nets monograph 1
TRANSCRIPT
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Neuroendocrine Tumors:From Carcinoid to Cancer
Nosology, Topographyand Epidemiology
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This monograph is the first in a series that explore the topicof neuroendocrine tumors (NETs). These monographs aredesigned to educate physicians and provide a quick referenceguide to important information regarding nomenclature, biology,classification, biomarkers, imaging, pathophysiology, andmanagement of neuroendocrine tumors.
Some of the topics covered in this series include the following:
Terminology This monograph is designed to provide a broad overview of thebiology, natural history, epidemiology, and classification of NETs andto bring clarity and perspective to the terminology used to describethese tumors.
Biomarkers The role of biomarkers in the diagnosis of NETs, specifically the roleand clinical implications of chromogranin A (CgA).
NET Classification Current and proposed classification systems and the clinicalpresentation of NETs.
Imaging Techniques Imaging techniques used for the diagnosis of NETs, such as
somatostatin receptor scintigraphy (SRS), their use and utility,strengths, and limitations.
Targeted Treatment Strategies Targeted therapeutic strategies for NETs and the evolving role ofsomatostatin receptors and the IGF-1 pathway as targets.
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Neuroendocrine Tumors:From Carcinoid to CancerNosology, Topography
and Epidemiology
Table of Contents
i
Carcinoid Tumor—The Quintessential Neuroendocrine Neoplasm . . . . . . . . . . . 1
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Natural History and Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
Diagnosis and Treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
Malignancy of Neuroendocrine Tumors—The 20th Century Confusion . . . . . . . 5
Oberndorfer: The Observation and the Error . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
The Concept of a Diffuse Neuroendocrine System . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
The APUD Concept . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Cell of Origin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Cell Types in Neuroendocrine Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Enterochromaffin Cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Islets of Langerhans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
Epidemiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Pathological Classification and Clinical Behavior . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
Clinical Presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
Key References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19Glossary of Terms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
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Although tumors exhibiting neuroendo-
crine characteristics were described in
the nineteenth century by Langhans (1867),
Lubarsch (1888), and Ransom (1890), it was
Oberndorfer in 1907 who first introduced the
term “carcinoid” (carcinoma-like). Thereafter
in 1914, Gosset and Masson further defined the
neuroendocrine nature of carcinoid tumors.
However, despite this early work, carcinoidtumors have remained a source of confu-
sion for many physicians. This represents the
many different terminologies that have been
applied, misunderstanding of the biology, nat-
ural history, and clinical presentation of neu-
roendocrine tumors, and the erroneous per-
ception that these tumors are not malignant.
Thus, despite the passage of almost a century
since the original recognition of neuroendo-
crine tumors (NETs), the pathological classifi-
cation and nomenclature of NETs is st ill under
debate. This reflects the ongoing delineation
of the morphological and biological hetero-
geneity of these tumors and advances in our
understanding of both the cellular and molec-
ular biology of the disease.
Neuroendocrine tumors of the diffuseneuroendocrine system were previously
referred to as carcinoid tumors. They com-
prise a heterogeneous group of neoplasia that
originate from neuroendocrine cells, which
have a regulatory function and are widely dis-
persed throughout the body. The vast major-
ity of NETs are localized in the gastrointesti-
nal (GI) tract and the lung, although they also
occur in other rare sites (eg, ovary and sali-
vary glands). In order for clinicians to identify
these tumors more definitively and avoid the
confusion associated with a variety of differ-
ent terms previously used to identify them
(eg, carcinoid, neural crest tumors, Apudoma,
etc), those found in the gastrointestinal tract
are now referred to as gastroentero-pancre-
atic neuroendocrine tumors (GEP NETs).
Epidemiology
Neuroendocrine tumors were oncethought to be relatively rare, however, it is evi -
dent from the US Surveillance Epidemiology
and End Results (SEER) database that the
incidence and prevalence have increased
substantially (approximately 500%) over the
past 30 years (Figure 1), most likely due to
increased use of endoscopy and improved
diagnosis. Similar trends have been observed
in several other global databases. Current
estimates of incidence are 5.25 cases per
100,000 (in 2004). Overall, GEP NETs are the
most common primary neoplasm of the small
bowel and the second most prevalent tumor
of the GI tract.
Natural History and Clinical Presentation
Although carcinoid tumors were initiallyconsidered to be relatively slow-growing and
benign, it is now apparent that the majority are
malignant and they exhibit a wide spectrum of
clinical behaviors that range from indolent to
aggressive and in some circumstances highly
metastatic. Their natural history varies from
local invasion and fibrosis in the peritoneal
cavity to metastatic spread, most commonly
to the liver and lungs. Their biological char-
acteristics (local invasion, fibrosis, and meta-
static potential) vary considerably depending
Carcinoid Tumor—The Quintessential
Neuroendocrine Neoplasm
Despite the passage of almost a century
since the original recognition of neuroendocrine tumors(NETs), the pathologicalclassification and
nomenclature of NETs is still under debate
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Despite their diversity in tissue origin and biological behavior,
NETs share manycommon features
including pathologically definable growth
patterns, secretion of bioactive products (most
commonly serotonin or peptides such as insulin,
gastrin, and glucagons), and expression of neuroendocrine
markers includingchromogranin A (CgA).
I n c i d e n c e o
f N E T s p e r 1 0 0 , 0
0 0
I n c i d e n c e o f a l l m a l i g n a n t n e o p l a s m s p e r 1 0 0 , 0
0 0
2.00
0
1.00
0
100
200
300
400
500
600
5.25
3.00
4.00
5.00
Incidence of all malignant neoplasms
Incidence of neuroendocrine tumors
6.00
Year
74 76 78 80 82 84 86 88 90 92 94 96 98 00 02 04
Figure 1. Annual age-adjusted incidence of neuroendocrine tumors in the US population between 1973 and 2004.Source: US Surveillance Epidemiology and End Results (SEER) database. Adapted with permission from Yao JC, et al.J Clin Oncol. 2008;26:3063-3072.
on anatomical site, neuroendocrine cell(s)
of origin, and secretory products. However,despite their diversity in tissue origin and
biological behavior, NETs share many com-
mon features including pathologically defin-
able growth patterns, secretion of bioactive
products (most commonly serotonin or pep-
tides such as insulin, gastrin, and glucagons),
and expression of neuroendocrine markers
including chromogranin A (CgA).
The primary tumor is usually small, and
overt clinical symptoms are often absent until
metastasis has occurred. The symptomatology
is usually reflective of the presence of liver
metastases, although some GI tumors becomeapparent when mechanical issues (eg, bowel
obstruction, perforation, or bleeding) super-
vene. In addition, “functional” NETs release
a variety of bioactive products (amines and
peptides) that occasionally result in a sys-
temic “carcinoid syndrome” (Figure 2)
characterized by flushing, diarrhea, bron-
choconstriction, and edema or fibrotic heart
disease (25% to 50% may exhibit right-sided
cardiac valve disease), and these symp-
toms may be attributed to other pathologies.
