A 65-year-old woman with a history of type 2 diabetes, coronary artery
disease with congestive heart failure and nephropathy presented with severe,
intermittent, crampy abdominal pain and chronic constipation alternating with
diarrhea. She complained of a long history of subjective flushing, but denied
wheezing and palpitations. She was felt to have a possible bowel obstruction,
and an abdominal CT scan was performed that showed a mass near the terminal
The patients subjective flushing symptoms with an ileal mass
suggested a carcinoid tumor. A 24-hour urine 5-hydroxyindoleacetic acid
(5-HIAA) test was mildly elevated at 18.4 mg per day (normal range 2 mg to 8 mg
per day). Somatostatin receptor scintigraphy (SRS) with indium-111 octreotide
was performed. Standard anterior and posterior imaging was unrevealing due to
normal isotope trapping in the overlying normal bowel, liver and kidneys
(Figure 1). However, single-photon emission CT revealed an area of increased,
persistent radiotracer activity within the right side of the abdomen (Figure 2)
that localized to the area of the terminal ileum. There were no other areas of
isotope accumulation suggesting metastases. These findings are consistent with
a midgut carcinoid tumor of the small intestine.
Carcinoid tumors are amine precursor uptake and decarboxylation-omas
that arise from the enterochromaffin cells of the gastrointestinal tract. They
are neuroendocrine tumors that secrete several hormones and amines. In midgut
tumors, 5-hydroxytryptophan is converted by an enzyme dopa decarboxylase into
serotonin (5-hydroxytryptamine). Monoamine oxidase in the blood rapidly
converts serotonin to 5-HIAA, which can be measured by laboratory testing.
Other potentially bioactive molecules, including histamine, prostaglandins,
kallikrein and other polypeptides, can also be secreted.
Carcinoid tumors are well-circumscribed, round and submucosal masses
that can be classified according to embryologic origin into foregut (bronchial,
stomach, duodenum, biliary tract and pancreas), midgut (small intestine,
appendix and proximal colon) and hindgut (distal colon, rectum and
The estimated prevalence is about five per 100,000, but the true
prevalence is probably higher because many indolent tumors are found
incidentally, such as this case.
Gastrointestinal carcinoid tumors are the most common (64%), followed by
lung and bronchial tumors (28%). Of the gastrointestinal tumors, the ileum is
the most common site (45%), followed by the rectum (20%), appendix (16%), colon
(11%) and stomach (7%). WHO divides carcinoid tumors into four grades: well
differentiated; moderately differentiated; poorly differentiated; and
undifferentiated. Typical tumors with characteristic growth patterns are
classified as well-differentiated neuroendocrine tumors and are slow-growing.
Metastatic tumors are divided into well-differentiated and poorly
Stephanie L. Lee
Most gastrointestinal carcinoids are sporadic and have a loss of
heterozygosity of chromosome 18. Midgut not foregut or hindgut
carcinoid tumors contain the enzyme dopa decarboxylase, which converts
5-hydroxytryptophan into serotonin. Carcinoid tumors of the foregut and hindgut
are usually biologically inactive. Clinical features vary with the location of
the tumor, the products secreted and the presence of liver metastases. For
example, gastric carcinoids can be associated with chronic atrophic gastritis
(type 1), with Zollinger-Ellison syndrome or with multiple endocrine neoplasia
1 (type 2); they may also be sporadic (type 3).
Hindgut tumors rarely secrete serotonin and usually present with
bleeding or obstruction. Midgut or small intestinal tumors can secrete
serotonin, but the most common clinical presentation is a prolonged,
nonspecific abdominal discomfort. Serotonin is a mediator of fibrosis with
intense desmoplastic and fibrotic reactions in the mesentery seen in the area
of these tumors, which may result in abdominal pain or obstruction.
These tumors are frequently multiple, malignant and diagnosed late with
partial, small intestinal obstruction with intermittent cramps. When the tumor
is limited to a gastrointestinal location, biochemically, they are silent. The
venous drainage of the gut goes through the liver before returning to the
systemic circulation. The liver inactivates gastrointestinal carcinoid
secretory products, so the presence of the systemic carcinoid syndrome depends
on having both a secretory tumor and either liver metastases or an
extraintestinal location that allows bypass of the portal circulation.
The typical carcinoid syndrome occurs in 10% of patients and is most
often associated with midgut tumors. It is characterized by episodic flushing
of the face, neck and upper chest, as well as the presence of watery diarrhea.
As the disease progresses, the episodes of flushing may last more than 30
minutes. The prolonged vasodilation results in venous telangiectasia of the
nose, upper lip and malar regions. Bronchospasm, wheezing, tachycardia and
hypotension are less common. Up to 50% of patients with carcinoid syndrome
develop carcinoid heart disease. The fibrous plaque-like lesions most commonly
develop on the tricuspid valve and cause tricuspid regurgitation. Baseline and
repeated echocardiograms are useful in monitoring for the development of
disease. Advanced disease can cause pulmonary fibrosis and pleural thickening.
