioning ampullary
NETs with special glandular features and somatostatin immunoreactivity possibly associated with neurofibromatosis type 1
(NF1), or NETs with special gangliocytic and paragangliomalike features, renamed “composite gangliocytoma/neuroma
and neuroendocrine tumor (CoGNET)” in the 2022 WHO
classification of neuroendocrine tumors (Rindi etal. 2022); and
finally III) functioning NETs with gastrin immunoreactivity
associated with Zollinger-Ellison syndrome (ZES) in patients
with or without MEN1 syndrome. Most common are small
nonfunctioning gastrin-producing NETs followed by somatostatin-producing NETs with glandular features.
Pathology
Nonfunctioning NETs without Special Histologic
Patterns
These duodenal NENs are usually well differentiated, smaller
than 2 cm, limited to the mucosa-submucosa, localized in the
proximal duodenum, and not associated with an inherited syndrome. Most of these tumors produce gastrin (Figure 3 A–B),
followed by somatostatin and serotonin, with multihormonality being common. They are positive for SSRT2A and ISLET-1.
24 NEUROENDOCRINE NEOPLASMS OF THE DIGESTIVE SYSTEM 479
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Figure 3 Histological and immunohistochemical images of duodenal neuroendocrine tumors (NETs). A: Immunohistochemical gastrin expression in a
nonfunctioning duodenal NET. B Multiple gastrinomas (arrows) with immunohistochemical gastrin expression in a MEN1 patient. C: Histological image of
a somatostatin-producing ampullary NET. D Immunohistochemical somatostatin expression in ampullary NET.
Lymph node and distant metastases are rare (5–10% of the
cases) (Delle Fave etal. 2016; Donow etal. 1991; Rosentraeger
etal. 2016; Vanoli etal. 2017).
ISL1), spindle-shaped Schwann-like cells, and ganglion cells
(positive for S-100 and synaptophysin). They usually occur in
the periampullary region and follow a benign course. However,
occasional, large tumors (size > 2 cm) may spread to local
Nonfunctioning NETs with Special Histologic
Patterns
Somatostatin-producing NETs with conspicuous glandularsolid and trabecular structures, often containing psammoma
bodies, occur predominantly in the ampullary and periampullary region (Figure 3 C–D) (Garbrecht etal. 2008; Vanoli etal.
2017). When they involve the muscular wall, they have a size of
2 cm or more and an increased proliferation rate, the metastatic
risk is over 50% (Vanoli etal. 2017). However, smaller tumors
may also metastasize to the paraduodenal lymph nodes.
Approximately 10–30% of the somatostatin-producing tumors
are associated with NF1 (Dayal etal. 1986; Garbrecht et al.
2008; Vanoli etal. 2017), occasionally combined with a gastrointestinal stroma tumor (GIST). A full somatostatinoma syndrome (diabetes mellitus, diarrhea, steatorrhea, hypo- or
achlorhydria, anemia, and gallstones) has not been described
so far in association with duodenal somatostatin-producing
NETs (Nesi etal. 2008; Vanoli etal. 2017) and its existence has
therefore been questioned (Garbrecht etal. 2008).
Composite gangliocytoma/neuroma and neuroendocrine
tumor (CoGNET) (traditionally called gangliocytic paraganglioma) are characterized by their triphasic cellular
differentiation and are composed of neuroendocrine cells
(positive for somatostatin and/or pancreatic polypeptide and
lymph nodes (Garbrecht etal. 2008; Vanoli etal. 2017).
Functioning NETs
Less than 10% of sporadic (non-inherited) duodenal NETs
that produce gastrin are functioning and associated with ZES
(Rosentraeger et al. 2016) and are called gastrinomas. In
20–35% of cases gastrinomas arise in the setting of MEN1
syndrome (Rosentraeger etal. 2016). The MEN1-associated
gastrinomas have, in addition to the MEN1-germ line mutation, an allelic loss of 11q13, which is also found in 46% of
sporadic gastrinomas. An important histologic difference
between sporadic and MEN1-associated gastrinomas is that
the latter are multicentric (Figure 3B), show precursor
lesions, and metastasize to lymph nodes more often than the
sporadic ones (Anlauf etal. 2006; Pipeleers-Marichal et al.
