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Wouter HerderNIH Public Access
Author Manuscript
Pancreas. Author manuscript; available in PMC 2011 May 24.
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Published in final edited form as:
Pancreas. 2010 August ; 39(6): 735–752. doi:10.1097/MPA.0b013e3181ebb168.
NANETS Treatment Guidelines:
Well-Differentiated Neuroendocrine Tumors of the Stomach and Pancreas
Matthew H. Kulke, MD*, Lowell B. Anthony, MD†, David L. Bushnell, MD‡, Wouter W. de
Herder, MD, PhD§, Stanley J. Goldsmith, MD||, David S. Klimstra, MD¶, Stephen J. Marx,
MD#, Janice L. Pasieka, MD**, Rodney F. Pommier, MD††, James C. Yao, MD‡‡, and Robert
T. Jensen, MD§§
*
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Department of Medical Oncology, Dana-Farber Cancer Institute, Boston MA † Division of
Hematology-Oncology, Louisiana State University Health Sciences Center, New Orleans, LA ‡
Department of Radiology, University of Iowa Hospitals and Clinics, Iowa City, IA § Department of
Internal Medicine, Erasmus MC, Rotterdam, the Netherlands || Division of Nuclear Medicine,
Department of Radiology, New York-Presbyterian Hospital, Weill Medical College of Cornell
University ¶ Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY #
Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases/
National Institutes of Health, Bethesda, MD ** Department of Surgery, University of Calgary,
Calgary Alberta, Canada †† Division of Surgical Oncology, Department of General Surgery,
Oregon Health & Science University, Portland, OR ‡‡ Department of Gastrointestinal Medical
Oncology, University of Texas, MD Anderson Cancer Center, Houston, TX §§ Digestive Diseases
Branch, National Institutes of Health, Bethesda, MD
Abstract
Well-differentiated neuroendocrine tumors (NETs) of the stomach and pancreas represent 2 major
subtypes of gastrointestinal NETs. Historically, there has been little consensus on the
classification and management of patients with these tumor subtypes. We provide an overview of
well-differentiated NETs of the stomach and pancreas and describe consensus guidelines for the
treatment of patients with these malignancies.
Keywords
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islet cell; gastric; carcinoid; guidelines; review
WELL-DIFFERENTIATED NEUROENDOCRINE (CARCINOID) TUMORS OF
THE STOMACH
Neuroendocrine tumors (NETs) of the stomach comprise less than 1% of gastric
neoplasms.1–3 In the pre-endoscopy era, they comprised 1.9% of all carcinoids, but in more
recent studies, 10% to 30% of all carcinoids are reported in the stomach.3 They can be
subclassified into 3 distinct groups: those associated with chronic atrophic gastritis/
pernicious anemia (type 1; 70%–80%), those associated with Zollinger-Ellison syndrome
(ZES) with multiple endocrine neoplasia type I (MEN I) (type 2; 5%), and sporadic NETs of
the stomach (type 3; 15%–20%).2,4
Copyright © 2010 by Lippincott Williams & Wilkins
Reprints: Matthew H. Kulke, MD, Dana-Farber Cancer Institute, 44 Binney St, Boston, MA 02115,
Matthew_kulke@dfci.harvard.edu.
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Etiology
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Both types 1 and 2 NETs of the stomach are associated with hypergastrinemia (Table 1).
High levels of gastrin are thought to result in hyperplasia of the enterochromaffin-like cells
in the stomach, ultimately leading to hyperplastic lesions and small, often multiple carcinoid
tumors.2,4 In contrast to types 1 and 2 carcinoids, type 3 carcinoids develop in the absence
of hyper-gastrinemia and tend to pursue an aggressive clinical course.2,4 Type 1 carcinoids
are generally small and frequently multiple; limited to the mucosa-submucosa, and
metastases occur in less than 2.5% to lymph nodes and less than 2.5%% to the liver.2,4 Type
2 carcinoids are almost always multiple and generally small (<1 cm) and are usually limited
to the mucosa-submucosa, but are slightly more aggressive than type 1 carcinoids, with up
to 30% showing lymph node metastases, and up to 10% may show liver metastases.4,5 Type
3 carcinoids are usually single, generally larger (>1 cm in 70%), and invasive through the
submucosa and deeper in most cases (>75%); 70% had accompanying lymph node
metastases, and 69% had distant metastases.4
Pathological Classification
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Neuroendocrine tumors of the stomach can be classified histologically in the same fashion
as carcinoid tumors arising at other sites. A variety of proposals regarding the classification
and nomenclature of NETs have appeared, and many of these differ somewhat regarding
specific terminology and criteria for grading and staging. Most proposed systems have
indeed proven useful to stratify prognostic subgroups of NETs. Features such as the
proliferative rate of the tumor and the extent of local spread (assessed based on similar
parameters used for nonneuroendocrine carcinomas of the same anatomical sites) are shared
by most systems. Recently, a multidisciplinary consensus group of experts in the field of
NETs has recommended such an approach and has developed a “minimum pathology data
set” (Table 2) of features to be included in pathology reports.6 The College of American
Pathologists has also developed similar “tumor checklists” for NETs that specify many of
the same parameters.7–10
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In general, NETs of the stomach and other NETs are divided into well-differentiated and
poorly differentiated categories. The concept of differentiation is linked to the grade of the
tumors (see below), but there are subtle differences between differentiation and grade.
Differentiation refers to the extent to which the neoplastic cells resemble their nonneoplastic
counterparts. In NETs, well-differentiated examples have characteristic “organoid”
arrangements of the tumor cells, with nesting, trabecular, or gyriform patterns. The cells are
relatively uniform and produce abundant neurosecretory granules, reflected in the strong and
diffuse immunoexpression of neuroendocrine markers such as chromogranin A (CGA) and
synaptophysin. Poorly differentiated NETs less closely resemble nonneoplastic
neuroendocrine cells and have a more sheet-like or diffuse architecture, irregular nuclei, and
less cytoplasmic granularity. Immunoexpression of neuroendocrine markers is usually more
limited. Grade, on the other hand, refers to the inherent biologic aggressiveness of the
tumor. Low-grade NETs are relatively indolent, high-grade tumors are extremely aggressive,
and intermediate-grade examples have a less predictable, moderately aggressive course. In
general, well-differentiated NETs are either low or intermediate grade, and poorly
differentiated NETs are considered high grade in all cases (Table 3). The concept that some
well-differentiated tumors could nonetheless be biologically high grade has been proposed
but is controversial.11
Well-differentiated (low and intermediate grade) tumors have been variably termed
carcinoid tumor (typical and atypical, respectively), neuroendocrine tumor (grade 1 and
grade 2, respectively), or neuroendocrine carcinoma (low grade and intermediate grade,
respectively), among other options. Table 4 displays a comparison of the various systems of
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nomenclature currently in use for NETs, along with for which organ systems each system is
most commonly used. Although the criteria that define each category do not perfectly match
between the various systems, there are several common themes. Each system recognizes 3
grades. In each, the low and intermediate grades are closely related, well differentiated, and
distinguished largely by proliferative rate (or necrosis). Finally, each system generally
recognizes that individual tumors rarely display hybrid well-differentiated and poorly
differentiated features.
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Most systems of grading rely extensively on the proliferative rate to separate low-,
intermediate-, and high-grade NETs. Some systems (such as the World Health Organization
[WHO] classification for lung and thymus) include the presence of necrosis as a feature to
distinguish intermediate grade from low grade within the well-differentiated group. The
proliferative rate can be assessed as the number of mitoses per unit area of tumor (usually
expressed as mitoses per 10 high-power microscopic fields, or per 2 mm2), or as the
percentage of neoplastic cells immunolabeling for the proliferation marker Ki67. The WHO
classification of lung and thymus tumors relies only on the mitotic rate, whereas the system
recently proposed for gastroenteropancreatic NETs (GEP NETs) by the European
Neuroendocrine Tumor Society (ENETS) and also now recommended by the WHO uses
either mitotic rate or Ki67 labeling index. A comparison of the most widely used grading
systems is shown in Table 4. The cut-points to distinguish the 3 grades vary somewhat
among the different systems, and some studies suggest that the optimal cut-points may differ
between organ systems.12,13 For these reasons, it is recommended to specify the actual
proliferative rate in the pathology report, in addition to designating a grade based on a
system that is specifically referenced.
The use of mitotic counts versus Ki67 index is controversial. In Europe, where the ENETS
system is already in widespread use, Ki67 labeling indices are commonly reported for all
NETs. When the amount of tumor tissue is limited (eg, in a biopsy from a primary tumor or
a metastatic focus), it may not be possible to perform an accurate mitotic count, because it is
recommended to count 40 to 50 high-power fields—more than most biopsy samples include.
In these cases, Ki67 staining provides a more accurate assessment of proliferative rate, and it
is particularly helpful to separate well-differentiated (low or intermediate grade) tumors
from poorly differentiated (high grade) neuroendocrine carcinomas, which usually have
dramatically different Ki67 labeling rates.14,15 However, when adequate tissue is present to
perform an accurate mitotic count, there are no data to demonstrate that the Ki67 labeling
index adds important additional information, and in some cases, the 2 measures of
proliferative rate may provide conflicting information about grading.
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As recently as a few years ago, no formal TNM-based staging systems existed for NETs.