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Local (peritoneal ~50%) or distant (cardiac
~25%) fibrosis may be an issue and is often
overlooked as attention is directed towards
more obvious symptoms. Carcinoid syn-
drome is most commonly associated with
retroperitoneal tumors. Approximately 50%
of GEP NETs are asymptomatic and are
characterized as “nonfunctional.” There is,
however, no biological evidence to indicate
that “nonfunctional” tumors are in any way
different from “functional” NETs; thus from
a therapeutic perspective, they should beregarded as identical.
Diagnosis and TreatmentClinically, NETs often present a consider-
able diagnostic and therapeutic challenge.
The most effective biochemical test to iden-
tify the presence of a NET is measurement
of plasma CgA, although assessment of deg-
radation products of serotonin such as uri-
nary 5-hydroxy indole acetic acid (5-HIAA)
is also widely used. (This will be reviewed in
Monograph 2.) Diagnostic radiological con-
trast studies (eg, barium meal enteroclysis)
are relatively insensitive. The most effective
diagnostic modalities are somatostatin recep-
tor scintigraphy (SRS) with CAT scan, whole
body positron emission tomography (11C-PET),
endoscopic ultrasound (gastric and rectal),
and capsule endoscopy. Nevertheless, defini-
tive diagnosis of NETs is typically delayed by 5
to 7 years from onset of symptoms and is usu-
ally so late that metastasis has occurred and
curative treatment with radical surgical resec-tion is rarely an option. Long-acting soma-
tostatin (SST) analogs are frequently used
to ameliorate symptoms and prevent tumor
progression. Although predictably effective
targeted treatments have been lacking, novel
agents targeting a variety of signaling path-
ways and radio-peptide targeted therapy are
emerging. In particular, the utility of tyrosine
kinase inhibitors such as the mTOR inhibitors,
either alone or in combination with soma-
tostatin analogs, is being investigated.
CarcinoidSyndrome
EdemaSymptoms
Food allergy
Functionalboweldisease
Irritablebowel
syndrome
Thyrotoxicosis
AlcoholismNeurosis
Asthma
Anxietyattacks
Arthritis
Other Pathologies
Menopause
Sweating
Diarrhea
AbdominalPain/Cramps
GI BleedingCardiacDisease
Broncho-constriction
Flushing
Figure 2. Constellation of symptoms associated with carcinoidsyndrome can be confused with other pathologies
Clinically, NETs often present a considerable
diagnostic and therapeuticchallenge.
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Biology
Cells
Tumors
Pathology
Treatment
Pearse coins term ‘APUD’ (Amine Precursor Uptake and Decarboxylation)to describe hormone-producing cells 1968
Soga and Yakuwa introduce a carcinoid histological classification 1971
First WHO classification of endocrine tumors 1980
Bauer identification of somatostatin analogue octreotide 1982
Introduction of long-acting octreotide LAR 1997
Modlin describes increasing incidence of NETs 2002
Investigational use of multi-receptor ligand somatostatin analogue SOM230 2003
Arnold demonstrates that octreotide LAR decreases tumor progression 2009
Feyter proposes that carcinoids are derived from the diffuse endocrine system 1938
Oberndorfer recognizes malignant propensity of carcinoids1929
Masson describes neural origin of Kulchitsky cells1928
Gosset and Masson demonstrate the argentaffin-staining properties of carcinoids
Masson speculates that gut Kulchitsky cells form a diffuse neuroendocrine organ1914
Oberndorfer introduces the term “karzinoide”1907
Ciaccio introduces the term “enterochromaffin”1906
Kulchitsky notes “EC”-like cells in the crypts of Lieberkühn1897
Notthafft describes three tumors in the upper jejunum1895
Ransom describes ileal tumors and notes liver metastases1890
Langhans describes a “carcinoid” tumor1867
Figure 3. Key events in the understanding and treatment of neuroendocrine tumors.
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While Oberndorfer was first to coin theterm “carcinoid” and describe the
idiosyncratic nature of these tumors, these
lesions had been previously observed during
the 19th century and documented by a num-
ber of physicians. In 1867, Langhans was the
first to describe a carcinoid tumor at autopsy
in a 50-year-old woman who had perished
of tuberculosis (Figure 3). Subsequentlyin 1890, Ransom described a 50-year-old
woman who initially presented with two egg-
sized lumps in the lower abdomen, menor-
rhagia, and severe diarrhea which persisted
for a further 2 years, at which time she pre-
sented with a large, palpable abdominal
mass and cachexia. Of particular interest was
the observation of severe attacks of wheez-
ing and diarrhea upon eating; arguably the
first report of carcinoid syndrome. Upon her
death soon thereafter, an autopsy revealed
several small nodules in the ileum, 6 inches
above the ileocecal valve, as well as extensive
hepatic tumors (presumably metastases).
In 1895, Notthafft described three tumors of
the upper jejunum found at autopsy that simi-
larly showed invasion to the muscular layer,and he referred to these as “beginning carci-
nomas.” Around the same time (1897), Nikolai
Kulchitsky noted enterochromaffin-like cells
in the crypts of Lieberkühn. The carcinoid
tumor then faded into obscurity once more,
and 17 years would pass before Oberndorfer’s
initial attempt to characterize and delineate
the properties of this enigmatic neoplasm.
Oberndorfer: The Observationand the Error
Malignancy of Neuroendocrine Tumors—
The 20th Century Confusion
Oberndorfer first presented his obser-
vations on carcinoid tumors at the German
Pathological Society convention in September
1907. In December of that year, he published his
seminal paper “Carcinoid Tumors of the Small
Intestine” in the Frankfurt Journal of Pathology ,
where he first erroneously described and char-acterized the tumor as a “benign carcinoma.”
The first case described a 48-year-old woman
who had presumably died of tuberculosis. At
autopsy, four pea-sized tumors were found in
the ileum. Each tumor was found in the submu-
cosa, with the surrounding intestinal mucosa
and neighboring serosa showing no reactive
inflammation. The histological findings were
consistent with those described by previous
authors (Figure 4).
The tumors were arranged in nests of
small polymorphic cells with large nuclei and
scant cytoplasm; there were distinguishable,
albeit atrophic, crypts of Lieberkühn; and
there was dense, fibrous connective tissue
comprising the surrounding stroma and ram-
pant epithelial vascular growth adjacent tothe tumor. In addition, the mucosa and mus-
cularis mucosae were completely intact, and
no cellular infiltration of the tumor into the
surrounding stroma could be observed. The
second case involved a 30-year-old woman
who had recently given birth and soon there-
after died of typhoid fever. At autopsy, three
small tumors, approximately the size of
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“peas,” were found in the ileum. Based on
his observations, Oberndorfer asserted that
these tumors could not be categorized as anyother small intestinal neoplasm and recog-
nized that their clinical behavior was incon-
sistent with that of a carcinoma and therefore
distinguished them as a completely different
clinical entity.
