CELEBRATING
YEA R S
Committed to improving
knowledge and care in NETs
Pancreatic Neuroendocrine Tumors
An educational guide for healthcare professionals
Overview
Pancreatic neuroendocrine tumors (pancreatic NETs) comprise a group
of neoplasms that are believed to arise from pancreatic endocrine
cells,1 which are scattered among the exocrine tissue of the pancreas.2
Pancreatic NETs are also called islet cell tumors,3 because the endocrine
cells of the pancreas are commonly located in clusters, anatomically
called islets of Langerhans.4 Pancreatic NETs can also arise from cells
other than islet cells2 as well as occur outside of the pancreas, for
example, in the duodenum.5,6
Long-term data from the US Surveillance, Epidemiology, and End
Results (SEER) Program registries (1973-2004) demonstrate that 64% of
patients diagnosed with well-differentiated pancreatic NETs have distant
metastases and a poor prognosis—the 5-year survival
rate in these patients is 27%.7
A word about neuroendocrine nomenclature
The NET Alliance™ uses the nomenclature established in the 2010 WHO Classification of
Tumours of the Digestive System8 to classify 2 broad types of neuroendocrine neoplasms:
• Neuroendocrine neoplasms: the entire spectrum of neoplastic cell types with
endocrine properties and phenotypes that express neural markers
•N
euroendocrine tumors (NETs): well-differentiated neuroendocrine neoplasms
that can be divided into grade 1 (G1) and grade 2 (G2) depending on proliferation
and histology
• Neuroendocrine carcinomas: poorly differentiated grade 3 (G3)
neuroendocrine neoplasms
NETs may be referred to using a variety of terms, such as “carcinoids,” “carcinoid
tumors,” or “endocrine tumors.” These terms can be used interchangeably with “NETs”
as defined above.
2
Characteristics of Pancreatic NETs
Most pancreatic NETs are well-differentiated (grade 1 and grade 2) tumors9,10 with very diverse presentations
(Table 1).3,5,6 These presentations are often related to the ability of some pancreatic NETs to secrete hormones
or peptides, such as insulin, gastrin, glucagon, vasoactive intestinal polypeptide (VIP), and somatostatin, causing
characteristic hormonal syndromes.3-5 However, not all pancreatic NETs are associated with secretion of hormone
products related to clinical symptoms; such tumors are considered nonfunctional.5,11,12
Table 1. Characteristics of Pancreatic NETs*
Type of
pancreatic NET6
Incidence
(cases per
million)13
Prevalence in patients
Prevalence of
with pancreatic NETs
metastases
(in surgical series)
Related
syndrome3,5,6
Major signs/
symptoms3,5,6,14
1-2†
None
May be first diagnosed
due to mass
effect, weight loss,
hepatomegaly, abdominal
mass, or incidentally
Occasionally symptomatic
58%-71%14,15‡
>50%6
Insulinoma
1.0-2.0
Insulin
Hypoglycemia
23%-33%14,15
<15%6
Gastrinoma§
1.0-1.5
Gastrin
Recurrent peptic ulcer,
abdominal pain, diarrhea
3%-5%14,15
<50%6
0.01-0.10
Glucagon
Diabetes/glucose
intolerance,
rash (migratory
necrolytic erythema),
thromboembolic disease
2%-3%14,15
Majority 6
VIPoma||
0.10
Vasoactive
intestinal
polypeptide
(VIP)
Severe watery diarrhea,
electrolyte disturbances
0.6%-1.0%14,16
Majority 6
Somatostatinoma
<0.10
Somatostatin
Diabetes, cholelithiasis,
diarrhea
.05%16
Majority 6
Nonfunctional
Functional
Glucagonoma
*Other exceedingly rare hormonal syndromes do occur6 but are not covered in this monograph.
†
Incidence of nonfunctional NETs is probably higher due to the fact that autopsies reveal undiagnosed nonfunctional NETs.
‡
The frequency with which nonfunctional pancreatic NETs are being identified and treated is increasing due to an increase in detection rather than a true increase
in incidence.14
§
Also known as Zollinger-Ellison syndrome.
||
Also known as Verner-Morrison syndrome, pancreatic cholera, and watery diarrhea, hypokalemia, and achlorhydria (WDHA) syndrome.
