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9 Pancreatic Neuroendocrine Tumors (pNETs)
frequently found. Because PP is sometimes the predominant hormone, these neoplasms have been called PPomas, although they do not represent a clinical entity.
Among the extrapancreatic tumors rich in PP cells are the majority of gangliocytic paragangliomas of the duodenum [124] and some rectal neuroendocrine
tumors [125]. A few nonfunctioning malignant tumors have been shown immunocytochemically to produce serotonin [126, 127]. Tumors described as neurotensinomas and calcitoninomas or those producing bombesin [127] are either
hormonally silent or are associated with syndromes that are difcult to relate to
the effects of these hormones.
139
9.8 Pancreatic Endocrine Tumors inMEN1
Pancreatic tumors are part of a tumor spectrum that involves the parathyroid glands
(80–98% of patients), the anterior pituitary (9–40%), and the duodenum (40–85%)
[128, 129], but occasionally also the stomach, ileum, lung, or thymus [130, 131].
The outstanding feature of the pancreatic lesions in MEN1 is diffuse microdenomatosis in association with one or several macrotumors (>0.5cm in diameter) [132].
Histologically, most of the small tumors display a distinct trabecular pattern and
may show a connective tissue capsule. Multihormonality is a consistent nding in
these tumors, with one hormone usually prevailing. Most frequent are glucagonomas and PPomas, followed by insulinomas. Serum PP has therefore been recommended as a screening hormone in MEN1 patients [133], although subsequent data
suggested a wider distribution of hormone type [134]. In MEN1 patients with hypoglycemia, it was noted that, despite the presence of multiple tumors, usually only
one of the macrotumors produced insulin. Removal of this tumor relieved the
patients’ hypoglycemic syndrome. In MEN1 patients with ZES, which occurs in
approximately 60% of MEN1 patients, pancreatic gastrinomas are surprisingly
uncommon, although the pancreas of these patients may be studded with tumors of
varying sizes producing other hormones. The gastrinomas in these patients reside
predominantly in the proximal part of the duodenum, are usually <1cm in diameter,
and show multicentricity (see section on gastrinomas, above). The occurrence of
WDHA syndrome, glucagonoma syndrome, [132, 133] or acromegaly due to a
tumor-secreting growth hormone-releasing factor is very rare in the setting of
MEN1.
9.9 Mixed Endocrine-Exocrine Tumors
True mixed endocrine-exocrine tumors (i.e., ductal endocrine or acinar-endocrine
tumors) of the pancreas, in which both components are clearly demonstrated, are
exceedingly rare [134]. Arguments supporting the endocrine-exocrine nature of
tumors are the presence of both elements in both the primary tumor and its metastases and the ultrastructural identication of cells containing both hormone granules
and zymogen or mucin granules. The inclusion of normal ducts within endocrine
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A. Sanguinetti et al.
tumors (so-called ductulo-insular tumors) or the occurrence of endocrine cells
attached to the neoplastic glands of ductal adenocarcinomas of the pancreas cannot
be regarded as evidence that a tumor is truly endocrine-exocrine in nature.
9.10 Diagnosis/Staging
9.10.1 History andPhysical
A detailed history and physical is essential in these patients. The history should
focus on signs of mass effect or metastasis, evaluate for symptoms of an endocrine
syndrome, and screen for family history suggestive of genetic syndromes associated
with pNETs. Physical exam should look for jaundice and abdominal masses.
9.10.2 Laboratory Evaluation
If a functional tumor is suspected, workup should include biochemical assessment
for the appropriate syndrome. Seventy two-hour fast is the gold standard for diagnosis of an insulinoma, with measurement of glucose and insulin levels at the time
of symptoms. It is also important to measure C-peptide to rule out surreptitious
insulin use [135]. With gastrinoma, an elevated fasting serum gastrin level is usually the rst test, and a level greater than ten times the limits of normal is virtually
diagnostic of this disease. Proton pump inhibitors elevate serum gastrin levels,
and it is important to draw labs after holding these drugs for 1week due to their
long-acting nature. ZE syndrome is usually conrmed with a secretin stimulation
test, but gastric acid secretion studies are sometimes required [136, 137].