Of paramount importance to Oberndorfer
was determining whether these tumors were
indeed true cancers. Although histologically
they appeared malignant, clinically, they
were not considered cancerous because
they did not exhibit rapid growth, the tumor
borders were sharply circumscribed, and they
appeared not to metastasize. Given that a true
carcinoma could not account for his obser-vations, Oberndorfer reasoned that perhaps
it could be described as “karzinoide” (car-
cinoma-like). Although Oberndorfer’s early
contributions to our understanding of carci-
noid tumors were prescient, it subsequently
became evident that his initial assessment
that these tumors were benign was incorrect.
Indeed, in 1929, 22 years later, Oberndorfer
described a series of 36 carcinoid tumors of
the appendix and small intestine and cor-
rected his erroneous description of the benign
Although
Oberndorfer’s earlycontributions to
our understanding of carcinoid tumors
were prescient, it subsequently became evident that his initial
assessment that these tumors
were benign was
incorrect.
Figure 4. Neuroendocrine tumor histology through the ages. Panel A: Oberndorfer’s original drawing from 1907.Panel B: Chromogranin A immunostaining circa 1980. Panel C: Electron microscopy of secretory vesicles of anenterochromaffin-like cell, circa 2007. Panel D: Synaptophysin immunostaining. Panel E: Somatostatin receptorimmunostaining. Panel F: Ki67 immunostaining. Photo credits: Panel A is from Oberndorfer S. Karzinoide tumorendes dunndarms. Frankf Z Pathol . 1907;1:425-429. Panels B-F are courtesy of IM Modlin.
A B C
D E F
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It was Pierre Masson who initially sug-
gested in 1914 that the endocrine cells
(known as “Kulchitsky cells”) in the gut
formed a diffuse endocrine organ, and these
cells corresponded to the enterochromaffin
(EC) cells previously described by Ciaccio
in 1906. Subsequently in 1938, the Austrian
pathologist Friedrich Feyrter established the
concept of a diffuse neuroendocrine system
(DNES). Feyrter suggested that the human
endocrine system consisted not only of com-
pact epithelial organs but also of scattered
endocrine cells occurring either individually
or in groups within the ductal system of the
pancreas and “columnar epithelial mucous
membranes” throughout the body, therebyforming what he called “diffuse endocrine
epithelial organs.” The relationship of the
DNES with neoplasia was initially pointed
out by Masson and Gosset in 1914. They rec-
ognized that the EC cells represent a single
functional neuroendocrine unit, and based
on their affinity for silver stain, classified
them as the cells of origin of “carcinoid”
tumors, thereby recognizing that carcinoid
tumors were indeed an endocrine neoplasm.
This connect was further corroborated by
behavior of these tumors, accepting that
these growths were indeed malignant and
could metastasize. However, in the mid-20th
century, the clinical preponderance of appen-diceal carcinoids with their very benign clini-
cal behavior further compounded the misun-
derstanding that all NETs are benign, and the
early diagnosis and prompt surgical excision
of appendiceal carcinoids further perpetu-
ated this misconception.
The Concept of a DiffuseNeuroendocrine System
subsequent studies showing that carcinoid
tumors produce bioactive amines. In 1948,
J.R. Dawson developed a technique by which
EC and EC-like (ECL) cells of the GI tract couldbe stained using silver nitrate, and Rapport
described and isolated serotonin, or 5-hy-
droxytryptamine (5-HT). In 1952, Erspamer
and Asero isolated 5-HT in the EC tissues of
Octopus and Discoglossus and suggested that
serotonin (“enteramine”) was the specific
hormone of the EC cell system. Then in 1953,
Lembeck confirmed biochemically the pres-ence of serotonin in an ileal carcinoid tumor.
The APUD ConceptThe term APUD (amine precursor uptake
and decarboxylation) was introduced in 1968
by A.G. Pearse. Pearse created a biochemical
classification system that unified the variety
of diffusely scattered neuroendocrine cells
and introduced the concept of APUD, which
recognized that the primary common his-
tochemical characteristic of neuroendocrine
cells was amine precursor uptake and decar-
boxylation. He noted that more than 40 differ-
ent cell types were capable of amine process-
ing and production of polypeptide hormones,
and he observed that these cells also shared
several cytochemical and ultrastructural fea-tures, which allowed them to be grouped as
one biochemical entity. These cells also local-
ized within classic endocrine glands, such as
the thyroid, and in neuroepithelial tissues like
the hypothalamus.
Pearse also proposed that all cells of the
APUD series were derived from the neural
crest, the epi- or ectoblast, and that these cells
were not only coordinated with each other in
terms of the production of peptides, paracrine
hormones, and neurotransmitters, but were
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Karzinoide
Carcinoid tumors
Neuroectodermal tumors
Neural crest tumors
Apudoma
Neuroendocrine tumors
Figure 5. Evolution of the terminology applied to neuroendocrine tumors
also coupled with the autonomic and somatic
nervous systems as a superordinate control-
ler. Then in 1969, the Hungarian endocrinolo-
gists Ilona Szijj and Kálmán Kovács intro-duced the term “Apudoma” when describing
a patient with an ACTH-producing medullary
carcinoma of the thyroid. Thereafter, the term
Apudoma was commonly used for all forms of
hyperplasia and neoplasia derived from cells
of the APUD series, comprising benign hyper-
plasia as well as carcinoids and carcinomas.
Apudomas were regarded as either orthoendo-crine (ie, secreting the normal peptides of the
cells), paraendocrine (ie, secreting amines,
hormones and peptides that are not regularly
produced by these cells), or polyhormone
secreting when associated with the multiple
endocrine neoplasia (MEN) syndrome.Thus, as a result of the many outstanding
contributions of these scientists, the under-
standing of NETs evolved, as did the termi-
nology applied to these tumors (Figure 5).
Over the past century, the terminology has
progressed from Oberndorfer’s concept of
karzinoide to neuroendocrine tumors.
Over the pastcentury, the
terminology has
progressed fromOberndorfer’s
concept ofkarzinoide to
neuroendocrine tumors.
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There has been prolonged debate regard-
ing the developmental origin of GI neu-roendocrine cells. Currently most scientists
accept the Unitarian Theory of intestinal
cytogenesis (Figure 6), which states that
intestinal and gastric cell lineages are derived
from a common stem cell precursor housed
in the base of intestinal crypts or in the neck
region of gastric glands. The debate was initi-
ated by the all-encompassing APUD concept,which postulated that neuroendocrine cells
originated in the neural crest and migrated to
the GI tract. However, this concept was subse-
quently challenged by experimental embryo-logical evidence reported by Le Douarin and
Andrew who noted in quail chick transplan-
tation experiments that, unlike the C cells in
the thyroid, which are of neural crest origin,
gut neuroendocrine cells are not. Moreover,
expression of stable reporter genes in trans-
genic mice provided robust evidence that
enteroendocrine cells differentiate from mul-tipotential progenitor cells and are of endo-
dermal origin.
