Small Intestine Chapter 50 1259

Carcinoids of the small bowel arise from enterochromaffin cells

(Kulchitsky cells), found in the crypts of Lieberkhn30; these
cells are also known as argentaffin cells because of their staining
by silver compounds. These tumors were first described by
Lubarsch in 1888; in 1907, Oberndorfer coined the term Karzinoide to indicate the carcinoma-like appearance and the presumed lack of malignant potential. Carcinoid tumors have been
reported in a number of organs, including most commonly the
lungs, bronchi, and gastrointestinal tract. Most patients with
small bowel carcinoids are in their fifth decade of life.
Carcinoids may be classified by the embryologic site of
origin and secretory product. Carcinoid tumors may be derived
from the foregut (respiratory tract, thymus), midgut (jejunum,
ileum and right colon, stomach, proximal duodenum), and
hindgut (distal colon, rectum). Foregut carcinoids characteristically produce low levels of serotonin (5-hydroxytryptamine) but
may secrete 5-hydroxytryptophan (5-HTP) or adrenocorticotropic hormone. Midgut carcinoids are characterized by having
high serotonin production. Hindgut carcinoids rarely produce
serotonin but may produce other hormones, such as somatostatin and peptide YY. The gastrointestinal tract is the most
common site for carcinoid tumors. After the appendix, the small
intestine is the second most frequently affected site in the gastrointestinal tract. In the small intestine, carcinoids almost
always occur within the last 2 feet of the ileum. Carcinoid
tumors have a variable malignant potential and are composed of
multipotential cells with the ability to secrete numerous humoral
agents, the most prominent of which are serotonin and substance P (Table 50-8). In addition to these substances, carcinoid
tumors have been found to secrete corticotropin, histamine,
dopamine, neurotensin, prostaglandins, kinins, gastrin, somatostatin, pancreatic polypeptide, calcitonin, and neuron-specific
enolase.
The primary importance of carcinoid tumors is the malignant potential of the tumors themselves. Although the carcinoid
syndrome, which is characterized by episodic attacks of cutaneous flushing, bronchospasm, diarrhea, and vasomotor collapse,
can occur and is dramatic in its most florid form, it occurs in
only a small percentage of patients with malignant carcinoids.
Pathology Carcinoid tumors may arise in organs derived from

the foregut, midgut, and hindgut. Seventy percent to 80% of

carcinoids are asymptomatic and found incidentally at the time
of surgery. In the gastrointestinal tract, more than 90% of carcinoids are found in three sitesappendix (45%), ileum (28%),
and rectum (16%; Table 50-9). The malignant potential (ability
to metastasize) is related to location, size, depth of invasion, and
growth pattern. Only approximately 3% of appendiceal carcinoids metastasize, but approximately 35% of ileal carcinoids are
associated with metastasis. Most (75%) gastrointestinal carcinoids are smaller than 1cm in diameter, and approximately 2%
of these are associated with metastasis. In contrast, carcinoid
tumors 1 to 2cm in diameter and larger than 2cm are associated with metastasis in 50% and 80% to 90% of cases,
respectively.
Grossly, these tumors are small, firm submucosal nodules
that are usually yellow on cut surface (Fig. 50-30). They may be
as subtle as a small whitish plaque seen on the antimesenteric
border of the small intestine. Typically, they are associated with
a larger mesenteric mass caused by nodal disease and

Table 50-8 Secretory Products of Carcinoid Tumors*

AMINES

TACHYKININS

PEPTIDES

OTHER

5-HT

Kallikrein

Pancreatic
polypeptide
(40%)

Prostaglandins

5-HIAA
(88%)

Substance P
(32%)

Chromogranins
(100%)

5-HTP

Neuropeptide K
(67%)

Neurotensin
(19%)

Histamine

HCG- (28%)

Dopamine

HCG-
Motilin (14%)

*Values in parentheses represent percentage frequency.

HCG, Human chorionic gonadotropin; 5-HIAA, 5-hydroxyindoleacetic acid;
5-HT, 5-hydroxytryptamine; 5-HTP, 5-hydroxytryptophan.

