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GASTROINTESTINAL
NEUROENDOCRINE TUMORS
Are tumors derived from the neuroendocrine system, composed of cells having special
secretory granules, and often producing biogenic amines and polypeptide hormones
(neurohormones).
Neuroendocrine cells do not form a gland; instead, they are found distributed in a wide
variety of body organs where they help regulate body function.
They are divided to pancreatic endocrine tumors (PETs) and carcinoid tumors, recent
pathologic classifications have proposed that they are all to be classified as gastrointestinal
neuroendocrine tumors (NETs), but the term carcinoid tumor is still widely used.
1‐ Pancreatic endocrine tumor
a‐ Zollinger‐Ellison Syndrome. b‐ Insulinoma.
c‐ Glucagonoma. d‐ Somatostatinoma.
e‐ GRFoma. f‐ ACTHoma
g‐ VIPoma (Verner‐Morrison syndrome, pancreatic cholera)
g‐ VIPoma (Verner‐Morrison syndrome, pancreatic cholera)
¾ Rare, (incidence/1 per 10,000,000 per year),
¾ VIPomas are usually large and solitary;
¾ 50 to 75% of these tumors occur in the pancreatic tail,
¾ Of these 90% originating from non‐β islet cell of the pancreas
¾ 40 to 70% of them are malignant at diagnosis.
¾ they produces vasoactive intestinal peptide (VIP).
¾ VIP is neuropeptide produced in many tissues, the gut, pancreas, and
suprachiasmatic nuclei of the hypothalamus in the brain.
VIP has a half‐life of about two minutes
Action of vasoactive intestinal peptide (VIP)
a‐ Stimulates contractility of the heart,
b‐ Increases glycogenolysis leading to hyperglycemia
c‐ Vasodilatation and Lowering of arterial blood pressure
d‐ Relaxes the smooth muscle of trachea, stomach and gall bladder that lead to the dilated
loops of bowel that are common in this syndrome as well as a dilated, atonic gallbladder
that is sometimes seen.
e‐ Stimulate secretion of water into pancreatic juice and bile,
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f‐ Cause inhibition of gastric acid secretion
g‐ potent stimulant of secretion in both the small and large intestine
h‐ Hypercalcemia (mechanism remains unclear).could be part of (MEN1 (Pituitary,
parathyroid and pancreatic tumors))
Clinical Features Due to VIP secretion causing
¾ Profound and chronic watery diarrhea (>1 L/day) and >3 L/day in 70 to 80%; secretory in
nature, occurs even during fasting and lead to dehydration, hypokalemia and non–
anion gap acidosis, due to excretion of large amounts of potassium and bicarbonate in
the stool.
¾ Achlorhydria.
¾ Flushing and hypotension due to vasodilatation occur in 20% of patients),
¾ Symptoms of hypercalcemia 41 to 50% (part of MEN1 (Pituitary, parathyroid and
pancreatic tumors))and of hyperglycemia 25 to 50% .
¾ Lethargy, muscle weakness, nausea, vomiting and crampy abdominal pain are frequent
symptoms.
Diagnosis
Typical history of profound diarrhea and the diagnosis is excluded when fasting stool
volume is less than 700 mL/day.
Fasting plasma VIP levels to differentiate VIPomas from other causes of large‐volume,
fasting diarrhea, including ZES, surreptitious use of laxatives, the pseudopancreatic cholera
syndrome and human immunodeficiency virus (HIV).
Investigation
•
Blood chemistry tests and Stool examination
•
CT scan or MRI of the abdomen
•
Fasting plasma VIP levels
Treatment
Correct dehydration and electrolyte disturbance is the first goal of treatment.
Octreotide 85% of patients can be controlled by daily doses of octreotide (50 to 400 μg
once to three times daily) or by monthly injections of the depot form, octreotide‐LAR
Before the availability of octreotide, small numbers of patients were reported to respond to
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a variety of agents including high‐dose prednisone, clonidine, lithium carbonate,
indomethacin, loperamide.
Surgical resection should be attempted if possible to remove all visible tumor; however,
more than 40‐70 % of patients have generalized liver metastases at diagnosis, so complete
resection may not be possible.