Data submitted to the Surveillance, Epidemiology, and End Results program of the National
Cancer Institute separated tumors into localized, regional, and distant stages based on the
presence of lymph node or distant metastases, but substratification of the extent of the
primary tumor was not performed.16 Recently, TNM staging systems have been proposed
(Table 5). The American Joint Committee on Cancer (AJCC) has recently published a new
TNM staging manual that includes NETs of all anatomical sites,17 and the ENETS has
previously published recommendations for TNM staging of GEP NETs18,19 There are some
differences between these systems, particularly for primary tumors of the pancreas and
appendix, but there is also considerable overlap. Additionally, the staging criteria for both
systems rely predominantly on the size of the tumor and the extent of invasion into similar
landmarks as used for the staging of nonneuroendocrine carcinomas of the same sites. It is
recommended that the extent of involvement of these structures be specifically indicated in
the pathology reports, in addition to providing a TNM stage based on a system that is
specifically referenced.
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Until very recently, the WHO classifications for NETs of the tubular gastrointestinal tract
(2000) and pancreas (2004) used a hybrid classification system that incorporated both
staging information (size and extent of tumor—limited to the primary site or metastatic) and
grading information (proliferative rate) into a single prognostic prediction system, with a
different name being applied to the tumors in each prognostic group.20–23 Although this
system did allow prognostic stratification of NETs, it did not allow for grading information
to be applied to advanced stages of disease, preventing prognostication once metastases
occurred and therefore limiting information for therapeutic decision making.24 Furthermore,
the implications of this classification were that the name for a NET limited to the primary
site was different than that to be used for the same tumor once metastases occurred in the
future, a relatively common occurrence for some NETs. Because of these limitations, the
most recent WHO classification that applies to all GEP NETs has abandoned the hybrid
classification system in favor of separately grading and staging the tumors (Tables 3 and 4).
This will bring the WHO system more closely in line with other widely used systems.
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A variety of other pathological findings may be of use in the prognostication and
management of patients with NETs (Table 1). Immunolabeling for general neuroendocrine
markers (CGA and synaptophysin) may not be needed in histologically typical resected
primary tumors, but it is very important in many cases to confirm the nature of the tumor
based on biopsy specimens. Immunolabeling for specific peptide hormones is useful only in
highly defined circumstances, however. Adverse prognostic factors not included in grading
and staging, such as vascular or perineural invasion, should be documented. Adequacy of
surgical resection should be indicated, and the number of involved lymph nodes (as well as
the total number of nodes examined) should also be stated. Histological abnormalities of the
neuroendocrine cells in the surrounding tissues (such as neuroendocrine hyperplasia in the
lung or stomach) should be described. A variety of prognostic or treatment-related biomarkers has been investigated, and some may have significant utility in the future, but
currently, none is recommended to be used routinely, outside specific research settings.
Imaging
Most NETs of the stomach are directly imaged and diagnosed during endoscopy. For larger
lesions, endoscopic ultrasound (EUS) may be performed to assess whether the NETs of the
stomach is invasive.
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Cross-sectional imaging with computed tomography (CT) or magnetic resonance imaging
(MRI) is recommended to assess for metastases in patients with type 1 or 2 NETs of the
stomach more than 2 cm in diameter, or for patients with type 3 NETs of the stomach in
whom metastatic risk is a concern.25 Neuroendocrine tumors are generally vascular tumors
that enhance intensely with intravenous contrast during early arterial phases of imaging with
washout during the delayed portal venous phase. The key to detecting small NETs on CT is
to maximize the contrast between the tumor and the adjacent normal parenchyma. For
abdominal and pelvic imaging, we recommend multiphasic CT that includes the arterial
phase and the portal venous phase. Rapid intravenous bolus of intravenous contrast is also
recommended. Thin sectioning and the use of a negative oral contrast agent also may be
helpful in detecting small primary tumor in the small bowel that may not otherwise be seen.
Magnetic resonance imaging is preferred over CT for patients with a history of allergy to
iodine contrast material or for those with renal insufficiency. Neuroendocrine tumors can
have variable appearances on noncontrast MRI. They can be hypointense or isointense on
T1-weighted images. Metastases to the liver typically are usually high signal on T2weighted images. Because T2-weighted images are obtained without intravenous contrast,
they do not have the problems of variations in the timing of phases of contrast enhancement.
T2-weighted imaging can be especially useful for patients unable to receive contrast.
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However, these metastases, especially when cystic or necrotic, can mimic the appearance of
other T2 high-signal-intensity lesions, such as hemangiomas and, occasionally, cysts.
Dynamic contrast-enhanced imaging can provide additional information about the nature of
the lesions and help to detect smaller lesions. We recommend T1-weighted, T2-weighted
imaging, and multiphasic (arterial, portal venous, and delayed) dynamic MRI for NETs.
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Somatostatin receptor scintigraphy (SRS) provides a second useful imaging modality for the
detection of metastatic disease in patients with malignant NETs of the stomach.25,26 Indium
In 111–labeled somatostatin analog [111In-DTPA0] octreotide was developed for
scintigraphy of NETs. It shares the receptor-binding profile of octreotide, which makes it a
good radiopharmaceutical for imaging of somatostatin receptor 2– and receptor 5–positive
tumors. The overall sensitivity of [111In-DTPA0]octreotide scintigraphy seems to be about
80% to 90%.27 Unlike cross-sectional imaging, which is generally site directed, [111InDTPA0]octreotide scintigraphy is done as whole-body imaging and thus can detect disease
at unsuspected sites. Imaging is generally performed at 4 to 6 hours and at 24 hours.
Imaging at 24 hours provides better contrast due to lower background activity. However,
there is often physiological bowel activity that may produce false-positive results. At 4 to 6
hours, some lesions may be obscured by relatively high background activity; however,
bowel activity is limited. In some cases, additional imaging at 48 hours may be needed when
there is significant bowel activity at the 24-hour scan, which may potentially obscure lesions
that provide additional information. SPECT (single photon emission CT) imaging with CT
fusion may be helpful in resolving the nature of indeterminate lesions found on CT and
enhance the sensitivity and specificity the study.
[111In-DTPA0]octreotide scintigraphy can be performed for patients on long-acting
octreotide but is best performed at the end of the dosing interval (3–6 weeks after the last
dose). Although [111In-DTPA0]octreotide scintigraphy can provide useful information about
the site of disease, it dose not give information about size. Some agents such as interferon
may upregulate somatostatin receptors and thus can lead to increased uptake without disease
progression, whereas glucocorticoids can downregulate somatostatin receptor expression,
thus causing false-negative results. [111In-DTPA0]octreotide scintigraphy is also sometimes
performed to evaluate the feasibility of peptide receptor radiotherapy (PRRT) as a scan with
intense uptake at all known sites of disease is associated with a higher response rate after
radiotherapy with somatostatin receptor targeting.
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Prior studies have shown [11C]–5-hydroxytryptophan (5-HTP) positron emission
tomography (PET) to be a promising imaging modality for the detection of NETs.28 The
serotonin precursor 5-HTP labeled with 11C was used and showed an increased uptake and
irreversible trapping of this tracer in NETs.28 [11C]–5-HTP PET proved better than SRS for
tumor visualization. However, the short half-life of 11C (t1/2 = 20 minutes) makes it difficult
to apply in clinical practice. Other new PET imaging agents for NETs include 18FFDOPA, 68Ga-DOTA-TOC, 68Ga-DOTA-NOC, and 18F-FPGluc-TOCA. In
addition, 99mTc-depreotide, which has a greater affinity to somatostatin receptor 3, has also
been used for tumor imaging. Although these novel imaging techniques are promising,
clinical experiences are limited. These techniques are generally not available in the United
States.
Follow-up radiological imaging may not be routinely required for types 1 and 2 carcinoids,
but is warranted after resection of type 3 carcinoids. Among patients undergoing
surveillance after complete resection, we recommend chest x-ray and periodic crosssectional imaging of the abdomen and pelvis. The role of routine [111In-DTPA0]octreotide
scintigraphy has not been defined by prospective studies. Many experts, however, would
advocate the use of [111In-DTPA0]octreotide scintigraphy as a yearly study for follow-up for
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patients without evidence of disease or on a as-needed basis to resolve difficult issues. For
patients with advanced disease, we generally recommend the use of cross-sectional imaging
for follow-up of known sites of disease. Chest x-ray can be used as a screening examination
for patients without evidence of thoracic disease. [111In-DTPA0] octreotide scintigraphy can
be used to test in vivo for the presence of somatostatin receptors 2 and 5. It can also be used
to evaluate if PRRT represents a good treatment option.
