NETS Monograph 1

8/18/2019 NETS Monograph 1

1/28

Neuroendocrine Tumors:From Carcinoid to Cancer

Nosology, Topographyand Epidemiology

1


2/28

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.


3/28

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


4/28ii


5/281

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


6/282

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.


7/283

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.


8/284

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.


9/285

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


10/286

“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


11/28

7

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


12/28

8

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.


13/28

9

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.


14/28

10

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


15/28

11

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


16/28

12

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


17/28

13

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.


18/28

14

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.


19/28

15

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


20/28

16

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%).


21/28

17

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.


22/28

18

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


23/28

19

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.


24/28

20

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


25/28

21

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


26/28

22

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.

Glossary of Terms


27/28


28/28

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.

Novartis Pharma AG

G-SDS-10123 GCT7267 CH-4002 Basel, Switzerland © Novartis 2009 June 2009

NETS Monograph 1

Documents

Transcript of NETS Monograph 1