Endocrine Tumors of

the Gastrointestinal
Tract and Pancreas
ANDREU LEO F. LOMINOQUE, MD
General Features
Gastrointestinal Neuroendocrine Tumors

• Gastrontestinal (GI) Neuroendocrine tumors (NETS)

• tumors derived from the diffuse neuroendocrine system
of the GI tract; that system is composed of amine- and
acid-producing cells with different hormonal profiles,
depending on the site of origin
• GI NETs
• GI-NET (carcinoid)
• Pancreatic Neuroendocrine Tumors (pNETS)
APUDomas (for amine precursor uptake and
decarboxylation), as were pheochromocytomas, melanomas,
and medullary thyroid carcinomas, because they share certain
cytochemical features as well as various pathologic,biologic,
and molecular features
Pathology

• composed of monotonous sheets of small

round cells with uniform nuclei, and mitos
es are uncommon
• tumors possess electron-dense neurosecret
ory granules and frequently contain sma
ll clear vesicles that correspond to synap
tic vesicles of neurons. NETs synthesize nu
merous peptides, growth factors, and bioact
ive amines that may be ectopically secreted,
giving rise to a specific clinical syndrome
Classifcations
Pathology
GI-NETs (carcinoids) can occur in almost any
GI tissue
• (70%) have their origin in one of three
sites: bronchus, jejunoileum, or colon/
rectum.
• bronchus/lung, rectum, and small intestin
e are now the most common sites.
• Overall, the GI tract is the most common
site for these tumors, accounting for 64%,
with the respiratory tract a distant second
at 28%
Neuroendocrine markers
Classification
• Foregut, Midgut,Hindgut
• World Health Organization (WHO), Europe
an Neuroendocrine Tumor Society (ENETS)
, and the American Joint Committee on C
ancer/International Union Against Cancer (
AJCC/UICC)
 G1 – low grade
 G2 – intermediate grade
 G3 – high grade
Genetic Syndromes

number of diseases due to v

arious genetic disorders are
associated with an increased
incidence of NETs
Caused by loss of the tumor
suppressor gene
GI-NETs (carcinoid) and
Carcinoid Syndrome
Characteristics of most
Common Carcinoid
Appendiceal NETs (Carcinoids)

• occur in 1 in every 200–300 appendect

omies, usually in the appendiceal tip,
have an incidence of 0.15/100,000 per
year
• tumors are well-differentiated
• G1 tumors (87%) with the remainder p
rimarily well-differentiated
• G2 tumors (13%); poorly differentiated
• G3 tumors are uncommon (<1%)
Characteristics of most
Common Carcinoid
Small Intestinal NETs (carcinoids)

• Small intestinal (SI) NETs (carcinoids) have

a reported incidence of 0.67/100,000 in th
e United States
• They characteristically cause a marked fibr
otic reaction, which can lead to intestinal
obstruction. Tumor size is an important var
iable in the frequency of metastases.
• SI NETs (carcinoids) are the most common
cause (60–87%) of the carcinoid syndrome
Characteristics of most
Common Carcinoid
Rectal NETs (carcinoid)

• 27% of all GI-NETs (carcinoids) and 16

% of all NETs and are increasing in fre
quency
• approximately 1 in every 1500/2500 pr
octoscopies/colonoscopies or 0.05–0.0
7% of individuals undergoing these pr
ocedures
Characteristics of most
Common Carcinoid
Gastric NET (Carcinoids)
• 3 of every 1000 gastric neoplasms and 1.3
–2% of all carcinoids, and their relative fre
quency has increased three- to fourfold ov
er the last five decades
• originates from gastric enterochromaffin-li
ke (ECL)
• Two subtypes are associated with hyperga
strinemic states
• chronic atrophic gastritis (type I) (80% of all
gastric NETs [carcinoids])
• Zollinger-Ellison syndrome, which is almost
always a part of the MEN 1 syndrome (type
II) (6% of all cases).
Clinical Presentation of Carcinoid
without Carcinoid Syndrome
• The presentation is diverse and related to the site of origin and ex
tent of malignant spread
• Common symptoms include:
A. Pain
B. Intestinal Obstruction
C. Ileus
D. GI Bleeding
Carcinoid Syndrome
Pathobiology
Pathobiology
Clinical Characteristics
Diagnosis