Biochemical Monitoring
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Fasting serum gastrin levels are important to differentiate types 1 and 2 NETs of the
stomach from type 3. 5-Hydroxyindoleacetic acid (5-HIAA) levels are generally not useful
in patients with NETs of the stomach, because development of the carcinoid syndrome is
uncommon.4 Furthermore, carcinoid syndrome, if it occurs in these patients, is reported to
be characteristically atypical with normal serotonin and 5-HIAA levels, although a recent
study reports the typical carcinoid syndrome can occur in rare patients with NETs of the
stomach.5 Plasma CGA levels are recommended because CGA is frequently elevated in both
patients with types 1 and 2 as well as type 3 NETs of the stomach,25 and changes in CGA
levels may be helpful in the follow-up.25 Chromogranin A should be used with caution as a
marker of disease activity in patients treated with somatostatin analogs, because these agents
significantly reduce plasma CGA levels, a change that may be more reflective of changes in
hormonal synthesis and release from tumor cells than an actual reduction in tumor mass.25,29
In patients on stable doses of somatostatin analogs, consistent increases in plasma CGA
levels over time may reflect loss of secretory control and/or tumor growth. Plasma CGA
levels have also been shown to have a prognostic value in patients with metastatic
disease.25,30
Management of Localized NETs of the Stomach
Because types 1 and 2 NETs of the stomach generally pursue an indolent course, tumors less
than 2 cm (up to 6) should be resected endoscopically, with subsequent interval followup.2,25,31 Patients with tumors measuring more than 2 cm, with recurrent tumors or with
more than 6 polyps, generally require more aggressive management, and local surgical
resection is recommended.2,25,31 In patients with type 1 NETs of the stomach arising in the
setting of chronic atrophic gastritis, antrectomy may be performed to eliminate the source of
gastric production. Antrectomy has been reported to result in tumor regression in such
cases.32,33 In patients with type 2 NETs of the stomach secondary to ZES/MEN I syndrome,
treatment with somatostatin analogs may be initiated and has resulted in tumor regression.34
The surgical management of type 3 isolated sporadic NETs of the stomach requires more
aggressive surgery, generally with partial gastrectomy and lymph node dissection.2,25,31
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Management of Metastatic NETs of the Stomach
In general, metastatic NETs of the stomach, which are infrequent and therefore usually
included in general studies including other more frequent malignant carcinoids (especially
midgut), are treated in a similar fashion as these other malignant carcinoids.
Hepatic Resection and Transplantation—A small percentage of patients (5%–15%)
with metastatic liver disease with a limited number of hepatic metastases localized
preferable to one lobe may be successfully treated with hepatic resection, providing both
long-term symptomatic relief and likely increasing survival times.35–37 The number of
patients with liver-isolated metastatic NETs in whom orthotopic liver transplantation (OLT)
has been attempted remains small, resulting in the role of OLT in such patients being
controversial and cannot, at this time, be routinely recommended.38,39 In a recent review of
85 cases, overall 5-year survival was 45%, and poor prognostic factors were prior extensive
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upper abdominal surgery, a neuroendocrine primary tumor in the duodenum or pancreas,
and hepatomegaly.39 Without any of these risk factors, the 5-year survival was 66%.39 It has
been proposed for the occasional, younger patient without any of these risk factors with a
metastatic carcinoid tumor that is unresectable and limited to the liver that liver
transplantation remains an option that should be considered.38–40
Hepatic Artery Embolization—Hepatic arterial embolization is recommended as a
palliative option in patients with hepatic metastases who are not candidates for surgical
resection, have an otherwise preserved performance status, have disease primarily confined
to the liver, and have a patent portal vein.35,41,42 The response rates associated with
embolization, as measured either by decrease in hormonal secretion or by radiographic
regression, are generally greater than 50%.35,41–43 Improved techniques have, in recent
years, reduced the incidence complications related to embolization, making embolization an
important and generally safe treatment.43 A number of techniques may be used and include
bland embolization, chemoembolization, embolization with chemotherapy beads, and
embolization using radioisotopes. There are currently no data confirming superiority of any
of these techniques compared with the others. This technique should be especially
considered for a patient with a functional carcinoid in which the hormone excess state
cannot be controlled by other methods.
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Radiofrequency Ablation and Cryoablation—Other approaches to the treatment of
hepatic metastases include the use of radiofrequency ablation (RFA) and cryoablation, either
alone or in conjunction with surgical debulking.35,42 These approaches can be performed
using a percutaneous or laparoscopic approach. Although they seem to be less morbid than
either hepatic resection or hepatic artery embolization, the clinical benefit of these
approaches in patients with asymptomatic, small-volume disease has not been clearly
established. Similarly, these approaches may not be applicable in patients with large-volume
hepatic metastatic disease. Ablative techniques should therefore be considered as a treatment
option only in carefully selected patients.35,42,44,45
Systemic Treatment of Metastatic Disease—Patients with metastatic NETs of the
stomach may develop an “atypical” carcinoid syndrome related to release of histamine and/
or 5-HTP or rarely a typical carcinoid syndrome as seen in patients with metastatic midgut
carcinoids.5 These patients frequently benefit from treatment with somatostatin analogs for
symptom control.5,46
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The addition of α-interferon to therapy with somatostatin analogs has been reported to be
effective in controlling symptoms in patients with carcinoid syndrome who may be resistant
to somatostatin analogs alone.47,48 Treatment with α-interferon may therefore be considered
in patients with metastatic NETs of the stomach refractory to somatostatin analogs. In
clinical trials, doses of α-interferon have ranged from 3 to 9 MU subcutaneously,
administered from 3 to 7 times per week.
The direct antineoplastic effects of somatostatin analogs either with or without interferon
remain uncertain, although recent studies suggest they have a cytostatic effect in 40% to
70% of patients.48,49 Treatment with somatostatin analogs can therefore be considered in
patients with NETs of the stomach and evidence of radiological progression. Whether this
cytostatic effect of somatostatin alone or with interferon results in increased survival is
largely unproven at present. A recent prospective study (PROMID study) demonstrates in
patients with metastatic midgut carcinoid tumors involving less than 10% of the liver the use
of octreotide long-acting release (LAR) resulted in an increased time to progression.50
However, it is unclear whether similar effects occur with patients with more extensive
metastases or with foregut (gastric, pancreatic, duodenal) or hindgut carcinoids as well.
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Cytotoxic Chemotherapy—Because of its rarity, there have not been any specific
studies of cytotoxic agents in only patients with malignant NETs of the stomach. However,
with malignant carcinoids in general, cytotoxic chemotherapy plays only a limited role, and
therefore, it is probable that similar results can be expected with malignant NETs of the
stomach. Studies of single-agent therapy with 5-fluorouracil, streptozocin, or doxorubicin in
patients with metastatic carcinoid tumors have shown that these agents are associated with
only modest response rates.41,51,52 Trials of combination chemotherapy in this disease have
failed to demonstrate superiority to single-agent therapy; furthermore, many of these
combination regimens have been associated with significant toxicity.41,52,53 Dacarbazine
(DTIC) has been evaluated as a potential alternative to streptozocin-based therapy in
carcinoid and pancreatic NETs (PNETs), although concerns regarding toxicity have limited
its use for this indication.54 Studies with the oral agent, temozolomide, have also shown
only limited activity in carcinoid tumors. Although streptozocin-, dacarbazine-, or
temozolomide-based therapy may therefore be considered in patients with metastatic NETs
of the stomach, careful consideration needs to be given to the relative benefit of such an
approach.51
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Investigational Approaches—In the absence of an approved systemic treatment for
metastatic carcinoid disease, treatment with investigational agents is appropriate for patients
with metastatic NETs of the stomach. Recent studies using vascular endothelial growth
factor pathway inhibitors such as bevacizumab, sunitinib, and sorafenib have suggested that
these agents may have antitumor activity.55–58 Similarly, the mTOR (mammalian target of
rapamycin) inhibitor, everolimus, has shown activity in patients with advanced carcinoid in
early studies.55–57,59 Randomized trials are currently ongoing to confirm activity with these
agents, and they remain investigational in patients with metastatic carcinoid disease.55–57
Treatment with radiolabeled somatostatin analogs represents another investigational
approach to the treatment of patients with advanced carcinoid tumors.60,61
WELL-DIFFERENTIATED NETS OF THE PANCREAS
Well-differentiated NETs of the pancreas (PNETs) have an estimated incidence of less than
1 per 100,000 individuals.62–64 Pancreatic NETs are divided into 2 groups: those associated
with a functional syndrome due to ectopic secretion of a biologically active substance and
those that are not associated with a functional syndrome (generally called nonfunctional
PNETs [NF-PNETs]; Table 6).62–65 This distinction is important for clinical presentation,
diagnosis, and treatment of these tumors.