1990; Vanoli etal. 2017). Both gastrinoma types share a low
proliferative activity (Ki67 < 2%), a trabecular growth pattern
with some solid or pseudoglandular structures, and often
produce large lymph node metastases, the size of which usually exceeds that of the primary (Anlauf etal. 2006, 2007;
Rosentraeger etal. 2016). SSTR2A labels cell membranes in
more than 90% of gastrinomas (Rosentraeger et al. 2016).
Serotonin-producing NETs causing a carcinoid syndrome
are unusual in the duodenum.
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NECs and MiNENs
These neoplasms are very rare and, in contrast to NETs, contain none
of the usual hormones and display aberrant p53 and Rb1 expression.
Both occur primarily in or close to the ampullary region.
Histologically, NECs are often of the large cell type, and become a
MiNEN when mixed with an adenocarcinoma. They present in
advanced stages, i.e., with lymph node, liver, and other remote metastases (Garbrecht etal. 2008; Yang etal. 2021; Zamboni etal. 1990).
Prognosis
The 10-year survival rate of somatostatin-producing ampullary
NETs is 71% and those associated with size < 2 cm have a better
prognosis (Garbrecht etal. 2008). The 10-year survival rate of
patients with duodenal gastrinomas is worse than that of nonfunctioning duodenal gastrin-producing NETs, but better than
that of patients with pancreatic gastrinomas, probably because
metastases to the liver are more frequent in pancreatic than
duodenal gastrinomas and the local lymph node metastases
seem to have little influence on survival (Garbrecht etal. 2008;
Jensen etal. 2006).
NECs and MiNENs are very rare. While NECs and MiNENs
are prognostically unfavorable, metastatic behavior in NETs is
correlated to size (>1 cm), grade (2 and 3), and invasive growth
beyond submucosa (Klimstra etal. 2019).
Clinical Presentation and Diagnosis
Matthias Schott
Small nonfunctioning duodenal NETs are detected incidentally; larger tumors can lead to intestinal obstruction or jaundice, depending on the localization. Gastrinoma represents the
most common type of functional duodenal NETs and is discussed in detail in the following section.
Gastrinoma
Symptoms and Clinical Signs
Most of the symptoms in patients with gastrinomas are associated with gastric acid hypersecretion. The latter can lead
to the development of peptic ulcer, erosive esophagitis, and
chronic diarrhea. Symptoms associated with peptic ulcers and
their complications (bleeding, perforation, pyloric stenosis)
are the most common presenting clinical features in patients
with gastrinoma (80%). Peptic ulcers in these patients are
often multiple, located in unusual anatomic sites, and resistant to treatment. They are less associated to Helicobacter pylori
infection compared to idiopathic peptic ulcers (24–48% vs. >
90%, respectively) and are not associated with nonsteroidal
anti-inflammatory drugs (NSAID). Erosive esophagitis, causing heartburn and potentially dysphagia, occurs in 50–60% of
these patients. Finally, chronic diarrhea is a result of inactivation of pancreatic enzymes (especially lipases), and damage of
the intestinal mucosa, due to acid hypersecretion. Gastrinomarelated diarrhea is usually watery, may be associated with malabsorption, and is the only diarrhea that responds dramatically
to proton pump inhibitors (PPIs). It occurs in 40–70% of
patients with gastrinoma and may be the only symptom in 20%
of them (Norton etal. 2018) (Table 4).
Diagnosis
The biochemical confirmation, following clinical suspicion, of
a gastrinoma requires a significant elevation of fasting serum
gastrin in combination with hyperchlorhydria. The presence of
the latter is very important, as hypergastrinemia alone can be a
result of chronic hyperchlorhydria/achlorhydria, which is associated with chronic fundus atrophic gastritis, chronic PPI use,
as well as vagotomy.