Cells of Origin
Endocrine cell types
Endocrine cell lineages
NGN3+
Math1+
Goblet cells
Stem cell
Non-secretory cell lineage
Secretory lineagesEnterocytes
Paneth cells
Gastrin
Secretin
CCK
SST
Beta2Pax4
Pax6
GIP
5-HT
SP
GLP-1, PYY/NT
Figure 6. Developmental origin of gastrointestinal neuroendocrine cells. NGN3 = neurogenin 3;CCK = cholecystokinin; SST = somatostatin; GIP = gastric inhibitory peptide; 5-HT = 5-hydroxy tryptamine;GLP-1 = glucagon-like peptide 1; PYY/NT = polypeptide YY (tyrosine,tyrosine)/neurotensin.Image courtesy of IM Modlin.
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These findings have since been con-
firmed in humans. For example, evaluation of
a rare mixoploid patient’s colonic tissue dem-
onstrated that all crypt cells, including CgA-positive neuroendocrine cells, originate from
a single multipotent stem cell. Recent studies
of human crypt cells harboring mutations in
cytochrome C oxidase have finally brought
some resolution to the argument. Thus, both
intestinal and gastric neuroendocrine cells
are derived from local tissue-specific stem
cells, probably through a committed precur-sor cell. The fate of these stem cells appears
to be regulated by the Notch signaling path-
way. Notch is inactive in neuroendocrine
precursors, whereas Math1 and neurogenin3
are expressed. Precursor cells induce Notch
in adjacent cells, thereby switching off neu-
roendocrine differentiation. Math1 commitscells to one of three secretory lineages (gob-
let, Paneth, or neuroendocrine), and neuro-
genin3 appears to be essential for neuroendo-
crine cell differentiation.
Cell Types in Neuroendocrine TumorsThe cells of origin of GEP NETs are diverse
and reflect the different neuroendocrine cellsin each organ, such as the ECL cell in the fun-
dus, gastrin (G) cell in the antrum, or EC cell
in the small intestine (Figure 7).
A DB
C
Figure 7. Neuroendocrine cell morphology. Panel A: Rat fundic ECL cell demonstrating long, dendritic-like processesaround parietal cells within the gastric gland. Panel B: Confocal immunofluorescence micrograph of naive humanintestinal EC cells demonstrating localization of serotonin in vesicles (green fluorescence). Panel C: Electronmicrograph (7,200x magnification) of EC cells demonstrating typical admixture of large granules and electroluscentempty vesicles (inset shows the characteristic dense content and pear or ovoid shape of the vesicles). Panel D: Ratrectal EC cell (red) with a lengthy dendritic-like basal extension. Photo credits: Panel A is courtesy of IM Modlin. PanelsB-D are reprinted with permission from Modlin IM and Öberg K. A Century of Advances in Neuroendocrine TumorBiology and Treatment. Hannover, Germany: Felsenstein CCCP; 2007.
The cells of origin ofGEP NETs are diverse
and reflect the different
neuroendocrine cells in each organ
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Overall, there are at least 12 different neu-
roendocrine cell types in the GI tract and 4 in
the pancreas with distinct anatomical localiza-
tion and secretory products (Table 1). Someof these are localized to a single organ (eg,
the gastric ECL cell) and others are distrib-
uted throughout the GI tract (eg, the EC cell).
Although diverse, neuroendocrine cells share
a number of common features including
1) Lineage derivation (largely neurogenin
3-expressing secretory progenitor cells)
2) Production of specific proteins (CgA)involved in secretory granule formation,
maturation and exocytosis
3) Transport (vesicular monoamine trans-
porters – VMAT1, VMAT2)
4) Amine synthesis through specific
rate-limiting enzymes (histamine andhistidine decarboxylase in gastric
ECL cells or serotonin and tryptophan
hydroxylase – Tph1 – in EC cells), and
amine uptake
5) Electron-dense secretory granules
(readily visible by electron microscopy)
6) Calcium and ERK1/2 signaling pathways
for secretion7) MAPK pathways for growth factor (eg,
gastrin/TGF-a) mediated proliferation.
Table 1. Gastrointestinal and Pancreatic Neuroendocrine Cell Types and Secretory Products
Cell type Localization Products
Delta (D) Entire GI tract Somatostatin
Enterochromaffin (EC) Entire GI tract Serotonin/substance P/guanylin/melatonin
Enterochromaffin-like (ECL) Gastric fundus HistamineGastrin (G) Gastric antrum & duodenum Gastrin
Ghrelin (Gr) Entire GI tract Ghrelin
I Duodenum CCK
K Duodenum/jejunum GIP
L Small intestine GLP-1, PYY, NPY
Motilin (M) Duodenum Motilin
Neurotensin (N) Small intestine NeurotensinSecretin (S) Duodenum Secretin
Vasoactive intestinal peptide (VIP) Entire GI tract VIP
Beta Pancreas Insulin, amylin
Alpha Pancreas Glucagon
Delta Pancreas Somatostatin
Pancreatic polypeptide (PP) Pancreas PP
CCK = cholecystokinin; GIP = gastric inhibitory peptide; GLP-1 = glucagon-like peptide 1; PYY = polypeptide YY
(tyrosine,tyrosine); NPY = neuropeptide Y (tyrosine); PP = pancreatic polypeptide.Adapted with permission from Modlin IM and Öberg K. A Century of Advances in Neuroendocrine Tumor Biology andTreatment. Hannover, Germany: Felsenstein CCCP; 2007.
Overall, there are at least 13 different neuroendocrine cell types in the GI tract and 4 in the pancreas with distinct anatomical localization and secretory products
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Figure 8. Intestinal enterochromaffin (EC) cell activation pathways. Reprinted with permission from Modlin IMand Öberg K. A Century of Advances in Neuroendocrine Tumor Biology and Treatment. Hannover, Germany:Felsenstein CCCP; 2007.
Enterochromaffin Cells
EC cells are distributed throughout the
GI tract, from the esophago-gastric junc-
tion to the rectal dentate line, and appearto include several different subpopulations.
They exhibit a variety of morphological
differences in shape, luminal endings and
secretory granules suggesting region-specific
functions. Most EC cells are of the “open”
type with apical cytoplasmic extensions that
project into the glandular lumen with short
microvilli and allow the cell to sense physi-
cal or chemical variations in luminal content.
Enterochromaffin cells are thus consideredto function as the “taste buds of the gut” and
represent sensory transducers responding
to mechanical events, luminal acidification,
or nutrients such as glucose and short-chain
fatty acids. The various stimuli that can acti-
vate EC cells are shown in Figure 8.
ECcell
Enterocyte
+/– ?
+/– ?
+/–
+
Goblet cell
Lymphocyte
Capillary
Neural regulation+ Adrenergic, PACAP– AcH, GABA
InfectionInflammation+ Interleukins
Hormonal/neural– SomatostatinSerotonin auto rec?