3
Epidemiology
The reported overall annual incidence of malignant pancreatic NETs is believed to be approximately 0.32 per
100,000 individuals, based on statistics from the largest database, the US SEER Program registries (1973-2004).7
In a separate analysis of the US SEER database (1973-2003) of patients with pancreatic NETs, the estimated
28-year limited duration prevalence of pancreatic NETs was 2705 cases on January 1, 2003.4 Both the incidence
and the 28-year limited duration prevalence may be underestimated, however, because benign-appearing tumors,
such as insulinomas, are not included in the US SEER Program registries used to generate these data.4,10
The most common pancreatic NETs are nonfunctional pancreatic NETs, insulinomas, and gastrinomas; other types
(glucagonomas, somatostatinomas, VIPomas, and others) are rare.3,6 Pancreatic NETs can be sporadic or associated
with genetic syndromes,6 such as multiple endocrine neoplasia type 1 (MEN-1), von Hippel-Lindau syndrome (VHL),
von Recklinghausen disease (neurofibromatosis [NF-1]), and tuberous sclerosis complex (TSC).17 MEN-1 is the genetic
syndrome most frequently associated with pancreatic NETs (Table 2).6,17 MEN-1 is an autosomal dominant condition
associated with neoplasms that develop in the pituitary gland, parathyroid glands, and enteropancreatic regions.3
Patients with MEN-1 usually have multiple pancreatic NETs, whereas those with sporadic pancreatic NETs generally
have solitary neoplasms.6,18 The relative frequency of MEN-1–associated pancreatic NETs, in descending order, is
nonfunctional pancreatic NETs, gastrinomas, insulinomas, glucagonomas, VIPomas, and somatostatinomas (Table 3).6,17
In patients with MEN-1, nonfunctional pancreatic NETs may be microscopic and asymptomatic.6,17
Table 2. Frequency of Pancreatic NETs in Patients With Inherited Disorders6,17
Inherited disorder
Frequency of pancreatic NETs (%)
MEN-1
80-100
VHL
10-17
von Recklinghausen disease (NF-1)
0-10
TSC
Uncommon
Table 3. Frequency of Pancreatic NETs in Patients With MEN-16,17
4
Type of pancreatic NET
Frequency in MEN-1 (%)
Nonfunctional
80-100, microscopic/asymptomatic
0 -13, large/symptomatic
Gastrinoma
20- 61 (mean 54)
Insulinoma
7- 31 (mean 18)
Glucagonoma
1- 6 (mean 3)
VIPoma
1-12 (mean 3)
Somatostatinoma
0- 1
Prognostic Factors
In pancreatic NETs, prognostic factors include location of the primary tumor, tumor stage, patient age, and years
since diagnosis; however, the most important predictor of outcome is stage.4 An analysis of the 1973-2004 US SEER
database showed that in patients with pancreatic NETs, 64% presented with distant metastases, and these patients
had a 5-year survival rate of 27%.7 The majority of patients with glucagonoma, VIPoma, and somatostatinoma
present with metastases at diagnosis.6 However, in patients with gastrinoma, metastases are present in less than
50%, and in insulinoma, metastases are present in less than 15%.6 This finding has clinical implications, because
the presence of distant metastases is an important predictor of outcome in patients with pancreatic NETs.16
When Bilimoria et al analyzed outcomes in 4793 patients with pancreatic NETs and applied the American Joint
Committee on Cancer (AJCC) staging system, distant metastasis was found to be the only predictor of survival
(P<.0001) and was associated with a 2-fold increased likelihood of death.19
When the US SEER database from 1973-2003 was used to specifically analyze 1157 patients with pancreatic NETs, the
longest survival (124 months) was in the smallest subpopulation of patients—those with localized disease (n=167).4
The majority of patients had distant disease (n=558) and the shortest median duration of survival (23 months) (Figure 1).
1.0
Localized
Regional
Distant
Survival probability
0.8
Figure 1. Extent of disease and survival from time of
diagnosis in patients with well-differentiated (grade
1 and grade 2) pancreatic NETs. Median duration of
survival of patients with localized (n=167), regional
(n=289), and distant disease (n=558) was 124, 70,
and 23 months, respectively (P<.001).4
0.6
0.4
0.2
Reproduced with permission from Springer Science + Business Media.