Migratory necrotizing dermatitis, while highly suggestive of a glucagonoma, can
also occur in celiac disease, cirrhosis, or pancreatitis, and the diagnosis must be
conrmed by elevated glucagon levels [138–140]. VIPoma and somatostatinoma
are conrmed by elevated levels of VIP and somatostatin, respectively [141, 142].
A variety of tumor markers have been proposed for functional and nonfunctional
pNETs. The most common of these is chromogranin A (CgA), an acid-soluble
protein that is found in secretory granules of neuroendocrine cells, although others, such as neuron-specic enolase (NSE), pancreatic polypeptide, pancreastatin,
and human chorionic gonadotropin, have been proposed. CgA is the most sensitive of these, with elevated levels present in 72–100% of patients. However, CgA
levels are highly variable, limiting specicity to 50–80% [
proton pump inhibitor use, impaired renal function, liver disease, and inammatory bowel disease can all cause an increase in CgA leading to false-positive
results. Higher CgA levels correlate with increased tumor burden and metastatic
disease and may be most useful in assessing response to therapy [55, 56]. The
sensitivity of NSE as a tumor marker is low at 30–40%, but its specicity is almost
100% [57]. Using a combination of CgA and NSE levels improves the sensitivity
of using either alone [58].
55, 56]. Furthermore,
9 Pancreatic Neuroendocrine Tumors (pNETs)
141
9.10.3 Imaging
Localization and staging of the tumor are essential to appropriate therapy for
pNET.A variety of imaging modalities exist to assist the clinician, including computed tomography (CT), magnetic resonance imaging (MRI), somatostatin receptor
scintigraphy (SRS), positron-emission tomography (PET), and endoscopic ultrasonography (EUS). In the rare case that the tumor cannot be located with these modalities, angiography with selective arterial stimulation and venous sampling may be
employed. If the tumor cannot be located prior to surgery, bimanual palpation with
intraoperative ultrasound often discovers the lesion as a last resort. This is a situation seen most often with small insulinomas that are only a few millimeters in size.
9.11 CT
CT is the most common initial imaging study in the evaluation of patients with
pNETs. Triple-phase contrast CT is the optimal study as pNETs are typically best
visualized during the arterial phase. They usually appear as spherical, hyper-dense,
and hyper-vascular mass that rarely obstruct the pancreatic duct. The reported sensitivity of CT ranges from 62 to 83% with a specicity of 83–100%, although it
varies with the size of the lesion [59, 60]. Although most pNETs are solid lesions,
about 10% will present as cystic lesions with smooth margins and peripheral
enhancement on both arterial and portal phases. Overall, it is difcult to differentiate cystic pNETs from other cystic pancreatic lesions on cross-sectional imaging
with a misdiagnosis rate of 43% in a recent series [61].
9.12 MR
pNETs are usually well visualized on MR. The MR signal is typically low in
T1-weighted sequences and high in T2-weighted sequences. Again, pNETs are best
visualized during the arterial contrast phase. The sensitivity of MR ranges from 85
to 100% with a specicity of 75–100% [59, 62]. In one recent series of 55 patients,
the sensitivity of MR was 95%, rivaling that of EUS [63]. Not as commonly used as
CT, MR is most often ordered when lesions are too small to be visualized on CT.In
detecting and following liver metastases, MR has been suggested to be superior to
CT [62, 64, 65].