Neuron
Hormonaleffects
Afferentneuron
activation
Mucus +
Water +Chloride +
Bicarbonate +
Luminalstimuli
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Upon stimulation, EC cells secrete at
least serotonin, melatonin, substance P, and
guanylin from granule stores into the submu-
cosa of the bowel. These bioactive productsinfluence adjacent cells via a neurocrine or
paracrine mechanism and, in addition, can
exert a classic hormonal effect on distant
cells via the circulation. Extensive and elon-
gated axon-like cytoplasmic processes that
abut adjacent cells have been demonstrated
at the base of the EC cells. These dendritic-
like processes enable the EC cell to discharge
its signal substances in direct proximity to
nerve endings in the lamina propria, adja-
cent mucosal cells, and immune cells. The
EC cell may, therefore, regulate a number of
physiological processes and also effectively
function as a synchronization mechanism
for an entire group of glands or villi, as well
as smooth muscle units, thereby acting as an
integrator of GI function.
Islets of Langerhans
The islets of Langerhans are clusters of
endocrine cells interspersed in the connective
tissue of the adult exocrine pancreas. Islets
secrete a wide variety of peptide hormones
including insulin, glucagon, somatostatin,
vasoactive intestinal peptide (VIP) and pan-
creatic polypeptide (PP). These agents have
both local and distant functional effects andare involved in both islet and acinar homeo-
stasis. The four major islet endocrine cell
types are
1) Insulin-producing b cells (70%)
2) Glucagon-producing a cells (20%)
3) Somatostatin-producing d cells
(5%-10%)
4) Pancreatic polypeptide-producing
(PP) cells.
Other less abundant cell types produce
VIP, substance P, 5-HT, and even gastrin,
although the latter cell type is only detect-
able during the perinatal period. Of partic-
ular relevance to the function of islets and
their regulatory role is the fact that they are
disproportionately highly vascularized and
have an intra-islet portal system. Althoughislets constitute only 12% of the entire pan-
creatic mass, they receive 10% to 20% of
the total pancreatic blood flow, which is
consistent with their complex metabolic
regulatory role.
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Analysis of the US SEER database (1973-
2004), which contains 35,618 NETs,demonstrated that in the United States the
incidence of NETs is increasing at a rate of
3% to 10% per year depending on the subtype
(Figure 9). The overall incidence of NETs has
increased significantly from 1.1 per 100,000 in
1973 to 5.25 per 100,000 in 2004, and similar
trends have been observed in other global
databases. Much of this increase probably
reflects the more widespread use of endos-
copy and introduction of more sensitive diag-
nostic tools, but dietary and environmental
factors may also be contributing to this trend.
It remains to be seen whether further improve-
ments in awareness and diagnosis will reveal
the true incidence of NETs to be substantially
higher than current estimates. The f requencyof NETs in a large autopsy series (1.22%)
also indicates that these tumors have previ-
ously been under diagnosed. Nevertheless,
irrespective of the cause, the incidence has
increased approximately 500% over the last
32 years, representing an annual percentage
increase of 5.8%. Using regression analysis,
conservative estimates predicted that by
2013 the incidence could be approximately
8 per 100,000. As a result of comparatively
longer 5-year survival rates, the prevalence
of NETs is considerably higher than that of
gastric, pancreatic, esophageal, and hepato-
biliary cancers.
Epidemiology
Lung andbronchus
Small intestineRectum
Stomach
Pancreas
Appendix
ColonCecum
I n c i d e n
c e p e r 1 0 0 , 0
0 0
Year
1.4
1.2
1.0
0.8
0.6
0.4
0.2
0
73 75 77 79 81 83 85 87 89 91 93 95 97 99 01 03
8
A B
5.9
6.75?
7.8?
83
7
N e u r o e n d o c r i n e t u m o r s i n t h e U S
( i n c i d e n
c e p e r 1 0 0 , 0
0 0 )
6
5
4
3
2
1
88 93 98
Year
03 08 13
0
Figure 9. Incidence of neuroendocrine tumors. Panel A: Extrapolation of overall incidence of neuroendocrine tumorsin the US population by regression analysis. Reprinted with permission from Modlin IM, et al. J Natl Cancer Inst .2008;100:1-8. Panel B: Annual age-adjusted incidence of neuroendocrine tumors in the US population by anatomicallocation between 1973 and 2004. Reprinted with permission from Yao JC, et al. J Clin Oncol . 2008;26:3063-3072.
The incidence has increased approximately
500% over the last 32 years, representing
an annual percentage increase of 5.8%. Using
regression analysis,conservative estimates predicted that by 2013
the incidence could be approximately 8 per 100,000.
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Evaluation of the US SEER database dem-
onstrates that NETs occur most frequently in
the GI tract (60.9%) with the second most
common location in the bronchopulmonarysystem (27.4%), followed by considerably
less frequent locations such as the ovaries,
testes, hepatobiliary system, and pancreas
(Figure 10). GEP NETs are most common
in the small intestine (33.9%), followed by
the rectum (23.2%), colon (19.0%), stomach
(7.7%), pancreas (7.5%) and appendix (6.6%).
In addition, approximately 60% to 85% of NETs
of the bowel and pancreas are metastatic at
presentation.
Small intestine
Rectum
Appendix
Colon
Stomach
Duodenum
Pancreas
Liver
Gallbladder
Digestive system
Trachea, bronchus, lung
Gonads
0 10 20 30 40
Percent of total
50 60 70
Figure 10. Anatomical distribution of neuroendocrine tumors accordingto the US SEER database. Image courtesy of IM Modlin.
Carcinoid tumors were initially classifiedby Williams and Sandler in 1963 accord-ing to their foregut, midgut, or hindgut deri-
vation. Foregut endocrine cells give rise to
NETs in the respiratory tract, the stomach,the first part of the duodenum, and the pan-
creas; midgut NETs appear in the bowel from
the second part of the duodenum through the
ascending colon and appendix; and hindgut
NETs appear in the transverse and descend-
ing colon and rectum. Neuroendocrine
tumors from different segments of the
embryologic gut typically vary in terms of
their bioactive products. However, with sub-
sequent elucidation of the different neuroen-
docrine cell types, it became apparent that
an embryological classification had little
mechanistic or physiological relevance. Then
in 1971, Soga and Yakuwa introduced a his-
tological classification based purely on mor-
phological characteristics, describing NETsaccording to their main growth pattern (insu-
lar, trabecular, glandular, mixed, or undiffer-
entiated). Unfortunately, both of these early
classification systems predated an under-
standing of the different neuroendocrine cell
types described above, and this hindered an
appreciation of the biological and pathologi-
cal roles of the many different cell types and
their varying secreted peptides and amines,
which ultimately affect the biologic behavior
of the tumor.