Clinical Presentation and Etiology
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Functional PNETs include insulinomas, gastrinomas, PNETs secreting vasoactive intestinal
polypeptide (VIPomas), somatostatinomas, glucagonomas, growth hormone–releasing
hormone secreting (GHRHomas), and a group of less common PNETs including PNETs
secreting adrenocorticotropic hormone (ACTH; AfCTHomas) and causing Cushing
syndrome, PNETs causing the carcinoid syndrome, PNETs causing hypercalcemia (via
parathyroid hormone [PTH]–related peptide [PTH-rP] secretion), and, very rarely, PNETs
ectopically secreting luteinizing hormone, renin, insulin like growth factor 2, or
erythropoietin.62 Functional PNETs and NF-PNETs also frequently secrete a number of
other substances (chromogranins, neuron-specific enolase, subunits of human chorionic
gonadotropin, neurotensin, ghrelin), but they do not cause a specific hormonal
syndrome.62–65 In terms of relative frequency, NF-PNETs are at present the most frequently
found PNET, occurring approximately twice as frequently as insulinomas, which are
generally more frequent than gastrinomas, followed by glucagonomas > VIPomas >
somatostatinomas > others.62,63,65,66
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Pancreatic NETs can occur both sporadically and in patients with various inherited
disorders.62,67 Pancreatic NETs occur in 80% to 100% of patients with MEN I, in 10% to
17% of patients with von Hippel-Lindau syndrome (VHL), up to 10% of patients with von
Recklinghausen disease (neurofibromatostis 1 [NF-1]), and occasionally in patients with
tuberous sclerosis.67 Each of these is an autosomal dominant disorder.67 Of these disorders,
MEN I is the most frequent, in patients with PNETs.67,68 Multiple endocrine neoplasia I is
caused by mutations in chromosome 11q13 region, resulting in alterations in the Menin
gene, which encodes for a 610–amino acid nuclear protein, menin, which has important
effects on transcriptional regulation, genomic stability, cell division, and cell cycle
control.67 Patients with MEN I develop hyperplasia or tumors of multiple endocrine and
nonendocrine tissues including parathyroid adenomas (95%–100%), resulting in
hyperparathyroidism, pituitary adenomas (54%–65%), adrenal adenomas (27%–36%),
various carcinoid tumors (gastric, lung, thymic; 0%–10%), thyroid adenomas (up to 10%),
various skin tumors (80%–95%), central nervous system tumors (up to 8%), and smooth
muscle tumors (up to 10%).67 In MEN I patients, 80% to 100% develop pancreatic NFPNETs, but in most patients, they are small and microscopic, causing symptoms in only 0%
to 13%.67 Gastrinomas (>80% duodenal) develop in 54% of MEN I patients, insulinomas in
18%, and glucagonomas, VIPomas, GHRHomas, and somatostatinomas in less than 5%.67
In VHL, 98% of all the PNETs that develop in 10% to 17% of the patients are NF-PNETs;
in the 0% to 10% of NF-1 patients developing a PNET, they are characteristically duodenal
somatostatinomas that do not cause the somatostatinoma syndrome, and in tuberous
sclerosis, rare functional and NF-PNETs are reported.67
Pathological Classification
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The pathological classification of PNETs generally parallels that of NETs of the stomach
and other NETs (described previously for NETs of the stomach), with some notable
differences. Because PNETs do not arise in the luminal gut, separate TNM staging systems
are used for PNETs (Table 6). The issue of functionality of NETs also impacts on the
nomenclature for PNETs. Functioning NETs are defined based on the presence of clinical
symptoms due to excess hormone secretion by the tumor (Table 7). Terms reflecting the
clinical syndromes may be applied to these NETs, such as insulinoma, glucagonoma,
gastrinoma, and so on. Although there are prognostic implications to some of the functional
categories (eg, insulinomas are generally very indolent), the biology of most functioning
NETs is still defined by the grade and stage of the tumor (although the clinical consequences
of the hormone hypersecretion can be significant). Furthermore, the functional status of the
tumor is defined by the clinical findings, not by the pathological appearance or
immunohistochemical profile. Thus, the pathological diagnosis of functioning NETs should
be the same as for analogous nonfunctional NETs of the same anatomical site, with the
descriptive functional designation appended to the diagnosis when there is knowledge of a
clinical syndrome.
Incidence, Clinical Features, and Diagnosis of Specific PNETs
Insulinoma—Insulinomas have an estimated annual incidence of 1 to 4 per million
persons. Approximately 4% of patients with insulinoma have MEN I.67 Insulinomas are
usually single tumors (except in patients with MEN I), generally small (ie, <1 cm), and
almost always (>99%) intrapancreatic in location and, in contrast to all other PNETs, are
benign in more than 85% to 95% of patients.67,69–71 Insulinoma patients characteristically
present with symptoms of hypoglycemia, especially neuroglycopenic symptoms (confusion,
altered consciousness) and symptoms due to sympathetic overdrive (weakness, sweating),
which are usually made worse by fasting.62,70,71 The diagnosis of insulinoma can be
established by determining plasma proinsulin, insulin, C-peptide, and glucose levels, which
are usually performed during a 72-hour fast.62,70,71 It is important to realize that insulin
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levels are increasingly being determined by immunochemiluminescent assays or specific
immunoradiometric assays that do not cross-react with proinsulin and give lower values than
that obtained with most insulin radioimmunoassays, which can effect the proposed criteria
listed in many reviews for diagnosis, which were based on radioimmunoassay results.62,72
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Gastrinoma—Gastrinomas ectopically secrete gastrin, resulting in hypergastrinemia,
which stimulates gastric acid hypersecretion, resulting in severe peptic disease (ZES).62,73,74
Currently, gastrinomas, in contrast to older studies, are found in the duodenum in more than
60% of patients with sporadic ZES (>85% with MEN I/ZES), are usually single in sporadic
ZES and invariably multiple in MEN I/ZES, are usually small in the duodenum (<1 cm), and
are malignant in 60% to 90% of cases.67,75–78 Recent studies show pancreatic tumors are
more aggressive than duodenal tumors, are much more likely to metastasize to liver and/or
bone, and are more likely to be present in the 25% of ZES patients with aggressive
gastrinomas.62,79–81 Patients typically present with abdominal pain due to peptic ulcer
disease (PUD), diarrhea, and reflux esophagitis.73 Zollinger-Ellison syndrome should be
suspected in patients with PUD with diarrhea, with ulcers in unusual locations, with severe
PUD or with complications of PUD, with PUD without Helicobacter pylori present, with
PUD with a family history of PUD or endocrinopathies, or with PUD with prominent gastric
folds, presence of an endocrinopathy, or with hypergastrinemia.62,73,74,82,83 The diagnosis
of ZES requires the demonstration of inappropriate hypergastrinemia (ie, hypergastrinemia
present at time of acid hypersecretion).62,73,74,82,83 When ZES is suspected, the initial
determination in most centers is a fasting gastrin level, because it will be elevated in 99% to
100% of ZES patients.62,82,83 The diagnosis can be complicated by the fact that other
conditions, some of which are much more common than ZES, can cause hypergastrinemia in
a range seen with ZES patients.62,73,74,82–85 These other conditions either can result in
hypergastrinemia due to their causing hypochlorhydria/achlorhydria (atrophic gastritis,
proton pump inhibitor [PPI] treatment) or can be associated with increased acid secretion
similar to ZES.62,73,82,83,86 Recent studies86,87 show that the widespread use of PPIs can
particularly complicate and delay the diagnosis of ZES. This occurs because PPIs, in
contrast to histamine H2–receptor antagonists, control the symptoms in most ZES patients
with conventional doses used to treat idiopathic PUD/esophagitis and thus mask the
diagnosis.62,83,86 Furthermore, PPIs cause hypergastrinemia in patients without ZES,
commonly in the range that is seen with most ZES patients.83,86–88 To exclude physiological
hypergastrinemia (associated with hypochlorhydria/achlorhydria), it is essential to measure
gastric pH if hypergastrinemia is detected because it is 2 or less in all patients with ZES not
taking anti-secretory drugs.89 Because of the presence of other conditions that can also cause
hypergastrinemia and an acidic pH, the diagnosis of ZES may require the assessment of
basal acid output as well as a secretin provocative gastrin test.62,74,83,84 Gastrinomas
ectopically express secretin receptors, and intravenous administration of secretin
characteristically causes an exaggerated release of secretin by the gastrinoma (ᚣ120-pg/mL
increase post secretin is positive for gastrinoma,84 if the patient is not taking PPIs).84,90
With some patients suspected of having ZES, there can be risk to stopping PPIs to assess
fasting gastrin levels and perform acid secretory studies or secretin provocative testing; thus,
it is best that these patients be referred to a clinical unit experienced in making the diagnosis
of ZES.