9.13 SRS
SRS (somatostatin receptor scintigraphy) uses radiolabeled somatostatin analogs
and relies on somatostatin receptors expressed by pNETs. This leads to an important caveat that insulinomas, in which somatostatin receptors are present only at low
levels or absent entirely, are not well visualized with this technique. However, for
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other functional pNETs and nonfunctional pNETs, the ability of SRS to localize the
tumor is good, with sensitivities ranging from 75 to 100% [62, 66]. SRS is often
used when a functional pNET is suspected and conventional cross-sectional imaging fails to localize the tumor. It can be particularly helpful with glucagonoma as
this have a greater propensity to present outside of the pancreas than other functional NETs [59]. SRS has an advantage over other imaging modalities in evaluating
patients for sufcient uptake for targeted radiation therapy using radiolabeled somatostatin analogs. SRS is also typically useful in evaluating the burden of metastatic
disease.
A. Sanguinetti et al.
9.14 PET
Standard PET imaging with 18F-uorodeoxyglucose (FDG) does not visualize
pNETs well, given that most pNETs are well differentiated with a low metabolic
rate. However, it can detect poorly differentiated pNETs and FDG avidity correlates
with early tumor progression and increased mortality [67, 68]. Alternatively, PET
imaging has increasingly utilized 68Ga-labeled somatostatin analogs with excellent
results. PET imaging with this utilization has been shown to be superior to both SRS
and conventional cross-sectional imaging [69, 70]. The results from fusion of PET
with CT images are better than either modality individually with sensitivities of
94–100% [71]. In one series, use of fused PET/CT images changed treatment decisions in 59.6% of patients compared to CT or MRI alone.
9.15 EUS
EUS (endoscopic ultrasound) has become an invaluable tool in the evaluation of
pancreatic lesions. In addition to radiologic examination of the pancreas, EUS offers
the additional benet of obtaining biopsies for diagnosis. EUS has an 82% sensitivity and a 92% specicity in identifying pNETs, although EUS is more sensitive in
the head of the pancreas than the tail and results are operator dependent [72, 73].
EUS is most useful in identifying small insulinomas, as these lesions infrequently
express somatostatin receptors and are not well visualized on SRS or PET.EUS has
the added benet of being able to tattoo smaller lesions for easier intraoperative
identication, facilitating laparoscopic resection [73].
9.16 Surgical Management
9.16.1 General Principles forSurgical Management ofpNETs
Pancreatic NETs should ideally be managed in a multidisciplinary setting. In choosing the appropriate therapy, physicians should adopt an individualized, patientfocused medical management strategy at centers with an interest in the disease,
9 Pancreatic Neuroendocrine Tumors (pNETs)
expertise in treating it, and a multidisciplinary approach to patient care. Surgery
with curative intent should be considered in all cases if clinically appropriate and
technically feasible. Enucleation for small (B2 cm) G1 pNETs is an acceptable
approach. Larger G1 and G2 pNETs and NECs require the same oncologic principles as those applied to pancreatic adenocarcinomas.
143
9.17 Surgical Approaches
9.17.1 Functioning Disease
Functioning PNETs primarily include insulinomas and gastrinomas, with an incidence of 70–80% and 20–25% of all PNETs and an incidence of malignancy of
<10% and 50–60%, respectively [9]. Insulinomas are generally solitary, benign,
and curable with surgery [74–76]. Recurrence after resection occurs in about 3%
[77, 78]. The procedures of choice are enucleation for small and isolated insulinomas and partial pancreatectomy for large and potentially malignant insulinomas
[143, 144]. Besides enucleation, middle pancreatectomy is an alternative
parenchyma- sparing technique for this tumor entity [79]. Also, laparoscopic management of insulinoma in the body and tail of the pancreas, with distal pancreatectomy or enucleation, is feasible and safe [80]. In the case of occult insulinoma, blind
distal pancreatectomy should be avoided [81]. However, explorative surgery with
intraoperative ultrasound may be indicated in cases where preoperative diagnostics
could not reveal any pancreatic lesions, as this is an excellent method for identifying
occult insulinoma [82]. Gastrinoma is associated with gastric ulcerations due to
overproduction of gastrin [145]. The clinical presentation of gastrinoma is referred
to as Zollinger-Ellison syndrome. With the introduction of proton pump inhibitors,
which prevent ulcer formation, surgery changed from being symptomatic to curative treatment in patients with Zollinger-Ellison syndrome. All patients with
Zollinger-Ellison syndrome without multiple neuroendocrine neoplasia type 1 or
metastatic disease should be offered surgical exploration for a possible cure [146].