Pathological Classification and Clinical Behavior
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Table 2. World Health Organization Classification forGastroentero-Pancreatic Neuroendocrine Tumors
Classification Tumor Type
1 Well-differentiated neuroendocrine tumor
1a Benign
1b Uncertain malignant potential
2 Well-differentiated neuroendocrinecarcinoma—low-grade malignant
3 Poorly differentiated neuroendocrinecarcinoma—high-grade malignant
Although the traditional classification
of NETs based on their embryonic origin has
little current validity, it nevertheless remains
in wide use. More recently, the World HealthOrganization developed a tumor-based (ie,
TNM) classification (2000 and 2004) that has
greater applicability (Table 2). This classifi-
cation system is based on tumor size, prolif-
erative index, localization, differentiation,
and hormone production as well as angioin-
vasion, extent of organ-specific invasion, and
metastases to lymph nodes or liver. Moreover,
distinction is made between well-differen-
tiated NETs (benign behavior or uncertain
malignant potential), well-differentiated NETs
(low-grade malignancy), and poorly differen-
tiated (usually small cell) NETs of high-grade
malignancy. This topic will be discussed in
further detail in Monograph 3.
The term “carcinoid” is still sometimes used
inaccurately as a synonym for “well-differenti-ated NET,” and the term “malignant carcinoid” is
often used synonymously with the term well-dif-
ferentiated neuroendocrine carcinoma (NEC).
However, according to the current classification
and nomenclature, “carcinoid” should be used
only in the context of “carcinoid syndrome” and
serotonin secreting tumors.
Clinical PresentationNeuroendrocrine tumors are heteroge-
neous in clinical presentation and behavior,
and yet, like their progenitor cells, they exhibita commonality of features consistent with their
lineage—common secretory mechanisms and
proliferative regulators. Most importantly, the
majority are malignant, and if left untreated
will evolve to metastatic disease (Table 3).
Within each group, however, there is variabil-
ity; some may be highly aggressive locally or
exhibit metastatic behavior indistinguishable
from an adenocarcinoma. Some NETs char-
acterized as poorly differentiated NEC exhibit
highly aggressive behavior. More detail on the
pathology and clinical presentation of NETs
will be provided in a subsequent monograph.
The etiopathogenesis of GEP NETs is
largely unknown except for gastric ECL cell-
derived NETs (gastric carcinoid) in which
hypergastrinemia (such as in hypochlorhy-dria associated atrophic gastritis or perni-
cious anemia), either alone or in combination
with a MEN Type I (MEN-I) genetic defect, cul-
minates in abnormal ECL cell proliferation. Of
clinical relevance is the observation that sev-
eral different genes and genetic abnormalities
are implicated in tumor development. GEP
NETs can be both sporadic (nonfamilial) orpart of familial syndromes such as MEN-I, von
Hippel-Lindau syndrome, and neurofibroma-
tosis. The most common chromosomal aber-
rations associated with GEP NETs include
translocational gains on chromosomes 17
and 19 (50%-62.5%) and deletion of parts of
chromosome 18 (43%-88%).
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Table 3. Characterization and Clinical Presentation of Gastroentero-Pancreatic Neuroendocrine Tumors
Gastrointestinal Neuroendocrine Tumors
Gastric Type IType II (MENI-ZES)Type III
Atrophic gastritis- gastrin dependentGenetic defect menin dependent-gastrin relatedGastrin independent
Duodenal Variety of differentphenotypes
Gastrinoma, “carcinoid,” somatostatinoma
Jejunal Classic “carcinoid” symptoms; >90% malignant
Ileal Classic “carcinoid” symptoms; >90% malignant
Appendiceal “Carcinoid”
Goblet cellcarcinoid (mucinouscarcinoid)
Usually present as appendicitis or incidental finding at
laparotomy/laparoscopy; can exhibit malignant behavior especiallyif goblet/mucinoid phenotype
Colonic Carcinoid symptoms are rare; presentation similar to adenocarcinoma;80% to 90% malignant
Rectal Local manifestations include pain and bleeding; malignant, althoughmicrocarcinoids manageable by local endoscopic resection
Hepatic >98% are metastases from GEP NET primary tumor in bowel or pancreas
Pancreatic Endocrine Tumors (PETs)
Gastrinoma (ZES) Peptic ulceration and secretory diarrhea; 60% to 90% malignant
Insulinoma Hypoglycemia; 5% to 15% malignant
Glucagonoma Skin rash, weight loss, diabetes; 60% malignant
VIPoma (Verner–Morrison) Secretory diarrhea; 80% malignant
SomatostatinomaDiabetes, gall stones; often a component of a genetic syndrome;60% malignant
GRFoma Acromegaly; 30% malignant
ACTHoma Present as Cushing syndrome; aggressive behavior; >90% malignant
PET causing carcinoid syndrome Diarrhea, flushing; 68% to 88% malignant
PET causing hypercalcemia Symptoms of hypercalcemia; 80% to 90% malignant
Nonfunctioning Local mass effects; 60% to 90% malignant
ZES = Zollinger-Ellison Syndrome; VIP = vasoactive intestinal peptide; GRF = gastrin releasing factor;ACTH = adrenocorticotropic hormone.
Neuroendrocrine tumors are heterogeneous inclinical presentation
and behavior, and yet, like their progenitorcells, they exhibit acommonality of featuresconsistent with their
lineage—common secretory mechanisms and proliferative regulators.
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Our understanding of NETs has evolved
substantially since their initial identifica-tion. In particular the erroneous observation
by Oberndorfer in 1907 that such tumors were
benign has been refuted. As a consequence,
the terminology applied to these tumors has
also evolved from the archaic concept of
karzinoide to the recognition that NETs are
malignant and exhibit a wide spectrum of
clinical behaviors ranging from indolent to
highly aggressive and metastatic. Over the
past 30 years, the widespread availability and
utility of endoscopy, advances in immuno-
histochemistry, and the introduction of diag-
nostic biomarkers have contributed to a dra-
matic (approximately 500%) increase in the
incidence of NETs. Nevertheless, early and
timely diagnosis of NETs remains a challenge
because of lack of awareness, prosaic clini-cal manifestations, and the lack of molecular
tools for early diagnosis and surveillance. As
a consequence, diagnosis is often delayed, on
average 5 to 7 years, and the majority of NETs
(>80%) are metastatic at presentation with
predictably suboptimal therapeutic outcomes.
Indeed, survival rates have not changed sub-
stantially over the past 30 years. Thus, thereremains the need to improve physician aware-
ness and earlier diagnosis of NETs.
Neuroendrocrine tumors exhibit hetero-
geneous clinical presentation and behavior
depending on their anatomical site, neuroen-
docrine cell(s) of origin, and secretory prod-
ucts, but also exhibit many common features
consistent with their lineage. Approximately
60% of all NETs occur in the GI system (mostfrequently in the small intestine, rectum,
colon, stomach, pancreas, and appendix),
and up to one-third of NETs occur in the bron-
chopulmonary system. The cells of origin ofGEP NETs are diverse but all originate from
a common precursor gut stem cell. The most
common GEP NETs are derived from EC cells,
which are ubiquitously distributed throughout
the GI tract. Secretion of bioactive amines or
peptides into the systemic circulation (mostly
commonly associated with pancreatic tumors
and liver metastases) engenders a variety of
symptoms, including the classic “carcinoid
syndrome” characterized by flushing, sweat-
ing, diarrhea, bronchospasm, and edema or
right-sided fibrotic heart disease. Elucidation
of the biology and malignancy of NETs has
led to more accurate and meaningful clas-
sification systems and a better delineation
of prognosis. Nevertheless, further progress
is needed to eliminate historical misconcep-tions and outdated pathological terminology,
to improve staging and prognostication, and to
better define the signaling pathways and biol-
ogy of these tumors in order to develop more
effective targeted therapeutic strategies.