The diagnosis of ZES in patients with MEN I can be complicated by the fact that the
presence or absence of hyperparathyroidism with the resultant hypercalcemia can have a
marked effect on fasting gastrin levels, basal acid output, and the secretin test
results.67,68,91–93 Each of these parameters can markedly decrease after correction of the
hyperparathyroidism, by an effective parathyroidectomy (ᚣ3.5 glands removed) and thus
can mask the diagnosis of ZES in MEN I patients.67,68,91–93
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Glucagonoma—Glucagonomas cause glucose intolerance (40%–90%), weight loss
(80%), and a pathognomonic rash, migratory necrolytic erythema (70%–90%).62,66,94–96
Glucagonomas are generally single, large tumors (mean, 6 cm), associated with liver
metastases in more than 60% of cases at diagnosis, and are almost entirely intrapancreatic in
location.62,66,94–96 Although glucagonomas may be associated with glucose intolerance,
clinically significant hyperglycemia occurs in only half of such patients. Patients with
glucagonomas are frequently initially diagnosed by a dermatologist, after presenting with
necrolytic migratory erythema. This rash, characterized by raised erythematous patches
beginning in the perineum and subsequently involving the trunk and extremities, is found in
more than two thirds of all patients.62,66,94–96 However, necrolytic migratory erythema is
not specific for glucagonomas because it can also occur in cirrhosis, pancreatitis, and celiac
disease.62 The diagnosis of a glucagonoma requires the demonstration of increased plasma
glucagon levels (usually 500–1000 pg/mL; normal, <50 pg/mL) in the presence of the
appropriate symptoms.62,66,94–96
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VIPomas (Also Called Verner-Morrison Syndrome, Pancreatic Cholera, or
WDHA [Watery Diarrhea, Hypokalemia, and Achlorhydria] Syndrome)—
Vipomas are PNETs ectopically secreting VIP, which leads to profound, large-volume
diarrhea (>700 mL/d in 100%, >3 L/d in 70%–80%), hypokalemia, and
achlorhydria.62,66,94,97,98 VIPomas are usually single tumors, metastatic at presentation in
70% to 80% of cases, and in adults are intrapancreatic in location in more than 95% of
cases, whereas in children they often are ganglioneuromas/ganglioblastomas.62,66,94,97,98
The diagnosis requires the demonstration of an elevated plasma VIP level in a patient with
large-volume secretory diarrhea.62,66,94,97,98
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Somatostatinoma—Somatostatinomas are PNETs that can occur in the duodenum or
pancreas.62,66,94,99–101 In the literature, there is no general agreement of what is a
somatostatinoma and whether a functional component is required for the diagnosis.62,94
Most of the cases reported in the literature are PNETs containing somatostatin by
immunohistochemistry, without an specific somatostatinoma syndrome, which includes the
presence of diabetes mellitus, gallbladder disease, weight loss, diarrhea, steatorrhea, and
anemia.62,66,94,99–101 Somatostatinomas are usually single tumors; approximately 50% are
intrapancreatic and the remainder primarily in the duodenum or the rest of the small
intestine, and 50% to 60% are malignant; however, the malignancy rate is higher with
pancreatic than duodenal tumors.62,66,94,99–101 The diagnosis of the somatostatinoma
syndrome is confirmed by the presence of a PNET with the appropriate symptoms and an
elevated plasma somatostatin level.62,66,94,99,100 In contrast to pancreatic somatostatinomas,
duodenal somatostatinomas, which can occur in up to 10% of patients with von
Recklinghausen disease (NF-1), are usually not associated with metastatic disease and are
rarely associated with the somatostatinoma syndrome.62,66,94,99,100
Other Rare Functional PNETs—GHRHomas ectopically secrete growth hormone–
releasing hormone, which results in acromegaly, which is generally clinically
indistinguishable from that caused by pituitary adenomas.62,94,102 GHRHomas in the
pancreas are generally single, large tumors at diagnosis; one third have liver metastases, and
they are found in the pancreas in 30% of cases, 54% in the lung, and the remainder primarily
in other abdominal locations.62,94,102 The diagnosis is made by establishing the presence of
increased plasma growth hormone levels accompanied by increased plasma Growth
hormone releasing factor levels.62,94,102 Pancreatic NETs causing hypercalcemia usually
secrete PTH-rP as well as other biologically active peptides and are similar to pancreatic
ACTHomas associated with ectopic Cushing syndrome in that both are usually large tumors
at diagnosis, with 80% to 90% associated with liver metastases.62,94,103,104 With
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ACTHomas or PNETs causing hypercalcemia, the diagnosis is made by the presence of a
PNET with the appropriated elevated hormonal assay result.
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Nonfunctional PNETs—Nonfunctional PNETs are intrapancreatic in location,
characteristically large (>5 cm in 70%), and at an advanced stage when first diagnosed, with
60% to 85% having liver metastases in most series.62,64,65,94,105 Because NF-PNETs are not
associated with a clinical hormonal syndrome, they present clinically with symptoms due to
the tumor per se, which include primarily abdominal pain (40%–60%), weight loss, or
jaundice.62,64,65,94,105 In recent years, NF-PNETs are increasingly being discovered by
chance on imaging studies being performed for various nonspecific abdominal
symptoms.62,106 Even though NF-PNETs do not secrete peptides causing a clinical
syndrome, they are not biologically inactive, because they characteristically secrete a
number of other peptides, which are frequently used in their diagnosis. These include
chromogranins, especially CGA (70–100%) and pancreatic polypeptide (PP) (50%–
100%).62,64,65,94,105 The presence of an NF-PNET is suggested by the presence of a
pancreatic mass in a patient without hormonal symptoms, who has an elevated serum PP or
CGA level or a positive Octreoscan (SRS) (discussed in the next section). It is important to
remember that an elevated PP level or CGA level is not specific for NF-PNETs.62,64,65,94,105
Imaging
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General—Imaging of the primary tumor location and the extent of the disease is needed for
all phases of management of patients with PNETs. It is needed to determine whether
surgical resection for possible cure or possible cytoreductive surgery is needed, to determine
whether treatment for advanced metastatic disease is appropriate, and during follow-up to
assess the effects of any antitumor treatment as well as the need for deciding whether
additional treatments directed at the PNET are indicated.62,94,107,108 Functional PNETs
(especially insulinomas, duodenal gastrinomas) are often small in size, and localization may
be difficult.62,94,107,108 A number of different imaging modalities have been widely used
including conventional imaging studies (CT, MRI, ultrasound, angiography),62,107,109–111
SRS,62,112–114 EUS,62,115,116 functional localizations studies measuring hormonal
gradients,62,117–119 intraoperative methods particularly intraoperative ultrasound,62,120,121
and, recently, the use of PET preoperatively.28,114,122,123 A few important points in regard
to each are made in the following section.
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Conventional Imaging Studies for PNETs Studies (CT, MRI, Ultrasound,
Angiography)—Even though PNETs are highly vascular tumors, and most of these studies
are now performed with contrast agents, the results with conventional imaging studies are
dependent to a large degree on the tumor size.62,107,109–111 Although conventional imaging
studies detect more than 70% of PNETs that are greater than 3 cm, they detect less than 50%
of most PNETs that are less than 1 cm, therefore frequently missing small primary PNETs
(especially insulinomas, duodenal gastrinomas) and small liver metastases.62,107,109–111 At
least one of these modalities is generally available in most centers, with CT scanning with
contrast being most frequently use as the first imaging modality.
Somatostatin Receptor Scintigraphy—Pancreatic NETs, similar to carcinoid tumors,
frequently (>80%, except nonmetastatic insulinomas) overexpress somatostatin receptors
(particularly subtypes sst 2 and 5), which bind various synthetic analogs of somatostatin
(octreotide, lanreotide) with high affinity.62,112–114,124 A number of radiolabeled
somatostatin analogs have been developed to take advantage of this finding to image
PNETs, with the most widely used worldwide and the only one available in the United
States being 111In-DTPA-octreotide (Octreoscan).62,112–114,124 Somatostatin receptor
scintigraphy combined with CT detection (SPECT imaging) is more sensitive that
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conventional imaging for detection of both the primary (except nonmetastatic insulinomas)
PNET and metastatic PNETs to liver, bone, or other distant sites.81,112–114,124,125 This
sensitivity allows SRS to detect 50% to 70% of primary PNETs (less frequent with
nonmetastatic insulinomas or duodenal gastrinomas) and more than 90% of patients with
metastatic disease.62,112–114,126,127 It has the advantage of allowing total body scanning
quickly at one time, and its use has resulted in a change in management of 24% to 47% of
patients with PNETs.62,112–114,126,127 False-positive localizations can occur in up to 12% of
patients, so it is important to interpret the result within the clinical context of the patient, and
by doing this, the false-positive rate can be reduced to 3%.62,113,127,128
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Endoscopic Ultrasound—Endoscopic ultrasound combined with fine-needle aspiration
can be useful in distinguishing a NF-PNET from adenocarcinoma or some other cause of a
pancreatic mass.62,115,116 Fine-needle aspiration is rarely used to diagnose functional
PNETs because they are suggested by symptoms, and the diagnosis is established by
hormonal assays.62,94,116 Endoscopic ultrasound is much more effective for localizing
intrapancreatic PNETs than extrapancreatic PNETs such as duodenal gastrinomas or
somatostatinomas.62,94,115,116 Endoscopic ultrasound is particularly helpful in localizing
insulinomas, which are small, almost always intrapancreatic, and frequently missed by
conventional imaging studies and SRS.62,94,115,116 Endoscopic ultrasound can identify an
intrapancreatic PNET in about 90% of cases.62,115 Endoscopic ultrasound can also play an
important role in the management of patients with MEN I who contain NF-PNETs in 80% to
100% of cases or in patients with NF-PNETs with VHL syndrome, which occur in 10% to
17%, which are often small and whose management is controversial.62,67,69,129–131
Endoscopic ultrasound can detect many of these small NF-PNETs, and it has been proposed
that serial evaluations with EUS be used to select which MEN I or VHL patients should
have surgery.62,67,69,130–132
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Functional Localization (Assessing Hormonal Gradients) and PET Scanning
for PNETs—Assessment of hormonal gradients is now rarely used except in occasional
patients with insulinomas or gastrinomas not localized by other imaging
methods.62,110,117–119,133 When used, it is usually performed at the time of angiography and
combined with selective intra-arterial injections of calcium for primary insulinomas or
secretin for a primary gastrinoma or possible metastatic gastrinoma in the liver with hepatic
venous hormonal sampling.62,110,117–119,133 Positron emission tomographic scanning for
PNETs is receiving increasing attention because of its increased sensitivity.28,62,114,122,123
With PNETs, 11C–5-HTP or 68gallium-labeled somatostatin analogs have been shown to
have greater sensitivity than SRS or conventional imaging studies and therefore may by
clinically useful in the future. At present, neither of these methods is approved for use in the
United States and are therefore not available in the United States.28,62,114,122,123
Intraoperative Localization of PNETs—During surgery, the routine use of
intraoperative ultrasound is recommended especially for PNETs,62,120,121 and for small
duodenal tumors (especially duodenal gastrinomas), endoscopic transillumination62,134,135
in addition to routine duodenotomy is recommended.62,78,115,135–137 These are discussed in
more detail in the surgical section below.