• measurement of urine 5-HIAA is used most frequently (N: 2–8 mg/d)

• Platelet serotonin levels are more sensitive than urinary 5-HIAA but are n
ot generally available
• The diagnosis of carcinoid tumor can be suggested by the carcinoid synd
rome, recurrent abdominal symptoms in a healthy-appearing individual, o
r the discovery of hepatomegaly or hepatic metastases associated with m
inimal symptoms
• Serum chromogranin A levels are elevated in 56–100% of patients with GI
-NETs (carcinoids), and the level correlates with tumor bulk
Treatment
• Symptomatic treatment
• avoiding conditions that precipitate flushing,dietary supplementatio
n with nicotinamide, treatment of heart failure with diuretics, treat
ment of wheezing with oral bronchodilators, and control of the diar
rhea with antidiarrheal agents such as loperamide and diphenoxyla
te.
• Serotonin receptor antagonist (methysergide, cyproheptadine, and
ketanserin)
• Somatostatin analogues (octreotide, lanreotide)
Pancreatic NETs
• present clinically with symptoms du
e to the hormone-excess state
• functional pNETs may present with
severe symptoms with a small or un
detectable primary tumor, whereas
nonfunctional tumors usually prese
nt late in the disease course with la
rge tumors, which are frequently m
etastatic
Pancreatic NETs
Treatment

• Treatment must be directed at the hormone-excess state such as t

he gastric acid hypersecretion in gastrinomas or the hypoglycemia
in insulinomas
• all the tumors except insulinomas, >50% are malignant
GASTRINOMA
(ZOLLINGER-ELLISON SYNDROME)
• gastrinoma is an NET that secretes gastrin; the resultant hypergastrine
mia causes gastric acid hypersecretion (Zollinger-Ellison syndrome)
• gastric acid hypersecretion and growth of the gastric mucosa with incr
eased numbers of parietal cells and proliferation of gastric ECL cells.
• gastrinomas (50–90%) in sporadic ZES are present in the duodenum, fo
llowed by the pancreas (10–40%) and other intraabdominal sites (mese
ntery, lymph nodes, biliary tract, liver, stomach, ovary)
• most common presenting symptoms are abdominal pain (70–100%), di
arrhea (37–73%), and gastroesophageal reflux disease (GERD) (30–35%)
GASTRINOMA
(ZOLLINGER-ELLISON SYNDROME)
Diagnosis

• fasting hypergastrinemia
• increased basal gastric acid output (BAO) (hyperchlorhydria)
• potent gastric acid suppressant drugs such as proton pump inhibi
tors (PPIs) (omeprazole, esomeprazole, pantoprazole, lansoprazole,
rabeprazole) can suppress acid secretion sufficiently to cause hype
rgastrinemia
GASTRINOMA
(ZOLLINGER-ELLISON SYNDROME)
Treatment
• controlled in almost every case by oral gastric antisecr
etory drugs
• With long-term PPI use in ZES patients, vitamin B12 de
ficiency can develop; thus, vitamin B1 levels should be
assessed during followup
INSULINOMAS

• NET of the pancreas that is thoug

ht to be derived from beta cells th
at ectopically secrete insulin
• Most common clinical symptoms a
re due to the effect of the hypogl
ycemia on the CNS (neuroglycemi
c symptoms) and include confusio
n, headache, disorientation, visual
difficulties, irrational behavior, and
even coma
• Usually involved in patients with
MEN1
INSULINOMAS

Diagnosis

• Elevated plasma insulin at the time of hypoglycemia

• most reliable test to diagnose insulinoma is a fast up
to 72 h with serum glucose, C-peptide, proinsulin, and
insulin measurements every 4–8 h
INSULINOMAS

Treatment

• Only 5–15% of insulinomas are malignant; therefore, a

fter appropriate imaging (see below), surgery should
be performed
• Diaxozide is a benzothiadizine which is an inhibitor of
insulin release
GLUCAGONOMA

• Excessive mounts of glucagon, which causes a distinct syn

drome characterized by dermatitis (migratory necrolytic e
rythema), glucose intolerance or diabetes, and weight loss
• characteristic laboratory finding is hypoaminoacidemia, whi
ch occurs in 26–100% of patients
• Diagnosis is confirmed by demonstrating and increased lev
el of plasma glucagon
• Long acting somatostatin analogue impoves disease proce
ss
THANK YOU!