Ann Surg Oncol, vol 14, 2007, p3496, Yao JC et al, Figure 3.
0.0
0
12
24
36
48
60
72
84
96
108 120
Months
Patient age and neoplasm grade are other prognostic factors to consider.16 In 2008, Bilimoria and colleagues compared
patients 55 years of age or younger to those aged 55 to 75 years and to those aged 75 years or older. Both the middle
age and the oldest age groups had an increased risk of death after resection (hazard ratios, 1.57 and 3.04, respectively;
P<.0001). Likewise, patients with high-grade pancreatic neuroendocrine neoplasms had a 2-fold increase in the
postresection risk of death compared with those who had low-grade pancreatic NETs (hazard ratio, 2.03; P<.0001).16
Predictive biomarkers
In a recent study in patients with metastatic pancreatic NETs, chromogranin A (CgA) and neuron-specific enolase (NSE)
levels were monitored. When CgA and NSE levels were elevated at baseline, normalization of these biomarkers
during treatment correlated with improved progression-free survival rates, indicating that CgA and NSE may be
predictive biomarkers in patients with pancreatic NETs.20
5
Classification
Until recently, the World Health Organization (WHO) classified pancreatic NETs using a hybrid system that
incorporated both staging and grading information.21,22 Although this system allowed prognostic stratification,
it did not allow the information to be applied to advanced stages of disease.21
The WHO 2010 classification system (Table 4) now follows that of the AJCC/International Union Against Cancer
(UICC) for pancreatic adenocarcinoma.19,23,24 The tumor-node-metastasis (TNM) classification embraced by WHO
is different from the one used by the European Neuroendocrine Tumor Society (ENETS). The WHO system is
for well-differentiated NETs only. The ENETS system is also meant for high-grade neoplasms.24 The ENETS
classification system is shown in Table 6.
Table 4. WHO TNM Classification of Tumors of the Pancreas*25
T-Primary Tumor
TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
Tis
Carcinoma in situ, includes PanIN-3†
T1
Tumor limited to the pancreas, ≤2 cm in greatest dimension
T2
Tumor limited to the pancreas, >2 cm in greatest dimension
T3
Tumor extends beyond the pancreas
T4
Tumor involves the celiac axis or the superior mesenteric artery
Stage Grouping
Stage
T
N
M
Stage 0
Tis
N0
M0
Stage IA
T1
N0
M0
Stage IB
T2
N0
M0
Stage IIA
T3
N0
M0
Stage IIB
T1
T2
T3
N1
N1
N1
M0
M0
M0
Stage III
T4
Any N
M0
Stage IV
Any T
Any N
M1
N-Regional Lymph Nodes
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph-node metastasis
N1
Regional lymph-node metastasis
M-Distant Metastasis
M0
No distant metastasis
M1
Distant metastasis
Adapted from Bosman FT, Carniero F, Hruban RH,Theise ND. World Health Organization Classification of Tumours of the Digestive System. IARC, Lyon, 2010.
*This classification applies to carcinomas of the exocrine pancreas and pancreatic neuroendocrine tumors.
†
PanIN, pancreatic intraepithelial neoplasia.
6
Pancreatic NETs should also be classified by grade, a fundamental predictor of outcome, which estimates
the biologic aggressiveness (ie, potential for metastatic spread) of the neoplasm.6,26 The WHO grading system
(Table 5) is one of many grading systems, which differ in both terminology and criteria.6,8,26 To address
these differences, a multidisciplinary group of specialists in the field of NETs recently recommended that
the grading system used must be specified on the pathology report.26
Table 5. WHO 2010 Grading System for Pancreatic Neuroendocrine Neoplasms8
Grade
Criteria
Low grade
NET G1
Intermediate grade
NET G2
High grade
neuroendocrine carcinoma G3
<2 mitoses/10 HPF AND/OR <2% Ki-67 index
2 - 20 mitoses/10 HPF AND/OR 3% - 20% Ki-67 index
>20 mitoses/10 HPF AND/OR >20% Ki-67 index
HPF, high-power field.