Follow-Up Imaging of PNETs—Among patients undergoing surveillance after complete
resection, we recommend chest x-ray and periodic cross-sectional imaging of abdomen and
pelvis. The role of routine [111In-DTPA0]octreotide scintigraphy has not been defined by
prospective studies. Many experts, however, would advocate the use of [111InDTPA0]octreotide scintigraphy as a yearly study for follow-up for patients without evidence
of disease or on a as-needed basis to resolve difficult issues. For patients with advanced
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disease, we generally recommend the use of cross-sectional imaging for follow-up of known
sites of disease. Chest x-ray can be used as a screening examination for patients without
evidence of thoracic disease. [111In-DTPA0]octreotide scintigraphy can be used to test in
vivo for the presence of somatostatin receptors 2 and 5. It can also be used to evaluate if
PRRT represents a good treatment option.
Biochemical Assessment and Monitoring
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Specific hormonal assays are needed to establish the diagnosis of each functional PNET, as
outlined in the discussion of each tumor type in the previous sections. Specifically, for
insulinomas, an assessment of plasma insulin, proinsulin, and C-peptide is need at the time
of glucose determinations, usually during a fast.62,71,138 For ZES, serum gastrin is needed
either alone or during a secretin provocation test.62,71,82,84,138 For VIPomas, a plasma VIP
level is needed; for glucagonoma, plasma glucagon levels; for GRFomas, plasma growth
hormone and GRF levels; for Cushing syndrome, urinary cortical, plasma ACTH and
appropriate ACTH suppression studies; for hypercalcemia with a PNET, both serum PTH
levels and PTH-rP levels are indicated; and for a PNET with carcinoid syndrome, urinary 5HIAA should be measured.62,66,94,138,139 Plasma CGA can be used as a marker in patients
with both functional and NF-PNETs.62,138–140 Chromogranin A should be used with caution
as a marker of disease activity in patients treated with somatostatin analogs, because these
agents significantly reduce plasma CGA levels, a change that may be more reflective of
changes in hormonal synthesis and release from tumor cells than an actual reduction in
tumor mass.29,139 In patients on stable doses of somatostatin analogs, consistent increases in
plasma CGA levels over time may reflect loss of secretory control and/or tumor
growth.30,69,138–140
Surgical Management of Localized PNETs
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All experts agree that surgical resection of a functioning PNET should be considered
whenever possible,36,62,64,141 except in the case of patients with MEN I with either ZES or
small NF-PNETs (ie, <2 cm).62,67,142 The role of routine surgery is controversial in MEN I/
ZES patients, because these patients are almost never cured without extensive resections
(Whipple operations).67,74,78,115 Almost every MEN I patient (80%–100%) has small,
microscopic NF-PNETs which in only 0% to 13% of patients do they grow larger and/or
become symptomatic, and similar to the small gastrinomas in MEN I/ ZES patients, without
surgery, these patients have an excellent prognosis, if there are no PNETs that are greater
than 2 cm.62,67,74,142,143 Many PNETs, especially insulinomas, small NF-PNETs (<2 cm),
and small gastrinomas, can be treated by surgical enucleation.36,62,64,141 Local resection or
enucleation of the PNET is generally recommended, and more advanced surgical resections
such as Whipple resections are not routinely recommended and should be used in only
carefully selected patients.36,62,64,78,115,141 In general, except for insulinomas (see below),
PNETs are surgically approached by a laparotomy to allow an extensive exploration of the
entire abdomen and search for lymph node metastases.36,62,64,141,144 Insulinomas in non–
MEN I patients are increasingly being treated by laparoscopic approach; in 85% of patients,
they are single tumors, they are almost invariably intrapancreatic, and if they can be
localized preoperatively, they can be cured in 70% to 100% using a laparoscopic
approach.62,115,145,146 At present, surgical cure rates for insulinomas approach
100%62,70,71,147; for sporadic gastrinomas, 60% immediately postoperatively and 30% to
40% at 5 years62,74,78,115,136,148; and for other PNETs, the cure rates are lower because
many of the patients present with advanced disease.36,62,64,141 In general, surgical resection
of the primary PNET should be attempted whenever it may be possible if the patient does
not have another medical condition limiting life expectancy or increasing surgical risk,
diffused metastatic liver disease, or one of the inherited PNET syndromes discussed in the
previous sections. This recommendation is made because recent studies in patients with
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gastrinomas demonstrate for the first time that surgical resection decreases the subsequent
rate of developing metastases and extends survival by preventing the development of
advanced or progressive disease.149,150
Medical Management of PNETs
Management of Symptoms Related to Hormone Hypersecretion—Management
recommendations for patients with symptoms of hormonal hypersecretion related to a PNET
is dependent on the hormone secreted.
Insulinoma—With insulinomas, dietary modification with frequent small feedings may
help control the hypoglycemia. Administration of diazoxide (200–600 mg/d) successfully
controls hypoglycemia in 50% to 60% of patients.62,70,71,151,152 Diazoxide frequently leads
to fluid retention requiring diuretics as well as nausea at higher doses and occasional
hirsutism.62,70,71,151 Long-acting somatostatin analogs (octreotide, lanreotide) control
hypoglycemic symptoms in up to 50% of patients with nonmetastatic insulinomas; however,
they need to be used with care because, in some cases, they may worsen the
hypoglycemia.62,153 Recent studies in small numbers of patients show that mTOR inhibitors
(rapamycin, everolimus) may control hypoglycemia in patients with metastatic
insulinomas.154–156
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Gastrinoma—Both histamine H2–receptor antagonists and PPIs (omeprazole,
esomeprazole, lansoprazole, pantoprazole, rabeprazole) can control the acid hypersecretion
in almost every patient with ZES.74,75,83,157 However, with frequent use of H2-receptor
antagonists, high doses are required by many patients,74,75,83,157 making PPIs the drug of
choices, because with their high potencies and long durations of action, once- or twice-a-day
dosing is possible in most ZES patients.74,75,83,157,158 It is recommended that control of acid
hypersecretion (<10 mEq/h before the last dose of drug [intact stomach] or <5 mEq/h)
(previous gastric surgery) be documented whenever possible.62,74,83,159 Patients with ZES
with complicated disease (MEN I, moderate to severe gastroesophageal reflux disease or
prior Billroth 2 resection) may require more frequent dosing (usually twice a day instead of
once a day), higher doses, and greater control of the acid hypersecretion, which can result in
drug doses varying markedly from patient to patient.74,83,157,160,161 This requires, for the
management of complicated ZES, the dose of antisecretory drug needed to control the acid
hypersecretion be determined by titration in regard to symptoms and endoscopic findings in
each patient.74,83,157,160,161 Long-term follow-up of patients with ZES treated with PPIs for
up to 10 years demonstrates no evidence of tachyphylaxis and an excellent safety
profile,62,74,75,83,157,158,162 although drug-induced achlorhydria can lead to nutrient
deficiencies (vitamin B12 is more of a concern than iron).62,83,162,163 In some patients with
ZES, parenteral antisecretory drug treatment is required during their disease course, and
both intermittent use of intravenous PPIs (2–3 times a day) (pantoprazole, lansoprazole,
esomeprazole) or continuous administration of histamine H2–receptor antagonists can be
used.62,148,158,164,165 Somatostatin analogs are also effective in reducing both gastrin and
acid secretion in ZES patients; however, they are rarely used because excellent oral
medications are available.166
Other Functional PNETs—Long-acting somatostatin analogs (octreotide, lanreotide) are
generally successful in the initial management of patients with glucagonomas, VIPomas, and
GRFomas and, in some patients, somatostatinomas.49,58,59,62,64,66,167 With long-term
treatment, symptomatic breakthrough may occur, and the dose may need to be increased,
frequency of administration increased, or, on occasion, the drug stopped and restarted. The
availability of the long-acting depot forms of octreotide and lanreotide (octreotide LAR,
lanreotide autogel) has greatly improved patient convenience because they allow once-a-
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month dosing in many patients.49,58,62,167,168 Adverse effects of treatment with somatostatin
analogs occur in approximately 50% of patient with octreotide, are generally mild, and
include flatulence, diarrhea/steatorrhea, nausea, gallstones, and glucose
intolerance.49,58,62,64,167–169 In long-term treatment of patients with acromegaly with
somatostatin analogs, only 5% developed adverse effects severe enough to require stopping
the drug.62,168,169 In these patients, 29% developed gallstones with long-term treatment;
however, in only 1% did symptoms develop.168 In occasional patients, if somatostatin
therapy is not adequate, then stating α-interferon or the addition of α-interferon to
somatostatin analogs may help control symptoms.64
Management of Advanced PNETs
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General—Pancreatic NETs demonstrate highly variable growth patterns, with most
insulinomas being benign s(>85%), whereas in most series, greater than 50% of the other
symptomatic PNETs and the NF-PNETs demonstrate liver metastases.62,64 Furthermore,
even within these groups, there is marked variability in tumor growth, with a prospective
study demonstrating that up to 60% of metastatic gastrinomas to the liver demonstrated no
growth or slow growth over a 2-year period, whereas the other 40% demonstrated rapid
growth, with all the deaths occurring in the latter group.170 Five-year survival rates of 90%
to 100% are seen with patients with PNETs resected, or PNETs were so small they are not
seen on imaging; incomplete resections have rates of 20% to 75%, and patients with diffuse
liver disease have 5-year survival rates of 10% to 50%.35,62,65,80,171,172 Therefore, in a
number of these patients, treatment for advanced metastatic disease is needed.