Chemotherapy For patients with advanced cases and refractory symptoms,
2‐ Carcinoid tumors
Slow‐growing tumor that arise from the enterochromaffin cells throughout the body; most
commonly GI tract 70% and the lung 15%.
Most common site of GI tract carcinoid is the appendix, with maximum potential for
malignancy is in the pancreas. 95–100% of carcinoid tumors are malignant
Carcinoid tumors produce the vasoactive substance, mainly serotonin, possibly tachykinins,
motilin, prostaglandins, and histamine.
Clinical Manifestations
¾ Intestinal obstruction and other complications associated with tumor growth may result
from the primary tumor.
¾ Carcinoid syndrome Only 8 to 10% of all carcinoid tumors lead to carcinoid syndrome.
The carcinoid syndrome occurs when mediators produced by the tumor escape into the
systemic circulation bypassing the liver or if the primary tumor is from the GI tract
(hence releasing serotonin into the hepatic portal circulation), carcinoid syndrome
generally does not occur until the disease is so advanced that it overwhelms the liver's
ability to metabolize the released mediators leading to.
1‐ Flushing (63–80%) due to tachykinins or histamine and may be prostaglandin, is a
common clinical feature. The typical flush is dark red to violaceous and involves the head,
neck, and upper trunk that usually lasts for 30 seconds to 3 minutes, associated with
lacrimation and periorbital edema, tachycardia, Low or normal blood pressure.
Flushing may be provoked by excitement, exertion, eating, and ethanol ingestion. In
patients with the bronchial carcinoid variant, flushing may last for hours.
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2 ‐Diarrhea (32–84%) due to Serotonin and may be prostaglandin, Chronic diarrhea with a
secretory component
3‐ Cramping Pain (10–34%)
4‐ Heart disease (11–41%) Plaque like thickening of the endocardium of the valvular cusps
and cardiac chambers occurs primarily on the right side of the heart, the left side may be
minimally involved.
leading to , heart failure, palpitation and peripheral edema.
5‐ Asthma (4–18%) Bronchoconstriction, usually most pronounced during flushing attacks,
is a less common feature of the syndrome, but it may be severe, both histamine and
serotonin may be responsible
Other features of the tumor
1. Telangiectasia primarily on the face and neck.
2‐ Pellagra (3%): Serotonin overproduction shunts dietary tryptophan into the
hydroxylation pathway, thus leaving less tryptophan available for the formation of niacin
Carcinoid crisis
Attacks of severe and sustained flushing with life‐threatening hemodynamic compromise
and bronchoconstriction may occur. Precipitating factors include anesthesia or surgery,
tumor necrosis, and catecholamine infusion.
Death usually is caused by cardiac or hepatic failure due to metastasis.
Diagnoses
Recurrent abdominal symptoms in a healthy appearing individual, or the discovery of
hepatomegaly or hepatic metastases associated with minimal symptoms. Or bowel
obstruction with abdominal pain, flushing, or diarrhea.
Lab
Overproduction of 5‐hydroxyindoles accompanied by increased excretion of urinary 5‐
Hydroxyindoleacetic acid (5‐HIAA). Before the test dietary 5‐hydroxyindoles are stopped as
bananas, walnuts, avocados, drugs as acetaminophen, salicylates, or l‐dopa that contain
serotonin
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Flushing occurs in a number of other diseases, including systemic mastocytosis, chronic
myeloid leukemia with increased histamine release, menopause, reactions to alcohol,
calcium channel blockers, nicotinic acid and VIPoma. None of these conditions cause
increased urinary 5‐HIAA.
Plasma chromogranin A levels may be elevated by all neuroendocrine tumors, and may
serve as a marker of tumor mass.
CT scan to assess the extent and localization of both primary and metastatic tumor of the
abdomen and chest and by imaging with radionuclide‐labeled somatostatin receptor
ligands.
Treatment
(1) Pharmacologic therapy for humorally mediated symptoms
(2) The reduction of tumor mass.
Somatostatin analogues Octreotide Somatostatin can prevent the flushing and other
endocrine symptoms of the carcinoid syndrome.
Surgery Given the slow progression of this neoplasm, effective reduction in tumor mass can
ameliorate morbidity and improve the quality of life even after metastases have occurred.
د
ﻋﻤﺮ
ﻓﺎروق
اﻟﻌﺰاوي
2014/2015