Table 6. ENETS Modified Clinical, Radiological, and Pathological TNM Staging
of Pancreatic Endocrine Tumors27
Stage
T*
N†
M‡
I
T1 or T2
N0-NX
M0
II
T3
N0-NX
M0
III
T4
N0-NX
M0
Any T
N1
Any T
Any N
IV
M1
*T1, tumor limited to the pancreas and size <2 cm; T2, tumor limited to the pancreas and size between 2 and 4 cm; T3, tumor
limited to the pancreas and size >4 cm; T4, tumor invasion of any adjacent structure (including duodenum, common bile duct and
peripancreatic fat), documented by histology or clinical/imaging signs of malignancy (jaundice or duodenal bleeding due to infiltration,
dilation of main pancreatic or common bile duct).
†
NX, lymph nodes not assessed; N0, absence of lymph node metastasis; N1, invasion of regional lymph nodes.
‡
M0, absence of distant metastasis; M1, presence of distant metastasis.
Adapted from Scarpa A et al with permission of Nature Publishing Group ©2010.
7
Comparison between pancreatic NETs and other NETs
Pancreatic NETs comprise a spectrum of malignancies that vary in clinical aggressiveness, depending on
histology.7,28 Like other NETs, pancreatic NETs generally produce and secrete marker proteins, such as CgA, and
express somatostatin receptors (SSTRs) (Table 7).29,30 Pancreatic NET management strategies are, for the most
part, similar to those for other NETs (Table 7).
Table 7. Similarities Between Pancreatic NETs and Other NETs
Pancreatic
NETs
Other NETs
Elevated CgA
levels
(% sensitivity)
Functional,
50%29
Nonfunctional,
57%29
60%-90%31*
MEN-1–associated NETs, 53%29
Expression of
high-density
SSTRs
Insulinomas,
50%-70%30
Gastrinomas,
80%-100%30
Glucagonomas,
80%-100%30
VIPomas,
80%-100%30
Foregut, 80%-100%30
Midgut, 80%-100%30
Hindgut, 80%-100%30
Hormonal
syndromes
Pancreatic
NETs6‡
Stomach
Hormonal
syndromes
can occur
✓
✓
Characteristics
6‡
Midgut
32‡§
✓
Possible courses
of action for welldifferentiated
NETs†
Pancreatic
NETs6‡
Stomach6‡
Midgut32‡§
Colorectal33‡
Surgery/resection
✓
✓
✓
✓
Liver-directed
therapy
✓
✓
✓
✓
Systemic therapy
✓
✓
✓
#
✓
Peptide receptor
radiotherapy**
✓
✓
✓
✓
Radiation
therapy34††
✓
✓
✓
✓
*Except medullary thyroid carcinoma, <50%.
†
Management is based on several factors (eg, site, stage, grade, etc).
‡
Well differentiated.
§
Jejunum, ileum, appendix, and cecum.
II
Lung, thymus.
¶
Published data on treatment outcome for patients with advanced colorectal NETs
is not currently available.
8
Colorectal33‡
Medullary
thyroid
carcinoma34
Pheochromocytoma/
Paraganglioma34
Thorax35‡II
✓
✓
✓
Medullary
thyroid
carcinoma34
Pheochromocytoma/
Paraganglioma34
Thorax35‡II
✓
✓
✓
✓
¶
¶
✓
✓
✓
✓
✓
✓
✓
✓
A survival benefit of cytotoxic chemotherapy has not been clearly shown in
patients with advanced midgut NETs.
**Investigational therapy.
††
Used to palliate bone metastases.
#
Retrospective analyses of cancer registries indicate that patients with pancreatic NETs present with distant
metastases more often than patients with any other NET (Table 8).4,7,28 In the US SEER database, patients who
had pancreatic NETs with distant metastases had a median survival of 24 months, whereas those with other
advanced disease NETs had a median survival of 33 months.7
Studies in large treatment centers report longer median survival times for patients with pancreatic NETs. In one
such recent series, Strosberg et al evaluated all cases of differentiated, metastatic pancreatic NETs seen at the
center between the years 1999 and 2003, measuring survival from time of diagnosis of distant metastases.36
In this analysis, the median overall survival for patients with metastatic pancreatic NETs was 70 months; more
than half of all patients survived for more than 5 years.