Release of peptides such as adrenocorticotropin-releasing hormone or growth
hormone-releasing factor may rarely cause Cushings syndrome, acromegaly
or other clinical syndromes.
Indium-111 octreotide scintigraphy. Standard
anterior and posterior gamma camera views after administration of indium-111
octreotide. The normal trapping of isotope in the normal overlying structures
of the liver, kidney and bowel prevent localization of the carcinoid tumor.
Arrows indicate location of kidneys.
Photos courtesy of: Stephanie L. Lee,
Single-photon emission CT images of the
indium-111 octreotide scan. Two adjacent tomographic images are shown. The
yellow area in the left side of the panel indicates the uptake of tracer into
the midgut carcinoid tumor located in the terminal ileum. The right side of the
panel shows isotope uptake into the carcinoid tumor at the intersection of the
crosshairs in the three orthogonal planes: coronal, sagittal and axial.
Carcinoid crisis is a potentially fatal complication that can develop in
patients during anesthesia induction after manipulation of a tumor mass or
after chemotherapy or hepatic artery embolization. Symptoms include flushing,
bronchoconstriction, hypotension or hypertension, and mental status changes
that last for several hours or days. Prophylaxis with octreotide is required
before such procedures.
Biochemical diagnosis of carcinoid syndrome is made with measurement of
the 24-hour urinary 5-HIAA, which has a sensitivity of 75% and a specificity of
100%. Malabsorption syndromes, such as celiac disease, small bowel obstruction,
ingestion of tryptophan-rich foods and several medications (See chart) can
alter the levels of 5-HIAA and should be avoided if possible before urine
collection. Even with this interference, generally, a secretory tumor is
associated with very high levels of 5-HIAA, between 99 mg and 2,070 mg per day.
Chromogranin A, proteins stored in neuroendocrine cells and whole blood
serotonin, are sensitive but nonspecific markers. In patients with flushing due
to carcinoid syndrome, the epinephrine provocation test will result in
transient flushing, hypotension and tachycardia. Other secretory products can
be measured if clinically indicated, such as gastrin and histamine.
SRS with indium-111-labeled somatostatin analogue octreotide can be used
to localize primary and metastatic tumors with a sensitivity of 73% to 90%. CT
or MRI scans can be used to assess the size and location of the primary or
metastatic tumors, calcifications and mesenteric fibrosis with a sensitivity of
more than 80%. False positives on SRS can occur with granulomas, thyroid
diseases and activated lymphocytes. Bronchial carcinoids are diagnosed by chest
X-ray and CT scans. Endoscopy may detect tumors that were not identified on
Localized disease can often be cured with surgical resection. Surgery is
an option for bronchial or ovarian tumors, for small bowel neoplasms to prevent
the desmoplastic reaction and in select cases for hepatic metastasis resection.
Medical treatment is generally effective for symptomatic treatment in
patients with extraintestinal or metastatic disease. Treatment can be
symptom-specific. For example, ondansetron is a serotonin antagonist and can be
used for refractory diarrhea, and histamine-secreting gastric carcinoids may
respond to a histamine blocker. If symptoms are more severe, somatostatin
analogues can be used.
Octreotide and lanreotide are well tolerated, available in
sustained-release form and can be titrated to symptom control. These
medications do not reduce the carcinoid size or slow the growth of the tumor.
Interferon-alpha may be used alone or in combination with octreotide, but its
use is limited by side effects. Chemotherapy and radiation have been used in
patients unresponsive to medical therapies without much success. Selective
ligation, embolization or chemoembolization of the branches of the hepatic
artery is an alternative treatment to metastatic hepatic lesions.
Prognosis is based on tumor size, location, histology and the presence
of carcinoid syndrome or metastatic disease. Median survival for patients with
metastases is 5 to 8 years, although those with severe carcinoid heart disease
have a 30% 5-year survival.
The patient presented underwent resection of the terminal ileum mass,
which was confirmed by pathology as a carcinoid tumor without liver lesions or
a documented carcinoid syndrome. Postoperatively, her 5-HIAA was lower within
the reference range at 11.2 mg per day. Her intermittent mild flushing,
constipation and diarrhea were unchanged postoperatively, suggesting that the
carcinoid tumor was not the cause of her gastrointestinal symptoms or
Varsha Vimalananda, MD, is a fellow in endocrinology; and Stephanie
L. Lee, MD, PhD, is professor of medicine and associate chief, both in the
section of endocrinology, diabetes and nutrition at Boston Medical Center.
For more information:
- Feldman JM. Clin Chem. 1986;32:840-844.
- Ghevariya V. So Med J. 2009;102:1032-1040.
- Janson ET. Ann Oncol. 1997;8:685-690.
- Jensen RT. Harrisons Principles of Internal Medicine. 17e:
- Sjoblom SM. Scand J Gastroenterol. 1988;23:779-787.