The diagnostic criteria for ZES are as follows: basal acid
output (BAO) ≥ 15 mmol/h is suggestive of ZES diagnosis but
can overlap with other situations. A threshold value with 100%
specificity is obtained only for BAO ≥ 38 mmol/h (Jaïs and
Mignon 1995). Elevated fasting serum gastrin is suggestive of
ZES, but can be observed in other conditions, like H. pylori
infection, antral G-cell hyperplasia/hyperfunction, atrophic
gastritis, or use of PPIs. Very high fasting serum gastrin levels
>100-fold normal (5–9% of ZES patients) are specific of ZES.
Normal fasting serum gastrin values have been reported in less
than 3% of patients with ZES (Berna etal. 2006). Two-thirds of
ZES patients have fasting serum gastrin values <10-fold normal,
not specific of ZES. In these two latter situations, gastrin provocative tests are needed to establish the diagnosis. A secretin
infusion (2 U/kg intravenously in 2 min) induces a marked
increase in both serum gastrin and acid output (≥18 mmol/h)
in 90% of ZES patients (Jaïs and Mignon 1995). An increase of
serum gastrin >200 pg/mL is diagnostic of ZES (Campana etal.
2005). Recently, a large prospective study proposed new diagnostic criteria (Berna etal. 2006). An increase from fasting gastrin to post-secretin gastrin ≥120 pg/mL has the highest
Clinical feature % of patients
Peptic ulcers resistant to treatment, multiple, located in unusual anatomic sites, less
associated with H. pylori, and not associated with nonsteroidals
Erosive esophagitis causing heartburn and potentially dysphagia, resistant to treatment 50
Diarrhea responding to proton pump inhibitors 40–70
The above features in combination with other endocrinopathies 20
The above features in combination with family history of neuroendocrine tumors 25
Table 4 Clinical features of
gastrinomas.
80
24 NEUROENDOCRINE NEOPLASMS OF THE DIGESTIVE SYSTEM 481
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sensitivity (94%) and specificity (100%) for diagnosis. The
authors suggest that secretin stimulation should be used as the
first-line provocative test because of its greater sensitivity and
simplicity and lack of side effects. The calcium test should be
considered in patients with a strong clinical suspicion of ZES
but a negative secretin test. There is agreement in the literature
that calcium and meal tests are less useful than secretin for
detecting ZES (Norton etal. 2018; Rossi etal. 2021).
Diagnostic Imaging
Clarisse Dromain & Nicolas Villard
Multiphasic CT that includes the arterial phase and the portal
venous phase is the first-line imaging modality. Thin sectioning
and the use of a negative oral contrast agent are mandatory for
the detection of small primary tumor in the duodenum that
may not otherwise be seen.
NENs of the duodenum are most often small (mean 1.28
cm), multifocal and preferentially located in the first and the
second part of the duodenum. Association with pancreatic
NENs is frequent in case of G-cell duodenal gastrinoma associated with MEN-1. On CT or T1W MR images, they present as
intraluminal polyps or mural masses showing intense enhancement during the arterial phase with an increase of enhancement on portal phase images. Less often, some tumors present
as circumferential wall thickening (Heymann etal. 2004). If a
primary tumor is not seen in the duodenum, adjacent
enhancing lymphadenopathy, present in 46% of cases, can be a
clue to the presence of a duodenal NET (Tsai etal. 2015).
D-cell duodenal somatostatin-secreting tumor usually manifests as a periampullary tumor that may obstruct the common
bile duct with upstream dilatation (Ganeshan etal. 2013).
Surgical Treatment
Levent Dizdar & Wolfram Trudo Knoefel
Gastric NENs
Surgical treatment of gastric NENs depends crucially on the
tumor type which is important for the prediction of malignant
potential and prognosis. In addition, tumor size and the
presence of lymph node or distant metastases play an important
role in determining the indication for surgical intervention.
The only chance for cure is complete resection of the tumor.