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Hepatic Resection (Cytoreductive Surgery) and Transplantation for Metastatic
Disease—Unfortunately, similar to described above for malignant NETs of the stomach,
surgical resection of at least 90% of all visible tumor is possible in only 5% to 15% of
patients with PNETs with hepatic metastases.35,37,62,173–175 The role of cytoreductive
surgery in this situation is controversial.37,62,173–175 Whereas numerous uncontrolled studies
provide evidence that surgical resection may improve symptom control and perhaps extend
survival, neither result is proven at present.35,37,62,173–175 Nevertheless, because of the low
efficacies of other tumor treatments, most conclude that surgical resection should be
attempted in any patient with a malignant PNET if it is thought that at least 90% of the
visible tumor could be removed.35,37,62,173–175 The number of patients with liver-isolated
metastatic NETs in whom OLT has been attempted remains small, and the role of OLT in
such patients is unclear.35,62 The role of liver transplantation in selected patients with
advanced PNETs was discussed in more detail in the previous sections dealing with NETs of
the stomach. As pointed out in this section, in a recent review of 85 cases of carcinoids and
PNETs treated by liver transplantation, the overall 5-year survival was 45%, and poor
prognostic factors were prior extensive upper abdominal surgery, presence of a PNET rather
than a carcinoid tumor, and hepatomegaly.39 Without any of these risk factors, the 5-year
survival was 66%.39 It has been proposed for the occasional, younger patient with a
metastatic PNET that is unresectable and limited to the liver, especially if it is symptomatic
and cannot be controlled by other available therapies, that liver transplantation remains an
option that should be considered.35,38–40
Hepatic Artery Embolization/Chemoembolization—As discussed above with NETs
of the stomach, hepatic arterial embolization is recommended as a palliative option in
patients with PNETs with hepatic metastases who are not candidates for surgical resection,
have an otherwise preserved performance status, have disease primarily confined to the
liver, and have a patent portal vein.35,41,42 Similar to gastric and other carcinoid tumors, the
response rates associated with embolization, as measured either by decrease in hormonal
secretion or by radiographic regression, are generally greater than 50%.35,41–43 Improved
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techniques have, in recent years, reduced the incidence complications related to
embolization, making embolization an important and generally safe treatment.35,41,42,176 A
number of techniques may be used and include bland embolization, chemoembolization,
embolization with chemotherapy beads, and embolization using radioisotopes. There are
currently no data confirming superiority of any of these techniques compared with the
others. This technique is considered especially for a patient with a functional PNET in which
the hormone excess state cannot be controlled by other methods.41–43,62
RFA and Cryoablation—Similar to those described in the previous sections for advanced
carcinoid tumors, other approaches to the treatment of hepatic metastases in a patient with a
malignant PNET include the use of RFA and cryoablation, either alone or in conjunction
with cytoreductive surgery.35,42 These approaches can be performed using a percutaneous or
laparoscopic approach. Although they seem to be less morbid than either hepatic resection
or hepatic artery embolization, the clinical benefit of these approaches in patients with
asymptomatic, small-volume disease has not been clearly established. Similarly, these
approaches may not be applicable in patients with large-volume hepatic metastatic disease.
Ablative techniques should therefore be considered as a treatment option only in carefully
selected patients with advanced PNETs.35,42,44,45
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Peptide Receptor Radionuclide Therapy—The overexpression of somatostatin
receptors by almost all PNETs is increasingly being investigated to target possible
radiolabeled cytotoxic agents to the malignant PNET.60,61,177 One recent study61 reported
results with 129 patients with malignant NETs treated with [177Lu-DOTA-Tyr3]octreotate
and found a complete response in 2%, partial in 32%, and stabilization in 34%. At present,
no controlled studies have demonstrated this form of treatment prolongs survival, and this
treatment is still investigational in the United States; however, this from of treatment is
undergoing widespread evaluation because of its promising results.62
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Traditional Chemotherapeutic Agents—In contrast to carcinoid tumors, a number of
chemotherapeutic agents either alone or in combination have been reported to have
sufficient antitumor activity to be clinically useful in patients with advanced
PNETs.35,41,51,52,75,178 The traditional chemotherapeutic agents with most effect in welldifferentiated malignant PNETs are the combination of streptozocin/doxorubicin,
streptozocin/fluorouracil, or streptozocin/doxorubicin/ fluorouracil.5,17,179 A large
retrospective analysis of 84 patients with either locally advanced or metastatic PNETs
receiving a 3-drug regimen of streptozocin, 5-fluorouracil, and doxorubicin showed that this
regimen was associated with an overall response rate of 39% and a median survival duration
of 37 months.51 In patients with poorly differentiated PNETs, chemotherapy is
recommended with the combination of cisplatin and etoposide or its analogs, because it has
been shown to have a 40% to 70% response rate; however, the duration of the responses is
short.35,41,51,52,180,181
Biotherapy—Even though widely used in advanced PNETs for their possible effect on
tumor growth, the clinical benefit of the direct antineoplastic effects of somatostatin analogs
either with or without interferon remains uncertain, although recent studies suggest they
have a cytostatic effect in 40% to 70% of patients and cause a tumor reduction of less than
15% of cases with both agents.48,56,62 The tumoristatic effect can be long lasting in some
patients with advanced PNETs, and it is seen more frequently in PNETs with PNETs with a
lower proliferative rate.48,64,182–184 Even though no study has shown that this results in
prolonged survival in these patients, SS analogs are still frequently used first because they
are well tolerated and because of their tumoristatic effect.62 A recent prospective study
(PROMID study) demonstrates the use of octreotide LAR resulted in an increased time to
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progression in patients with metastatic midgut carcinoid tumors involving less than 10% of
the liver.50 However, it is unclear whether similar effects occur with patients with more
extensive metastases or with malignant PNETs as well.
Newer Agents With Possible Use for Advanced PNETs—Recently, a number of
newer chemotherapeutic agents with some efficacy in malignant PNETs have been
described. The overall response rate associated with temozolomide-based therapy has been
reported to be 34%, a rate similar to that of streptozocin-based therapy.185 Temozolomidebased regimens represent an acceptable alternative to streptozocin-based therapy in patients
with advanced PNETs. Temozolomide has been commonly administered as a single agent or
in combination with capecitabine. There are currently no data comparing the efficacy of
temozolomide monotherapy to combination therapy, and either regimen is considered
acceptable.54
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Investigational approaches are appropriate for minimally symptomatic patients before
streptozocin- or temozolomide-based therapy or for patients who fail streptozocin- or
temozolomide-based therapy for advanced PNETs. Recent studies using vascular endothelial
growth factor pathway inhibitors such as bevacizumab, sunitinib, and sorafenib have
suggested that these agents may have modest antitumor activity in patients with malignant
PNETs.55–57,186–188 In a randomized placebo-controlled trial, treatment with sunitinib was
shown to result in significantly longer time to tumor progression and improved survival
when compared with placebo.189 The mTOR inhibitor everolimus has shown activity in
early studies.188
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TABLE 1
Hypergastrinemia
Gastric Acid Secretion
Typical Size, cm
No. Tumors
Clinical Features
Type 1 (in setting of chronic atrophic
gastritis type A)
Yes (as a result of achlorhydria)
Low
<1
Multifocal
Rarely invasive; endoscopic removal often
adequate
Type 2 (in setting of ZES)
Yes (as a result of ectopic gastrin
secretion)
High
<1
Multifocal
Rarely invasive; may respond to
somatostatin analogs
Type 3 (sporadic)
No
Normal
>1
Solitary
Kulke et al.