Routine use of duodenotomy in cases of pancreatic gastrinoma increases short- and
long-term cure rates due to a higher detection rate of duodenal gastrinomas, as multiple gastrinomas are relatively common [147]. The incidences of other functioning
PNETs, such as vasoactive intestinal peptide-producing tumors (VIPoma), glucagonoma, and somatostatinoma, are very low. These patients should undergo tumor
resection to correct the severe hormonally caused metabolic derangements.
9.17.2 Neuroendocrine Carcinoma
Neuroendocrine carcinomas (NECs) are dened as neuroendocrine tumors with a
Ki-67 index above 20%, according to the WHO 2010 classication. Such tumors are
highly malignant and typically invade adjacent structures or metastasize before the
diagnosis is made [148]. NECs of the pancreas are very rare and account for only
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about 2–3% of all PNETs [149, 150]. The outcome is generally poor and most
patients die within 5years after diagnosis [151]. However, curative resections have
been reported in single cases [149]. Therefore, radical surgery should be attempted
in localized disease [152, 153], while surgery in metastatic disease is not
recommended.
9.17.3 Locally Advanced Disease
Locally advanced disease extends beyond the limits of the pancreas directly into
surrounding organs or tissue, involves regional lymph nodes, or fullls both of
these criteria. As many PNETs are nonfunctioning and slow-growing, a large proportion of these present with locally advanced disease. Resection for locally
advanced PNETs is in general technically feasible and can result in favorable disease-free and overall survival in selected patients [154]. However, most patients
will develop recurrence [155]. When not operated, patients with locally advanced
PNETs may suffer from complications related to local mass effect and inltrative
growth, including gastrointestinal bleeding, vascular/intestinal/biliary obstruction,
and occlusion of the superior mesenteric (SMV) or portal vein (PV) [156]. Hill
etal. found that resection of the primary tumor in patients with PNETs is associated with improved survival across all stages of disease [157]. Based on this, surgery of locally advanced PNET without metastasis should be attempted.
Interestingly, R1 resections of PNET are not associated with a worse overall survival compared to R0 resections [158].
9.17.4 Metastatic Disease
PNETs commonly metastasize to the liver. This is especially true for nonfunctioning tumors as these are generally diagnosed at a late stage. In selected patients,
resection of the primary PNET in the setting of unresectable but limited hepatic
metastases may be indicated [159, 160] as this may prolong survival [161, 162]. As
mentioned earlier, it has been shown that resection of the primary tumor in patients
with PNETs is associated with improved survival across all stages of disease.
However, there is currently no clear answer to when and whether resection of the
primary tumor should be performed in metastatic disease [163]. Surgical resection
with curative intent or palliative debulking of more than 90% of liver metastases
from nonfunctioning PNETs provides favorable oncologic outcomes, despite a high
recurrence rate [164, 165]. Patients with metastatic disease in the liver may prot
from liver resection with long-term palliation and possibly cure in one-third of the
patients [166]. Number, size, and localization of tumor sites seem less important
than performing a complete resection of metastatic tissue from PNETs [167].
Patients with hormonally active liver metastases without prior extrahepatic or synchronous disease have the greatest survival benet from surgery. Two-stage procedures for synchronous bilobar liver metastases from NET, including portal vein
9 Pancreatic Neuroendocrine Tumors (pNETs)
embolization, enable complete resection and good long-term outcome in selected
patients [168]. Debulking extends survival although recurrence is expected [169,
170]. Surgical treatment of metastatic PNET should be performed in specialized
centers and managed with a multidisciplinary approach [171].