Table 8. Disease Stage at Presentation by Site 7
Disease stage (%)
Site
Localized
Regional
Distant
Pancreas
14
22
64
Stomach
76
9
15
Duodenum
81
10
9
Jejunum/ileum
29
41
30
Cecum
14
42
44
Appendix
60
28
12
Colon
45
23
32
Rectum
92
4
5
Liver
45
27
28
Lung
49
23
28
Thymus
28
41
31
Adapted with permission. © 2008 American Society of Clinical Oncology. All rights reserved. Yao JC et al.
A prospective study comparing prognostic factors and survival in 156 patients with pancreatic NETs or
gastrointestinal (GI) NETs (jejunum, rectum, appendix, duodenum, stomach, and colon) found that patients
diagnosed with pancreatic NETs had a poorer prognosis relative to patients with other NETs.37 In this study,
pancreatic primary tumor site was significantly associated with poor outcome in both univariate and multivariate
analyses (P = .0002 and .017, respectively),37 and survival rates were significantly worse in patients with
pancreatic NETs compared to those with GI NETs.37 The prevalence of advanced disease was relatively,
but not statistically, higher in patients with pancreatic NETs compared to those with GI NETs (55% vs 35%,
respectively).37 The prevalence of advanced disease, combined with the observation that 61.2% of patients with
pancreatic NETs had no associated hormonal syndrome, led the authors to conclude that diagnosis is usually late
in patients with pancreatic NETs due to the lack of specific symptoms.37
A second, larger prospective study of prognostic factors in 399 patients found that the occurrence of metastases
in pancreatic NETs was 77%, a rate lower than that among patients with NETs of the small intestine or colon,38
suggesting that a pancreatic NET may be diagnosed at an earlier stage than a NET of these other sites.
9
Comparison of pancreatic NETs to other pancreatic cancers
Pancreatic NETs are less common than pancreatic adenocarcinomas and other neoplasms of the
exocrine pancreas (Figure 2).39
Prevalence of major pancreatic cancer types among all pancreatic cancers
Exocrine
• Pancreatic adenocarcinoma,
61%-70%39-41
• Mucinous tumors, 6%-7%39-41
Endocrine
• Pancreatic NETs, 2%-4%39-41
Figure 2. Distribution of major histologic types among pancreatic cancers.
0.50
0.00
0.25
% Survival
0.75
1.00
Compared with tumors of the exocrine pancreas, pancreatic NETs have distinctly different tumor
biology and are associated with better long-term survival (Figure 3).39
0
6
12
18
24
30
36
42
48
54
60
Months
Histology Groups
Adenocarcinoma
Mucinous
Endocrine
Figure 3. Kaplan-Meier curves comparing percent survival for 5 years in the pancreatic
cancer histologic types: adenocarcinoma (n=31,357, solid line), mucinous tumors (n=2865,
dotted line), and endocrine tumors (n=1054, dashed line).39
Reproduced with permission of the American Association for Cancer Research, from Fesinmeyer MD et al, vol 14, ©2005;
permission conveyed through Copyright Clearance Center, Inc.
10
Clinical Features and Biochemical Diagnosis
The presentation of a pancreatic NET is highly variable2,13 and largely depends on the functional status of the
neoplasm.5,6,42 In a functional pancreatic NET, symptoms are usually determined by the type of hormone secreted
(Table 1),5,6 whereas in a nonfunctional pancreatic NET, symptoms generally reflect tumor growth or spread.5,6
Measurements of hormones and other secreted peptides may provide an initial clue in patients in whom a NET
diagnosis is being considered.6 Hormone measurements may be related to secretion by a particular neoplasm
(eg, insulin, proinsulin, gastrin, glucagon, somatostatin).42-45 Other markers are nonspecific and are produced
and secreted by most NETs (eg, CgA, pancreatic polypeptide [PP]).42,43,46
For diagnostic accuracy as well as continued disease management, a number of modalities should be
utilized. Because elevated levels of hormones and peptides may be nonspecific, abnormal laboratory values
suggestive of a NET (preliminary biomarker results) should be confirmed with imaging and endoscopic
techniques, as well as biopsy, to confirm a histopathologic diagnosis.47 Histologic examination of biopsy
specimens, including immunohistochemical studies, can provide additional information that may be useful for
the diagnosis and management of pancreatic NETs (eg, confirmation of neuroendocrine status and subtype).2,6
Nonfunctional pancreatic NETs
Because nonfunctional pancreatic NETs are not associated with a hormonal syndrome, symptoms at presentation
are indicative of mechanical problems caused by the tumor’s bulk or metastases (eg, jaundice, abdominal pain,
weight loss, diarrhea).5,6,14,46 However, pancreatic NETs can become very large without causing any symptoms,46
and often are discovered incidentally during surgery or abdominal imaging.2,6,14,46
Nonfunctional pancreatic NETs may not secrete peptides that cause specific clinical syndromes, but they are