Summary
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Key ReferencesCapella C, Heitz PU, Hofler H, Solcia E, Kloppel G. Revised classification of neuroendocrine tumours of the lung, pancreasand gut. Virchows Arch . 1995;425:547-60.
Chetty R. An overview of practical issues in the diagnosis of gastroenteropancreatic neuroendocrine pathology.Arch Pathol Lab Med . 2008;132:1285-9.
Gustafsson BI, Kidd M, Modlin IM. Neuroendocrine tumors of the diffuse neuroendocrine system. Current Opin Oncol. 2008;20:1-12.
Gustafsson BI, Siddique Z-L, Chan AK, Manku D, Drozdov I, Kidd M, Modlin IM. Uncommon cancers of the smallintestine, appendix and colon: An analysis of SEER 1973-2004, and current diagnosis and therapy. Int J Oncol. 2008;33:1121-31.
Klöppel G, Perren A, Heitz PU. The gastroenteropancreatic neuroendocrine cell system and its tumors:the WHO classification. Ann N Y Acad Sci . 2004;1014:13-27.
Metz DC, Jensen RT. Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology .
2008;135:1469-92.Modlin IM and Öberg K. A Century of Advances in Neuroendocrine Tumor Biology and Treatment. Hannover, Germany:Felsenstein CCCP; 2007.
Modlin IM, Champaneria MC, Chan AKC, Kidd M. A three-decade analysis of 3,911 small intestinal neuroendocrinetumors: the rapid pace of no progress. Am J Gastroenterol . 2007;102:1464-73.
Modlin IM, Kidd M, Drozdov I, Siddique Z-L, Gustafsson BI. Pharmacotherapy of neuroendocrine cancers.Exp Opin Pharmacother . 2008;9:2617-26.
Modlin IM, Moss SF, Chung DC, Jensen RT, Snyderwine E. Priorities for improving management of gastropancreaticneuroendocrine tumors. J Natl Cancer Inst . 2008;100:1282-9.
Modlin IM, Oberg K, Chung DC, Jensen RT, de Herder WW, Thakker RV, Caplin M, Delle Fave G, Kaltsas GA, Krenning EP,
Moss SF, Nilsson O, Rindi G, Salazar R, Ruszniewski P, Sundin A. Gastroenteropancreatic neuroendocrine tumors. LancetOncol . 2008;9:61-72.
Modlin IM, Wright NA, Gustafsson BI, Kidd M. Gastrointestinal neuroendocrine tumors. Gastroenterology . In press.
Oberg K. Molecular imaging in diagnosis of neuroendocrine tumours. Lancet Oncol . 2006;7:790-2.
Pape UF, Berndt U, Müller-Nordhorn J, Böhmig M, Roll S, Koch M, Willich SN, Wiedenmann B. Prognostic factors oflong-term outcome in gastroenteropancreatic neuroendocrine tumours. Endocr Relat Cancer . 2008;15:1083-97.
Plöckinger U, Rindi G, Arnold R, Eriksson B, Krenning EP, de Herder WW, Goede A, Caplin M, Oberg K, Reubi JC, NilssonO, Delle Fave G, Ruszniewski P, Ahlman H, Wiedenmann B; European Neuroendocrine Tumour Society. Guidelines for thediagnosis and treatment of neuroendocrine gastrointestinal tumours. A consensus statement on behalf of the EuropeanNeuroendocrine Tumour Society (ENETS). Neuroendocrinology . 2004;80:394-424.
Rindi G, Luinetti O, Cornaggia M, Capella C, Solcia E. Three subtypes of gastric argyrophil carcinoid and the gastricneuroendocrine carcinoma: a clinicopathologic study. Gastroenterology . 1993;104:994-1006.
Solcia E, Kloppel G, Sobin L. Histological Typing of Endocrine Tumours: WHO International Histological Classificationof Tumours. 2nd ed. New York, NY: Springer, 2000.
Tang LH, Shia J, Soslow RA, Dhall D, Wong WD, O’Reilly E, Qin J, Paty P, Weiser MR, Guillem J, Temple L, Sobin LH,Klimstra DS. Pathologic classification and clinical behavior of the spectrum of goblet cell carcinoid tumors of theappendix. Am J Surg Pathol . 2008;32:1429-43.
Toumpanakis C, Standish RA, Baishnab E, Winslet MC, Caplin ME. Goblet cell carcinoid tumors (adenocarcinoid) of theappendix. Dis Colon Rectum . 2007;50:315-22.
Yao J, Hassan M, Phan A, Dagohoy C, Leary C, Mares J, Abdalla E, Fleming J, Vauthey J, Rashid A, Evans D. One hundredyears after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the UnitedStates. J Clin Oncol . 2008;26:3063-72.
Zikusoka MN, Kidd M, Eick G, Latich I, Modlin IM. The molecular genetics of gastroenteropancreatic neuroendocrinetumors. Cancer . 2005;104:2292-309.
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Amylin A 37-amino acid peptide hormone cosecreted with insulin (amylin:insulinratio ~1:100) by beta cells in the pancreas. It modulates nutrient fluxes in the blood
by reduction of food intake, delay of gastric emptying, and decrease of postprandialglucagon secretion. It is also known as islet amyloid polypeptide (IAPP).
Atrophic gastritis Chronic inflammation of the stomach, especially the fundus, characterized by atrophicmucosa, decreased acid secretion, increased gastrin levels and hyperplasia ofenterochromaffin-like cells resulting in increased CgA levels and histamine production.
Bioactive amines Biologically active, nitrogen-containing, organic compounds synthesized bydecarboxylase and hydroxylase enzymes (eg, serotonin, melatonin, substance P).
Cholecystokinin A peptide hormone secreted into the blood by the duodenal I cells, which stimulates
gallbladder contraction and secretion of pancreatic enzymes.
Chromogranin A (CgA) An acidic, 48-kDa secretory glycoprotein present in the secretory granules ofneuroendocrine cells that is cosecreted with peptide hormones and amines. CgA is alsothe precursor to several functional peptides including vasostatin and pancreastatin.Detection of elevated plasma levels of CgA has been shown to be a sensitive biomarkerfor neuroendocrine tumors.
Crypts of Lieberkühn Tubular glands found in the epithelial lining of the small intestine and colon thatsecrete various digestive enzymes, including sucrase, maltase, endopeptidases, andexopeptidases. These glands were originally named after the 18th-century German
anatomist Johann Lieberkühn.