145
9.18 Technical Remarks
9.18.1 Resection Versus Enucleation
Standard surgical approaches to PNETs include pancreaticoduodenectomy and distal or subtotal pancreatectomy. Middle segment pancreatectomy is an alternative in
the management of PNETs located in the neck or body of the pancreas [172]. A
general risk of major pancreatic resections is functional impairment of the organ
due to loss of parenchyma, resulting in exocrine and/or endocrine insufciency.
Thus, parenchyma-sparing surgical techniques should be attempted when possible.
Enucleation is a feasible procedure for the radical treatment of benign and borderline pancreatic neoplasms [173] and is associated with long-term survival, despite a
relatively high risk of pancreatic stula formation [174, 175]. Before enucleating a
PNET, it is important to consider where the tumor is located in relation to the main
pancreatic duct, as enucleations of tumors located very close to this may result in
damage to the pancreatic duct and subsequent pancreatic leakage. Decisions regarding enucleations are highly individual compared to standard resections, underlining
the importance of treatment in experienced high-volume institutions. Tumor enucleation is associated with shorter operative time, less intraoperative blood loss, and
shorter hospital stay compared to pancreaticoduodenectomy and distal pancreatectomy [173].
9.18.2 Open Versus Laparoscopic Surgery
Over the last decade, there has been a trend toward more parenchyma-sparing
and minimally invasive techniques in the management of PNETs. This shift has
not increased morbidity or compromised survival [176]. Laparoscopic surgery
for small and solitary PNETs is feasible and safe [177, 178]. Advantages of the
minimally invasive approach are less intraoperative bleeding [179], faster postoperative recovery [180], shorter hospital stay [181, 182], and improved cosmesis,
compared to the open approach. Laparoscopic distal pancreatectomy (LDP) is
today an established procedure at several institutions worldwide [183]. The procedure provides similar short- and long-term oncologic outcomes as open distal
pancreatectomy and a selective use of it also seems to be a cost-efcient alternative to open distal pancreatectomy. LDP with preservation of the spleen is feasible with a moderate risk of postoperative splenic infarction [184]. However,
the signicance of spleen preservation on oncologic outcome in patients with
PNET remains unclear. Besides LDP of PNET in the pancreatic body and tail,
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laparoscopic enucleation of nonfunctioning PNETs in the pancreatic head [185]
and laparoscopic pylorus-preserving pancreatoduodenectomy are feasible procedures that can be considered in selected cases [186]. When performing laparoscopic pancreatic surgery for PNET, intraoperative laparoscopic ultrasound
should always be applied, as this allows safe tumor dissection and excision. If
the tumor cannot be identied precisely by laparoscopic ultrasound, conversion
to open surgery should be considered [187]. Laparoscopic pancreatic surgery
demands a high level of surgical skills in minimally invasive surgery and should
be performed in specialized centers [188].
9.18.3 Lymph Node Sampling
From studies performed on pancreatic ductal adenocarcinoma, it is known that
lymph node status is an important prognostic factor in resectable disease [189,
190]. This has also been demonstrated in studies on PNET, where lymph node
ratio is a signicant predictor of recurrence after curative resection for malignant
PNETs [191], and lymph node metastases in PNETs are related to better survival
[192]. In many surgical specimens of PNETs, lymph nodes are not evaluated by
the pathologist [125]. This may result in understaging of patients with potentially
inadequate resection. It is of great importance to know to what extent parenchymasparing and minimally invasive pancreatic surgery can provide sufcient lymph
node sampling for optimal oncologic outcome. When compared to open surgery,
there are studies concluding with a clear limitation of LDP as well as studies concluding with a comparable lymph node sampling after LDP. Enucleations are
associated with a low lymph node sampling rate compared with standard resections. Lymph node sampling should be performed routinely when performing
parenchyma-preserving or minimally invasive removal for small PNETs, to avoid
understaging. Moreover, frozen section examination should be performed, and
when malignancy is conrmed, oncologically appropriate lymph node dissection
is recommended.