not necessarily biologically silent11 and, in fact, can secrete a number of peptides,5,6,11 for example, CgA and
PP.3,5,6 When measuring these biomarkers and interpreting the results, it is important to keep in mind that
CgA and PP are also secreted by other types of NETs.6,42,46
Other conditions that can increase CgA levels and potentially cause a false-positive result include chronic
atrophic gastritis, chronic inflammatory diseases, renal or hepatic failure, arterial hypertension, and proton-pump
inhibitor (PPI) therapy.31 For PP, both physiologic (eg, meals, age) and pathologic (eg, kidney failure, inflammatory
diseases) conditions can cause false-positive results.31 Therefore, an elevated CgA or PP level alone is not
diagnostic of a NET.5,6
11
Insulinomas
Insulinomas are typically small (<1 cm), single tumors that are almost always (>99%) intrapancreatic in
location.6 Insulinoma patients usually present with symptoms of hypoglycemia, especially neuroglycopenic
symptoms (eg, confusion, altered consciousness).6 Insulinomas in non–MEN-1 patients can be treated by
laparoscopic approach, and, if they can be localized preoperatively, can be cured in 70% to 100% of cases.6
Clinical manifestations of insulinoma are related to hypoglycemia secondary to excessive, unregulated secretion
of insulin.11,48 Inappropriate hyperinsulinemia causes neuroglycopenic symptoms (eg, visual disturbances,
confusion, abnormal behavior, and, in extreme cases, loss of consciousness resulting in coma).11,46 In addition,
catecholamines released in response to the hypoglycemia cause adrenergic symptoms (eg, perspiration, anxiety,
heart palpitations, hunger).46,49 Weight gain is common, since patients learn early in the disease process that
eating resolves their symptoms.46,48 The diagnosis of insulinoma requires demonstration of hypoglycemia in the
presence of inappropriate hyperinsulinemia.11 Biochemical workup for 6 parameters should take place during a
72-hour fast (Table 9).43
Table 9. Biochemical Workup for Insulinomas (during a 72-hour fast)43
12
Biomarker
Levels in insulinoma
Glucose
Blood glucose levels ≤2.2 mmol/L (≤40 mg/dL)
Insulin
Concomitant insulin levels ≥6 μU/mL (≥36 pmol/L)
Proinsulin
Levels ≥5 pmol/L
C-peptide
Levels ≥200 pmol/L
ß-hydroxybutyrate
Levels ≤2.7 mmol/L
Sulfonylurea
Absence of sulfonylurea (metabolites) in plasma and/or urine
Gastrinomas
Gastrinomas can occur as isolated, sporadic neoplasms or as multiple, MEN-1–associated neoplasms6,50 and
usually are located in the pancreas or the duodenum.51 Patients typically present with abdominal pain related
to peptic ulcer disease (PUD), diarrhea, and gastroesophageal reflux disease.6,52 Gastrinomas cause a clinical
syndrome known as Zollinger-Ellison syndrome (ZES).5,51 ZES should be suspected if the PUD is recurrent,
resistant to treatment, severe, or familial; the PUD is associated with complications, endocrinopathies, prominent
gastric folds, or hypergastrinemia; or Helicobacter pylori and nonsteroidal anti-inflammatory drug (NSAID) use
are absent.6,44 A diagnosis of ZES should be suspected if there is evidence of hypergastrinemia in the presence
of gastric acid hypersecretion (Table 10).6,51
Table 10. Biochemical Workup for Gastrinoma
Biomarker
Rationale
Fasting serum gastrin
(FSG)
Hypergastrinemia is present at the time of acid hypersecretion in patients with gastrinomas6
Gastric pH
Gastric pH <2 in patients with ZES in the absence of antisecretory drugs can help in the
differential diagnosis by demonstrating inappropriate hypergastrinemia6,44,53
Basal acid output
Assessment in patients with known hypergastrinemia confirms inappropriate
hypergastrinemia6
Secretin stimulation test
This test can help to diagnose gastrinoma6
Gastric pH, basal acid output, and a secretin stimulation test should be performed after cessation of PPIs, if possible.3,44 There can be some risk in stopping PPIs in
patients suspected of having a gastrinoma6; these patients should be managed at a center experienced in diagnosing ZES.6,46
13
Glucagonomas
Glucagonomas are typically large and occur almost entirely within the pancreas.5,6,11 Glucagonomas secrete
excessive amounts of glucagon, causing glucose intolerance, weight loss, and a pathognomonic rash known
as necrolytic migratory erythema. This rash is characterized by raised erythematous patches that begin in
areas of friction, such as the perineum, and eventually can involve the trunk, extremities, and other parts
of the body (Figure 4).6,11 Although necrolytic migratory erythema is found in up to 90% of patients with
glucagonomas, it also can occur in cirrhosis, pancreatitis, and celiac disease. Thus, diagnosis of a
glucagonoma depends on the demonstration of pathologic hyperglucagonemia.5,6,11
Figure 4. Necrolytic migratory erythema.