Type 1 gastric NETs should be treated by surgical resection if
the tumor is larger than 2 cm, if the muscle wall is infiltrated, if
lymph node or distant metastases are detectable, or the resection margin is positive after endoscopic resection (endoscopic
mucosal resection/endoscopic submucosal dissection) (Basuroy
etal. 2014; Partelli etal. 2014). Little evidence exists regarding
the extent of resection. In the absence of lymph node metastases,
organ-preserving resections such as wedge resection or 2/3 gastrectomy without systematic lymphadenectomy appear to be
sufficient. If lymph node metastases are present, partial, subtotal,
or total gastrectomy with D2 lymphadenectomy should be performed. Antrectomy is a surgical treatment option for patients
with multifocal, invasive, or recurrent type 1 gastric NETs.
Resection of the antrum eliminates the G-cell-mediated hypergastrinemia, resulting in regression of gastric NENs in more than
90% of the cases (Ozao-Choy etal. 2010; Jenny etal. 2016).
Surgical resection for type 2 gastric NETs is indicated in
analogy to type 1 gastric NETs for invasive, metastatic, or endoscopically incompletely resected tumors. Antrectomy is not
indicated for type II NETs because the hypergastrinaemia does
not originate from the gastric antrum. Instead, the gastrinoma
causing the hypegastrinemia should be identified and resected.
For this purpose, surgical removal of duodenal gastrinomas (by
duodenotomy with lymphadenectomy or partial duodenopancreatectomy) may be required.
Type 3 NET and NECs are characterized by an aggressive
course with early metastasis. Therefore, depending on tumor
localization, a subtotal or total gastrectomy with D2 lymphadenectomy is indicated. An exception to this approach could
potentially involve small (<2 cm), G1/G2 type 3 gastric NENs,
which are confined to the submucosa and do not show lymphovascular invasion. Endoscopic resection could be a reasonable
alternative to surgery in this selected subgroup (Kwon etal.
2013). In patients with metastatic, poorly differentiated gastric
NECs, surgery is usually not recommended, and systemic
therapy should be initiated (Garcia-Carbonero etal. 2016).
Duodenal NENs
Basically, all duodenal NENs should be removed, unless
unresectable metastases or severe comorbidities are present.
Procedures used in the resection of duodenal NENs range
from endoscopic resections to transduodenal local excisions to
aggressive resection procedures such as partial pancreatoduodenectomy (PPD) (Delle Fave etal. 2012; Jensen etal. 2012). The
choice of the resection procedure is primarily based on the size,
location, histologic grade and stage, as well as hormonal activity
of the tumor. Small (≤1 cm) well-differentiated duodenal NETs
without metastases or hormonal activity can be resected with
endoscopic techniques if they are not located in the periampullary region (Delle Fave etal. 2012). For tumors localized in the
periampullary region, local surgical resection with lymphadenectomy or picking is recommended in current guidelines, even
for small tumors (≤1 cm). For NENs of the ampulla, surgical
resection by PPD is commonly recommended, as tumor size in
this location appears to be less closely associated with the malignant potential of the neoplasia (Delle Fave etal. 2012; Randle
etal. 2014). However, some studies indicate that for small (<2
cm), well-differentiated (G1) ampullary NETs, endoscopic papillectomy may represent a curative therapy if no metastases are
detectable (De Palma etal. 2010; Odabasi etal. 2013). Treatment
of duodenal NENs 1–2 cm in size is controversial, with some
data suggesting that endoscopic resection is reasonable if there
is no evidence of lymph node metastasis (Kachare etal. 2014),
while others recommend surgery for these tumors (Zyromski
etal. 2001). According to current evidence, duodenal NENs >
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2 cm or tumors of any size with suspected lymph node metastases should undergo surgical resection (Delle Fave etal. 2012).