9.18.4 Vascular Reconstruction
Surgery for locally advanced PNETs with vascular involvement is controversial.
Vascular reconstruction has already been established in the treatment of locally
advanced pancreatic adenocarcinoma [193]. Several case reports [194, 195] suggest
that a similar approach is feasible and benecial in selected patients with PNETs. In
most cases, even if the radiological evaluation suggests vascular involvement and at
surgery the PNET is found to partially encase or involve the vessel, the tumor can
be removed with careful dissection without requiring vascular reconstruction.
Conventional contraindications to surgical resection of pancreatic malignancy, such
as superior mesenteric vein invasion, should be reconsidered in patients with locally
advanced PNETs [196].
9 Pancreatic Neuroendocrine Tumors (pNETs)
147
9.19 Medical Management
In addition to surgery, diverse types of medical treatment are used in the management course for patients with pancreatic NETs as well as gastrointestinal NETs. The
main aim of the treatment should be clearly dened before choosing treatment;
there are two main aims of treatment: to ameliorate hormonal symptoms and to
improve the survival. Observation without any agents might be the best management for patients with stable disease for a long time or the elderly patients.
9.19.1 Medical Treatment ofFunctioning Pancreatic NETs
In patients with functioning NETs, medical management can often provide release
symptoms by inhibition of the secretion of bioactive agents. Administration of
diazoxide [197, 198] or long-acting somatostatin analogs (octreotide, lanreotide)
[199, 200] can control hypoglycemic symptoms in about 50% of patients with insulinoma. Histamine H2-receptor antagonists and proton pump inhibitors can control
the acid hypersecretion in most patients with ZES [201]. For patients with other
functioning pancreatic NETs, long-acting somatostatin analogs are generally successful in the initial management [202, 203].
9.19.2 Medical Treatment withMolecular-Targeted Therapy
Tumor grading is paramount for selecting patients who should receive chemotherapy, and platinum-based chemotherapy is recommended in patients with NEC G3
[204]. In some patients with NET G1/G2, molecular-targeted treatment or chemotherapy may provide a benet. The European Society for Medical Oncology
(ESMO) 2012 guidelines recommended use of molecular-targeted agents in
advanced pancreatic NETs G1/G2 [205]. According to the North American
Neuroendocrine Tumor Society (NANETS) guidelines, the level of recommendation is listed as “consider” to use of everolimus in metastatic functioning NETs
because there has been no sufcient evidence to recommend routine use of it [206].
Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR) [207], and
sunitinib, an inhibitor of VEGF and platelet-derived growth factor receptors [208],
are now registered worldwide for the treatment of pancreatic NETs. These two
agents have similar tumor-stabilizing effects in pancreatic NETs. Since there has
been no trial that compared the two agents directly, choice of the agent in each case
could be suggested in perspective of side effects. For example, in patients with
poorly controlled hormonal symptoms, congestive heart failure, poorly controlled
hypertension, high risk of gastrointestinal bleed, or a history of myocardial infarction or stroke, everolimus is thought to be the preferred agent of choice. In patients
with poorly controlled diabetes mellitus, pulmonary disease, or high risk of infection, sunitinib would be a more appropriate choice [209]. To evaluate the response
of these agents, several biomarkers have been investigated. It has been suggested
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that chromogranin A and neuron-specic enolase are useful as prognostic markers
in patients with advanced pNET treated with everolimus [210]. Soluble vascular
endothelial growth factor receptor 2 and 3, interleukin-8, and stromal cell-derived
factor 1-alpha have been reported to have a potential as biomarkers associated with
response to sunitinib.
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