Reproduced with permission from Springer Science + Business Media, LLC.
VIPomas
VIPomas cause a distinct clinical syndrome known by several names, including Verner-Morrison syndrome,
pancreatic cholera, and WDHA (for watery diarrhea, hypokalemia, and achlorhydria) syndrome.6 Patients typically
present with severe, large-volume, watery diarrhea, hypokalemia, and hypochlorhydria. The definitive
diagnosis requires demonstration of elevated serum concentrations of VIP and localization of a pancreatic
NET in the presence of large-volume secretory diarrhea.5,11
Somatostatinomas
Somatostatinomas cause a clinical syndrome characterized by diabetes mellitus, cholelithiases, diarrhea,
and steatorrhea.5,11 Diagnosis is based on the demonstration of hypersomatostatinemia in the presence of
a pancreatic or duodenal mass and at least some features of the clinical syndrome.5,6,11
14
Imaging
Imaging studies are used during all phases of the management of patients with pancreatic NETs to localize and
stage the neoplasm, to guide management plans (ie, curative resection, debulking, medical management only), to
monitor neoplasm growth, and for follow-up after therapy.5,6,11 A number of different modalities are available for
the imaging of pancreatic NETs (Table 11).6 Because the characteristics of each pancreatic NET subtype vary, a
combination of imaging studies may be utilized.2
Table 11. Modalities Available for Imaging of Pancreatic NETs
Modality
Rationale for use/application
Limitation/disadvantage
Conventional imaging
Computed tomography (CT),
magnetic resonance imaging
(MRI), ultrasound, angiography
• At least 1 conventional imaging method
is usually available at most centers6
• CT with contrast is the most frequently
used initial imaging method6
• Conventional imaging often misses
small primary pancreatic NETs
(especially insulinomas and
duodenal gastrinomas) and
small liver metastases6
Somatostatin receptor
scintigraphy (SRS)
• Radiolabeled tracers bind to
somatostatin receptors that are
overexpressed on pancreatic NET
cell surfaces6
• Combined with single photon emission
CT (SPECT) imaging is more sensitive
than conventional imaging for detection
of primary pancreatic NETs and
distant metastases6,54
• Allows quick total body scanning6
• False-positive localizations can occur
in up to 12% of patients6
• Unable to provide details about the
location of the tumor in relationship
to surrounding structures2
• Many insulinomas lack somatostatin
receptor 2,2 leading to negative
SRS studies
• Helpful in localizing insulinomas, which
are frequently missed by conventional
imaging and SRS6
Endoscopic ultrasound (EUS)
• Can identify 90% of intrapancreatic NETs6
• Can detect small nonfunctional
pancreatic NETs in patients with MEN-1
or VHL syndrome6
• Operator-dependent2
• Unable to evaluate hepatic and
distant metastases2
Intraoperative localization
• Intraoperative ultrasonography is the
most sensitive method to visualize small
tumors, eg, insulinomas54
• Intraoperative localization can only
be performed during surgery6
• Endoscopic transillumination is
recommended for small duodenal
pancreatic NETs6
Positron emission
tomography (PET)
PET with 5-HTP or -dopa can be an
option for detection of small tumors54
Less sensitive than other imaging
modalities54
15
Management
The management of localized pancreatic NETs is primarily surgical. In patients with metastatic pancreatic NETs,
management usually focuses on prolonging survival and controlling symptoms.2 Optimal management requires
an in-depth understanding of the disease process and may incorporate a variety of specialists from multiple
disciplines (eg, pathologists, endocrinologists, radiologists, and medical, radiation, and surgical oncologists)
with expertise in the use of specific biochemical, radiologic, and surgical methods.2-4
Management of localized pancreatic NETs
Occurrence of hormonal syndromes
As with many other NETs, hormonal syndromes can occur with pancreatic NETs.6 For example, glucose levels in