The choice of the type of surgical resection is largely based on
the size and localization of the tumor. NENs in the first part of
the duodenum can often be removed by local resection, those
in the fourth part by distal duodenectomy. NENs in the second
and third part of the duodenum, however, usually require a
PPD (Delle Fave etal. 2012). Duodenal NETs with potentially
resectable liver metastases but without other distant metastases
and without comorbidities that limit life expectancy or substantially increase the risk of surgery may be considered for resection (Delle Fave etal. 2012). However, when distant metastatic,
poorly differentiated neuroendocrine carcinoma of the duodenum is detected, an absolute contraindication to surgical
resection exists (Garcia-Carbonero etal. 2016).
Surgical Treatment of Zollinger-Ellison Syndrome
(ZES)/Gastrinoma
The vast majority of gastrinomas are located in the duodenum
or pancreas. In 60–90% of patients with both sporadic ZES and
MEN1/ZES, a gastrinoma is found in the duodenum. Patients
with sporadic gastrinoma, with potentially resectable disease
and without serious comorbidities, should undergo routine surgical exploration for cure as lymph node metastases are present
in at least half of all cases and surgery is known to decrease the
rate of hepatic metastases and to prolong disease-related survival
(Fraker etal. 1994; Norton and Jensen 2004). The extent of resection depends on the size and location of the gastrinoma, and
ranges from local excision to PPD. However, systematic lymphadenectomy (hepatoduodenal ligament, hepatic artery, and
retropancreatic) as well as an intraoperative sonography of the
liver should always be routinely performed given the high rate of
metastases (Bartsch etal. 2012). Up to 30% of sporadic gastrinomas cannot be precisely localized preoperatively. In this situation,
the indication for surgical exploration should still be made after
multidisciplinary discussion, since in up to 90% of these cases the
primary tumor can be detected intraoperatively by the surgeon
(Deutsche Gesellschaft fur Gastroenterologie, Verdauungs- und
Stoffwechselkrankheiten etal. 2018; Jensen etal. 2012; Morrow
and Norton 2009). In the case of negative preoperative imaging,
surgical exploration should include complete exposure of the
pancreas with bidigital palpation and intraoperative ultrasound
as well as a duodenotomy with duodenal transillumination, if
necessary, and a routine lymphadenectomy in the gastrinoma triangle (Deutsche Gesellschaft fur Gastroenterologie, Verdauungsund Stoffwechselkrankheiten (DGVS) etal. 2018; Morrow and
Norton 2009). Laparoscopic resection of gastrinomas is generally
not recommended as the primary tumor is often not detectable
during preoperative examinations and difficult to identify intraoperatively (Deutsche Gesellschaft fur Gastroenterologie V-uS
etal. 2018; Jensen etal. 2012).
MEN1-associated gastrinomas are usually multifocal,
involving the duodenum and only rarely the pancreas. Surgical
treatment of MEN1 gastrinomas is associated with a recurrence
rate of >90% if PPD is not performed (Jensen etal. 2012; Norton
and Jensen 2004). Furthermore, patients with only small
pancreatic tumors (<2 cm) have an excellent life expectancy.
Therefore, routine surgical exploration in patients with MEN1associated gastrinomas is controversial (Jensen et al. 2008,
2012; Norton and Jensen 2004). It is generally recommended
that surgery should be limited to MEN1 pancreatic tumors
larger than 2 cm to prevent metastasis (Deutsche Gesellschaft
fur Gastroenterologie V-uS etal. 2018; Jensen etal. 2008, 2012;
Norton and Jensen 2004). However, it should be discussed with
the patient that surgery at the time of biochemical evidence of
the disease offers the greatest chance of biochemical cure. PPD
is associated with the highest long-term biochemical cure rate
(80–90%) compared with so-called non-PPD resections (PPD
90% vs. non-PPD 30%). Nevertheless, non-PPD resections,
including duodenotomy with excision of gastrinomas of the
duodenal wall with or without distal pancreatic resection, are
associated with very good long-term survival. Consequently,
the role of PPD resection in patients with MEN1-associated
gastrinomas is currently unclear (Deutsche Gesellschaft fur
Gastroenterologie V-uS etal. 2018; Jensen etal. 2012).