Subtypes of NETs of the Stomach
Frequently invasive and metastatic
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TABLE 2
Minimum Pathology Data Set: Information to Be Included in Pathology Reports of Gastric NETs
NIH-PA Author Manuscript
For resection of primary tumors
Anatomical site of tumor
Diagnosis (functional status need not be included in pathology report)
Size (3 dimensions)
Presence of unusual histological features (oncocytic, clear cell, gland forming, etc)
Presence of multicentric disease
(Optional: immunohistochemical staining for general neuroendocrine markers)
Chromogranin
Synaptophysin
Peptide hormones, if a specific clinical situation suggests that the correlation with a functional syndrome may be helpful
Grade (specify grading system employed)
Mitotic rate (no. mitoses per 10 high-power field or 2 mm2; count 50 high-power fields in the most mitotically active regions, count
multiple regions)
(Optional: Ki67 labeling index [count multiple regions with highest labeling density, report average percentage; “eyeballed” estimate is
adequate])
NIH-PA Author Manuscript
Presence of nonischemic tumor necrosis
Presence of other pathological components (eg, nonneuroendocrine components)
Extent of invasion (use anatomical landmarks for the AJCC T-staging of analogous carcinomas of the same anatomical sites)
Stomach: depth of invasion into/through gastric wall
Small bowel: depth of invasion into/through bowel wall
Large bowel: depth of invasion into/through bowel wall
Appendix: depth of invasion into/through appendiceal wall; presence and extent of mesoappendiceal invasion
Pancreas: presence of extrapancreatic invasion or invasion of bile duct, duodenum, or ampulla
All sites: involvement of serosal/peritoneal surfaces; invasion of adjacent organs or structures
Presence of vascular invasion (optional: perform immunohistochemical stains for endothelial markers if needed)
Presence of perineural invasion
Lymph node metastases
No. positive nodes
Total no. nodes examined
TNM staging (specify staging system used)
NIH-PA Author Manuscript
Resection margins (positive/negative/close) (optional: measure distance from margin if within 0.5 cm)
Proliferative changes or other abnormalities in nonneoplastic neuroendocrine cells
For biopsy of primary tumors
Anatomical site of tumor
Diagnosis (functional status need not be included in pathology report)
Presence of unusual histological features (oncocytic, clear cell, gland forming, etc)
(Optional: immunohistochemical staining for general neuroendocrine markers)
Chromogranin
Synaptophysin
Peptide hormones, if a specific clinical situation suggests that the correlation with a functional syndrome may be helpful
Grade (specify grading system employed)
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Mitotic rate (no. mitoses per 10 high-power field or 2 mm2; count up to 50 high-power fields)
NIH-PA Author Manuscript
Ki67 labeling index, for biopsies in which a diagnosis of high-grade neuroendocrine carcinoma cannot be excluded (count multiple regions
with highest labeling density, report average percentage; “eyeballed” estimate is adequate)
Presence of nonischemic tumor necrosis
Presence of other pathological components (eg, nonneuroendocrine components)
For resection of metastatic tumors
Location of metastasis(es)
Diagnosis (functional status need not be included in pathology report)
No. metastases resected
Extent of involvement of resected tissue (percentage)
Greatest dimension of largest metastasis
Presence of unusual histological features (oncocytic, clear cell, gland forming, etc)
(Optional: immunohistochemical staining for general neuroendocrine markers)
Chromogranin
Synaptophysin
Peptide hormones, if a specific clinical situation suggests the correlation with a functional syndrome may be useful
Grade (specify grading system employed)
NIH-PA Author Manuscript
Mitotic rate (no. mitoses per 10 high-power field or 2 mm2; count 50 high-power fields in the most mitotically active regions, provide
separate mitotic rate for each major separate site of disease)
(Optional: Ki67 labeling index [count multiple regions with highest labeling density, report average percentage; “eyeballed” estimate is
adequate])
Presence of nonischemic tumor necrosis
Presence of other pathological components
Resection margins (positive/negative/close) (optional: measure distance from margin if within 0.5 cm)
Identification of primary site
Immunohistochemistry for CDX2, TTF1
For biopsy of metastatic tumors
Location of metastasis
Diagnosis (functional status need not be included in pathology report)
Presence of unusual histological features (oncocytic, clear cell, gland forming, etc)
Immunohistochemical staining for general neuroendocrine markers
Chromogranin
Synaptophysin
NIH-PA Author Manuscript
(Optional: peptide hormones, if a specific clinical situation suggests the correlation with a functional syndrome may be useful)
Grade for adequate biopsy specimens; fine-needle-aspiration specimens may not be adequate (specify grading system is used)
Mitotic rate (no. mitoses per 10 high-power field or 2 mm2; count up to 50 high-power fields)
Ki67 labeling index (count multiple regions with highest labeling density, report average percentage; “eyeballed” estimate is adequate)
Presence of nonischemic tumor necrosis
Presence of other pathological components (eg, nonneuroendocrine components)
Identification of primary site
Immunohistochemistry for CDX2, TTF1
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TABLE 3
Grade Versus Differentiation in NETs
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Differentiation
Well differentiated
Grade
Low grade (ENETS G1)
Intermediate grade (ENETS G2)
Poorly differentiated
High grade (ENETS G3)
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TABLE 4
Systems of Nomenclature for NETs
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Grade
Lung, Thymus (WHO)
GEP NETs (ENETS)
GEP NETs (WHO 2010)
Low grade
Carcinoid tumor
NET grade 1 (G1)
Neuroendocrine neoplasm grade 1
Intermediate grade
Atypical carcinoid tumor
NET grade 2 (G2)
Neuroendocrine neoplasm grade 2
High grade
Small cell carcinoma
Neuroendocrine carcinoma grade 3 (G3),
small cell carcinoma
Neuroendocrine carcinoma grade 3,
small cell carcinoma
Large cell neuroendocrine
carcinoma
Neuroendocrine carcinoma grade 3 (G3),
large cell neuroendocrine
Neuroendocrine carcinoma, grade 3,
large cell neuroendocrine carcinoma
The grade of the tumor must be included in the pathology report, along with a reference to the specific grading system being used. Unqualified
terms such as neuroendocrine tumor or neuroendocrine carcinoma without reference to grade do not provide adequate pathology information.
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TABLE 5
AJCC
ENETS
Pancreas. Author manuscript; available in PMC 2011 May 24.
Primary Tumor (T)
T—Primary Tumor
TX
Primary tumor cannot be assessed
TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
T0
No evidence of primary tumor
Tis
Carcinoma in situ/dysplasia (tumor size <0.5 mm), confined to mucosa
—
T1
Tumor invades lamina propria or submucosa and ᚢ1 cm
T1
Tumor invades lamina propria or submucosa and size ᚢ1 cm
T2
Tumor invades muscularis propria or >1 cm
T2
Tumor invades muscularis propria or size >1 cm
T3
Tumor penetrates subserosa
T3
Tumor invades pancreas or retroperitoneum
T4
Tumor invades serosa (visceral peritoneum) or other organs or adjacent structures
T4
Tumor invades peritoneum or other organs
Regional Lymph Nodes (N)
N—Regional Lymph Nodes
NX
Regional lymph node(s) cannot be assessed
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N0
No regional lymph node metastasis
N1
Regional lymph node metastasis
N1
Regional lymph node metastasis
Distant Metastasis (M)
M—Distant Metastases
—
M0
No distant metastasis
M1
Distant metastasis
Stage
Kulke et al.
Staging of NETs of the Stomach
MX
Distant metastasis cannot be assessed
M0
No distant metastasis
M1
Distant metastasis
T
N
M
Stage
T
N
M
0
Tis
N0
M0
0
Tis
N0
M0
I
T1
N0
M0
I
T1
N0
M0
IIA
T2
N0
M0
IIa
T2
N0
M0
IIB
T3
N0
M0
IIb
T3
N0
M0
IIIA
T4
N0
M0
IIIa
T4
N0
M0
IIIB
Any T
N1
M0
IIIb
Any T
N1
M0
IV
Any T
Any N
M1
IV
Any T
Any N
M1
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Table 6
AJCC
ENETS
Definitions of TNM
Proposal for a TNM Classification and Disease Staging for Endocrine Tumors
Primary Tumor (T)
T—Primary Tumor
TX
Primary tumor cannot be assessed
TX
Primary tumor cannot be assessed
T0
No evidence of primary tumor
T0
No evidence of primary tumor
Pancreas. Author manuscript; available in PMC 2011 May 24.
T1
Tumor limited to the pancreas, ᚢ2 cm in greatest dimension
T1
Tumor limited to the pancreas and size <2 cm
T2
Tumor limited to the pancreas, >2 cm in greatest dimension
T2
Tumor limited to the pancreas and size 2–4 cm
T3
Tumor extends beyond the pancreas but without involvement of the celiac axis
or the superior mesenteric artery
T3
Tumor limited to the pancreas and size >4 cm or invading duodenum or bile duct
T4
Tumor involves the celiac axis or the superior mesenteric artery (unresectable
primary tumor)
T4
Tumor invading adjacent organs (stomach, spleen, colon, adrenal gland) or the wall of large vessels
(celiac axis or superior mesenteric artery)
Kulke et al.
Staging of NETs of the Pancreas
Note: For any T, add (m) for multiple tumors
Regional Lymph Nodes (N)
N—Regional Lymph Nodes
NX
Regional lymph node(s) cannot be assessed
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N0
No regional lymph node metastasis
N1
Regional lymph node metastasis
N1
Regional lymph node metastasis
Distant Metastasis (M)
M—Distant Metastases
—
MX
Distant metastasis cannot be assessed
M0
No distant metastasis
M0
No distant metastasis
M1
Distant metastasis
M1a
Distant metastasis
Endocrine and Exocrine Pancreas
Endocrine Pancreas
T
N
M
Stage
T
N
M
0
T0
N0
M0
—
—
—
—
IA
T1
N0
M0
I
T1
N0
M0
IB
T2
N0
M0
—
—
—
—
IIA
T3
N0
M0
IIa
T2
N0
M0
IIB
T1
N1
M0
IIb
T3
N0
M0
T2
N1
M0
—
—
—
—
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Stage
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Endocrine and Exocrine Pancreas
IV
N1
M0
T4
Any N
M0
Any T
Any N
M1
IIIa
T4
N0
M0
IIIb
Any T
N1
M0
IV
Any T
Any N
M1
Kulke et al.
III
T3
Endocrine Pancreas
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Page 36
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Table 7
Clinical Presentation of Pancreatic NETs
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Tumor
Symptoms or Signs
Incidence of Metastases
Extrapancreatic Location
Insulinoma
Hypoglycemia resulting in intermittent confusion,
sweating, weakness, nausea; loss of consciousness may
occur in severe cases
<15%
Rare
Glucagonoma
Rash (necrotizing migratory erythema), cachexia,
diabetes, deep venous thrombosis
Majority
Rare
VIPoma, VernerMorrison syndrome,
WDHA syndrome
Profound secretory diarrhea, electrolyte disturbances
Majority
10%
Gastrinoma, ZES
Acid hypersecretion resulting in refractory PUD,
abdominal pain, and diarrhea
<50%
Frequently in duodenum
Somatostatinoma
Diabetes, diarrhea, cholelithiasis
Majority
Rare
Nonfunctional
May be first diagnosed due to mass effect
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Pancreas. Author manuscript; available in PMC 2011 May 24.
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