Cushing syndrome Hypersecretion of cortisol from the adrenal cortex, which may be secondary tohypersecretion of ACTH from the pituitary, resulting in rapid weight gain, particularly ofthe trunk and face with sparing of the limbs (central obesity), growth of fat pads alongthe collar bone and back of the neck (buffalo hump), and a round face often referred toas a “moon face.” Other symptoms include excess sweating, telangiectasia, thinning ofthe skin and bruising, fatigue, osteoporosis, and diabetes. Cushing was a pioneer in themanagement of pituitary tumors.
Gastric inhibitory peptide A peptide hormone produced by K cells in the duodenum and jejunum that wasoriginally thought to inhibit gastric acid production by parietal cells of the stomach.Subsequent investigation more accurately characterized its biological activity andredefining it as glucose-dependent insulinotrophic peptide.
Gastrin A classical peptide hormone secreted by the antral and duodenal G cells that isresponsible for activating enterochromaffin-like cells in the fundus to release histamine,which in turn stimulates parietal cells to produce gastric acid.
Ghrelin A peptide hormone produced throughout the GI tract that exerts its effect on neuronsin the hypothalamus, thereby stimulating hunger.
Glucagon A peptide hormone secreted by alpha cells in the pancreas that is responsible forincreasing blood glucose concentration by activation of hepatic glucogenolysis. Inaddition, it causes relaxation of intestinal smooth muscle.
Glossary of Terms
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Glucagon-like peptide 1 A peptide hormone produced by L cells in the small intestine that increases insulinsecretion (enteroinsular axis) and decreases pancreatic glucagon secretion. It also
inhibits gastric acid production and gastric emptying of the stomach and increasessatiety, thereby reducing food intake. Secretion of GLP-1 increases with rising bloodglucose levels.
Guanylin A 15-amino acid peptide hormone normally secreted by goblet cells in the colon thatregulates electrolyte and water transport in the intestinal epithelium.
Kulchitsky cells A historical term for enterochromaffin cells named after the anatomist NikolaiKulchitsky who described these cells in the crypts of Lieberkühn.
Math1 A basic helix-loop-helix transcription factor regulated by the Notch signaling pathway
that induces neuroendocrine stem cells to differentiate into one of three secretory celllineages (goblet, Paneth, or neuroendocrine).
Melatonin A bioactive amine produced in the pineal gland and by enterochromaffin cells of the GItract that is a component of circadian rhythms. Melatonin production is regulated bydaily patterns of light and dark.
Motilin A 22-amino acid peptide hormone produced by M cells of the small intestine (mainly inthe duodenum and jejunum) that stimulates motility (peristalsis) in the small intestine,regulates emptying of the gut, and increases the release of pancreatic polypeptide andsomatostatin.
mTOR Mammalian target of rapamycin; also known as FK506 binding protein 12-rapamycinassociated protein 1 (FRAP1). This serine/threonine kinase is central to many cellularsignaling pathways, including the PI3kinase and Akt pathways and regulates secretionof insulin and insulin-like growth factor-1.
Multiple endocrineneoplasia syndrometype I
An inherited genetic disorder caused by germ-line mutations in the MEN-1 gene(menin) on chromosome 11q13 that is associated with an increased risk of developingmultiple cancerous and noncancerous tumors in glands such as the parathyroid,pituitary, and pancreas. This disorder affects approximately 1 in 30,000 people.
Notch A highly conserved family of 4 transmembrane receptors first described in the fruitfly. The Notch signaling pathway regulates embryonic development, intracellularcommunication, and cellular differentiation, including cell fate specification ofendocrine cell lineages. Notch is inactive in differentiated endocrine cells, therebyrelieving repression of the genes encoding Math1 and neurogenin3, which inducesecretory and neuroendocrine differentiation, respectively. In turn, neuroendocrinecells activate Notch signaling in neighboring cells, thereby preventing endocrinedifferentiation of surrounding cells.
Neurogenin3 A basic helix-loop-helix transcription factor regulated by the Notch signaling pathway
that induces neuroendocrine stem cells to differentiate into neuroendocrine cells withinthe intestinal epithelium.
Glossary of Terms
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Neuropeptide Y A 36-amino acid peptide neurotransmitter produced by the hypothalamus andby L cells of the small intestine that functions to increase food intake and decrease
physical activity. It also increases the proportion of energy stored as fat and blocksnociceptive signals to the brain.
Neurotensin A 13-amino acid neuropeptide with a putative role in the regulation of luteinizinghormone and prolactin release that modulates cortical dopamine signaling. It haseffects similar to some antipsychotic drugs. It is secreted by N cells in the smallintestine in response to lipids.
Pancreatic polypeptide A 36-amino acid peptide hormone secreted by PP cells in the pancreas whose precisefunction is poorly understood. Pharmacologically it can regulate the secretory activitiesof the pancreas (endocrine and exocrine), and it also modulates hepatic glycogen levels
and aspects of gastrointestinal secretion.
Peptide YY A 36-amino acid peptide hormone produced by L cells in the GI tract, especially inthe ileum and colon, that reduces appetite, inhibits gastric motility, and may reducepancreatic secretion. Secretion of PYY increases with food intake and rising bloodglucose levels.
Secretin A 27-amino acid peptide hormone produced by S cells in the duodenum that regulatesduodenal pH by increasing pancreatic secretion of water and bicarbonate.
Somatostatin A ubiquitous peptide hormone initially identified in the hypothalamus that inhibits
the release of somatotropin. It has widespread inhibitory effects on the secretion ofbioactive amines and peptide hormones by neuroendocrine cells. It is also known assomatotropin release-inhibiting factor (SRIF).
Substance P An 11-amino acid neuropeptide that is involved in pain perception and the modulationof smooth muscle contraction.
Vasoactive intestinalpeptide
A 28-amino acid peptide hormone that stimulates GI secretion of water andelectrolytes and relaxes smooth muscle. In addition, it stimulates pancreaticbicarbonate secretion and inhibits gastrin-stimulated gastric acid secretion.
von Hippel-Lindausyndrome
An inherited genetic disorder associated with renal angioma, renal cell carcinoma, andpheochromocytoma (a neuroendocrine tumor of the medulla of the adrenal glands).The disorder is caused by mutations of the VHL tumor suppressor gene on the shortarm of chromosome 3.
Zollinger-Ellison syndrome A disorder caused by excess secretion of gastrin from a duodenal or pancreaticneuroendocrine tumor resulting in excessive secretory diarrhea and intractablepeptic ulcers.
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Clockwise from left to right: A pancreatic neuroendocrine tumor(macroscopic view) with H&E stained sections in background showinghistopathology; immunostaining of small intestinal neuroendocrine tumor
at 100x and 400x magnification showing that connective tissue growth factoris colocalized with chromogranin A; original sketch of a carcinoid tumor bySiegfried Oberndorfer published in the Frankfurter Zeitschrift für Pathologie in 1907; 0.5-cm duodenal gastrinoma associated with Zollinger Ellisonsyndrome. Photo credits from left: Reprinted with permission from ModlinIM and Öberg K. A Century of Advances in Neuroendocrine Tumor Biology andTreatment. Hannover, Germany: Felsenstein CCCP; 2007. All other images arecourtesy of IM Modlin.
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