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Pancreas
Epidemiology and Pathology
Irene Esposito, Lena Häberle & Björn Konukiewitz
Epidemiology
Epidemiological studies about pancreatic NENs (PanNENs)
mostly refer to the category of well-differentiated NETs,
whereas much less data is available regarding NECs due to their
rarity and, possibly, to difficulty in classification.
PanNETs represent about 10% of all GEP-NETs according to the
SEER data (Lee etal. 2019) and their incidence is increasing in all
age groups, with a linear increase in the > 50 age group (Das and
Dasari 2021) and an incidence rate of 0.33/100.000 without any
relevant sex difference. The median age at diagnosis is 63 years,
and the peak incidence is found at the age of 70–75; PanNETs are
rare before the age of 35 (Lee etal. 2019). In some geographical
areas, PanNETs represent the most frequent GEP-NETs, as for
example in some European countries like Portugal and some
Asiatic countries, like India and China (Das and Dasari 2021).
PanNET show the lowest 5-years survival rate (37.6%)
among GEP-NETs according to the SEER data (Lee etal. 2019).
Higher survival rates have been reported in other countries,
such as Canada (48.8%) (Hallet etal. 2015) and Norway (43%)
(Hauso etal. 2008). The tumor stage and the grading are the
most relevant factors associated with prognosis.
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PanNECs are exceedingly rare and make-up about 20% of all
GEP-NECs according to a SEER database analysis (Dasari etal.
2018). The incidence of GEP-NECs has been increasing steadily
in the last 40 years, but it remains <1 case/100.000/year, same
holding true for PanNECs. PanNECs are slightly more common
in male than in females (56 vs. 44%) and the median age at
diagnosis is 67 years. Most cases (75%) have distant metastasis
at the time of diagnosis and poor median survival of only 5.7
months. Large cell histology seems to be more common (about
60%) (Basturk etal. 2014).
The recently defined category of G3 NET (see Introduction)
has been most probably neglected in the available datasets, so
that their frequency can be only inferred from retrospective
series. For example, Kasajima etal. reported a frequency of 9%
of G3 NETs in a consultation series comprising 1513 NENs
from all sites; in 42% of the cases, the G3 NET originated from
the pancreas (Kasajima etal. 2022). A single institution series
from China, which included 480 Pan-NENs, identified 64
NETs G3 (13%), and 108 NECs (22.5%) (Yang et al. 2020).
Altogether, G3-NET seems to represent about one-fourth of all
G3 GEP-NENs (Heetfeld etal. 2015; Scoazec etal. 2017), but
this figure might be underestimated.
Risk factors for PanNENs include a positive family history
for cancer, smoking, alcohol consumption, obesity, and diabetes
(Leoncini et al. 2016). In addition, 10–20% of PanNETs are
associated with hereditary syndromes (see below, GEP-NENs
and Hereditary Syndromes).
Pathology – General Considerations
PanNENs are classified in well-differentiated NETs and poorly
differentiated NECs based on their morphologic appearance.
PanNETs occur everywhere in the pancreas; they are usually
well circumscribed, but they may show a multinodular infiltrative growth, or a cystic appearance. Size at diagnosis usually
ranges between 2 and 5 cm; the consistency varies depending
on the amount of stroma, the color is reddish to yellowishbrown, necrosis is rare (Figure 4). PanNETs with a size of <
5 mm are designated microtumors and are usually detected
incidentally at histological examination (WHO Classifications
of Tumours Editorial Board. Endocrine and neuroendocrine
tumours [Internet] 2022).
PanNETs display a wide spectrum of growth patterns, including
solid-nested, reticulated-trabecular, gyriform, glandular, and
solid-paranganglioma-like (Figure 5). The tumor cells are usually
cuboidal to cylindrical with monotonous nuclei displaying the
classical “salt and pepper” chromatin appearance; clear-cell and
oncocytic variants as well as pleomorphic cells with prominent
nucleoli have been described. The stroma is mostly scant and
richly vascularized, but it may be abundant and sclerotic; calcifications, sometimes in form of psammoma bodies, may occur
(Konukiewitz etal. 2022).