patients with insulinomas should be stabilized with diet and/or diazoxide. Gastric hypersecretion in patients with
gastrinomas should be treated with PPIs.3
Surgery
All localized pancreatic NETs should be resected, if possible, since surgery is the only curative option for a
pancreatic NET.2,5,6,11 Exceptions include patients who have another medical condition that limits life expectancy
or increases surgical risk6,11 and, in some situations, patients who have MEN-1 or VHL.6,17 Surgery for patients
with MEN-1 or VHL is rarely curative since their tumors are often too small and numerous for complete
surgical resection.6,17
Management of advanced disease
Options for patients with advanced pancreatic NETs include surgical resection of hepatic metastases; hepatic
arterial embolization; radiofrequency ablation and cryoablation, either alone or in conjunction with cytoreductive
surgery; traditional chemotherapy; and investigational approaches, including liver transplantation (Table 12).6,46
Table 12. Management of Advanced Pancreatic NETs
Management options
Surgical resection of hepatic metastases
Hepatic arterial embolization/
chemoembolization
In cases of malignant pancreatic NETs in which ≥90% of the visible tumor could
be removed6,54
When surgery is not an option, these modalities may provide palliation in
patients who have hepatic metastases and an otherwise preserved performance
status, disease primarily confined to the liver, and a patent portal vein6,54
Radiofrequency ablation and
cryoablation, either alone or in
conjunction with cytoreductive surgery
When surgery is not an option, these techniques may be used in carefully
selected patients with advanced pancreatic NETs6,54
Peptide receptor radiotherapy (PRRT)
Using radiolabeled somatostatin analogs, PRRT is used for inoperable or metastatic
NETs6,55
Traditional chemotherapy
Either alone or in combination6,54
Investigational approaches
Liver transplantation
16
Comment(s)
Clinical studies may be appropriate according to each one’s specific protocol
and are subject to the discretion of the treating physician
In the occasional younger patient with a metastatic pancreatic NET that is
unresectable and limited to the liver6,54
Follow-up
In general, patients with localized pancreatic NETs should be followed up 3 to 12 months after resection and
at intervals thereafter with a physical examination, appropriate biomarkers, and structural (eg, CT, MRI) and
functional imaging studies (eg, SRS).3 Follow-up with chest x-ray has also been recommended.6 Patients with
metastatic disease are generally followed more frequently, as dictated by their requirement for concurrent therapies.
Conclusion
Pancreatic NETs are rare tumors that, depending on subtype and histologic features, vary in clinical aggressiveness.
Although they share similarities with other NETs, pancreatic NETs are associated with a worse prognosis when
compared with certain other NETs.7 The majority of patients (64%) with pancreatic NETs present with metastases
at diagnosis, and these patients have a 5-year survival rate of 27%.7
In patients with localized disease, the unique hormonal symptoms associated with pancreatic NETs may
require specific attention prior to surgical resection. In patients with more advanced disease, possible courses
of action to consider include systemic therapy. Participation in ongoing clinical trials should be considered for
appropriate patients.
Some of this material is referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Neuroendocrine Tumors V.1.2012. © 2012 National Comprehensive
Cancer Network, Inc. All rights reserved. The NCCN Guidelines™ may not be reproduced in any form for any purpose without the express written permission of the NCCN. To view the most recent and
complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES™, and all other NCCN Content are trademarks owned by
the National Comprehensive Cancer Network, Inc.
17
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19
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