Some morphological patterns are associated with specific
hormone-producing entities (see below, Specific Entities).
PanNETs are usually diffusely positive for cytokeratins, synaptophysin, INSM1 (Konukiewitz et al. 2022), CD56, and
CD57. Chromogranin A is usually positive, but the expression
is more frequently focal and shows an apical localization within
the cytoplasm. Independently from their functional activity,
PanNETs often express specific hormones, the most common
being glucagon, somatostatin, and pancreatic polypeptide. In
addition, they are positive for the transcription factor ISLET1
and they usually show a strong membranous expression of the
somatostatin-receptor 2A (SSTR2A).
Depending on the proliferation rate, as assessed by the Ki-67
staining or on the number of mitoses/2mm
2
, PanNETs are
graded into G1, G2, or G3 categories, as discussed above
(Introduction, Table 1).
PanNECs are usually larger at diagnosis (mean size: 4 cm);
they have a whitish color and a fleshy consistency and often
display necrosis and hemorrhage. The small-cell subtype consists of solid sheets of cells with scant cytoplasm and round
nuclei with inconspicuous nucleoli. Mitoses and apoptosis are
common. The more frequent large-cell subtype often displays
organoid, nested, or trabecular patterns of growth; the cells
have large nuclei with evident nucleoli and a wider, eosinophilic or amphiphilic cytoplasm (Basturk etal. 2014).
PanNECs express cytokeratins, often with a punctuated
pattern. Synaptophysin is quite sensitive for the diagnosis of
PanNECs, whereas chromogranin A is very specific, but it displays a limited sensitivity. ISLET1 and SSTR2A are usually negative in PanNECs. The Ki-67 proliferation rate of PanNECs
usually exceeds 50–60%. Altered expression pattern of p53 or Rb
indicates a mutation of the respective gene, and it is useful for the
differential diagnosis between highly proliferating NETs
(G3-NETs) and NECs (Konukiewitz etal. 2017; Tang etal. 2016).
Pathology – Specific Entities
Nonfunctioning PanNETs account for approximately 70% of all
PanNETs. This group comprises a plethora of heterogenous
tumors either without or with production of peptide hormones
that are not associated with a clinical syndrome linked to the
secretion of hormones. Hormone-producing nonfunctioning
PanNETs can be characterized by the production of orthotopic
(insulin, glucagon, somatostatin, pancreatic polypeptide) or
ectopic hormones (gastrin, serotonin, ACTH, among others).
The hormones are located in the cytoplasm of the tumor cells
and can easily be detected by immunohistochemistry
(Konukiewitz etal. 2022). The spectrum of hormone expression ranges from single cells to a strong and diffuse positivity in
all tumor cells. Multihormonal tumors are common (Kapran
etal. 2006; Konukiewitz etal. 2020). Nonfunctioning PanNETs
nearly show the whole spectrum of organoid neuroendocrine
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Figure 4 PanNET. A: Intraoperative finding of a patient with a glucagonoma involving the pancreatic tail. The spleen as well as the distal pancreas were
mobilized before performing the resection. B: Surgical specimen of a pancreatic NET after spleen-preserving resection. C: Resection specimen of a
malignant insulinoma with infiltration of the transverse colon. The black arrow indicates the transverse colon, the white arrow marks the duodenum. D:
Intraoperative finding of a glucagonoma in the pancreatic corpus. The white arrow indicates the superior mesenteric vein, the black arrow the
glucagonoma.
Figure 5 Morphological subtypes of PanNENs. A: NET, gyriform pattern; B: NET, cord-like pattern; C NET, reticulated-trabecular pattern; D NET
eosinophilic trabecular patter; E NET, clear-cell nested-trabecular pattern; F NET, glandular pattern; G NET, mixed microacinar (left) and gyriform-trabecular
pattern; H small cell NEC; I large cell NEC.
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