Table 50-9 Distribution of Gastrointestinal Carcinoids: Incidence of Metastases and of Carcinoid Syndrome
AVERAGE
METASTASIS
(%)

CASES OF
CARCINOID
SYNDROME

SITE

CASES

Esophagus

Stomach

93 (2%)

23

Duodenum

135 (4%)

20

Jejunoileum

1032 (28%)

34

91

Meckels
diverticulum

42 (1%)

19

Appendix

1686 (45%)

Colon

91 (2%)

60

Rectum

592 (16%)

18

Ovary

34

17

Biliary tract

10

30

Pancreas

Total

3718

136

Adapted from Cheek RC, Wilson H: Carcinoid tumors. Curr Probl Surg (Nov):431,
1970.

desmoplastic invasion of the mesentery, which is often mistaken

for the primary tumor. They tend to grow very slowly but, after
invasion of the serosa, the intense desmoplastic reaction produces mesenteric fibrosis, intestinal kinking, and intermittent
obstruction. Small bowel carcinoids are multicentric in 20% to
30% of patients. This tendency to multicentricity exceeds that
of any other malignant neoplasm of the gastrointestinal tract.
Another unusual observation is the frequent coexistence of a
second primary malignant neoplasm of a different histologic
type. This is usually a synchronous adenocarcinoma (most commonly in the large intestine) that can occur in 10% to 20% of
patients with carcinoid tumors. Carcinoid tumors are associated
with multiple endocrine neoplasia type 1 in approximately 10%
of cases.
Clinical Manifestations In the absence of carcinoid syndrome,
symptoms of patients with carcinoid tumors of the small bowel

SECTION X ABDOMEN

Carcinoid Tumors

1260 SECTION X ABDOMEN

FIGURE 50-30 Gross pathologic characteristics of carcinoid tumor. A, Carcinoid tumor of the distal ileum demonstrates the intense desmoplastic
reaction and fibrosis of the bowel wall. B, Mesenteric metastases from a carcinoid tumor of the small bowel. (Adapted from Evers BM, Townsend
CM Jr, Thompson JC: Small intestine. In Schwartz SI [ed]: Principles of surgery, ed 7, New York, 1999, McGraw-Hill, p 1245.)

are similar to those of patients with small bowel tumors of other

histologic types. The most common symptoms include abdominal pain, which is variably associated with partial or complete
small intestinal obstruction. Obstructive symptoms can be
caused by intussusception but usually occur secondary to a local
desmoplastic reaction, apparently produced by humoral agents
elaborated by the tumor. Diarrhea and weight loss may also
occur. The diarrhea is a result of a partial bowel obstruction
rather than the secretory diarrhea noted in patients with the
malignant carcinoid syndrome. As mesenteric and nodal extension progress, local venous engorgement and ultimately ischemia
of the affected segment of intestine contribute to most symptoms and complications related to the tumor.
Malignant Carcinoid Syndrome The malignant carcinoid syn-

drome is a relatively rare disease, occurring in fewer than 10%

of patients with carcinoid tumors. The syndrome is usually
associated with carcinoid tumors of the gastrointestinal tract,
particularly from the small bowel, but carcinoids in other locations, such as the bronchus, pancreas, ovary, and testes, have also
been described in association with the syndrome. Because of the
first-pass metabolism of the vasoactive peptides responsible for
carcinoid syndrome, hepatic metastasis or extra-abdominal
disease is necessary to elicit the syndrome. The classic description
of the carcinoid syndrome typically includes vasomotor, cardiac,
and gastrointestinal manifestations. A number of humoral
factors are produced by carcinoid tumors, but those considered
to contribute to the carcinoid syndrome include serotonin,
5-HTP (a precursor of serotonin synthesis), histamine, dopamine, kallikrein, substance P, prostaglandin, and neuropeptide
K. Most patients who exhibit malignant carcinoid syndrome
have massive hepatic replacement by metastatic disease. However,
tumors that bypass the liver, specifically ovarian and retroperitoneal carcinoids, may produce the syndrome in the absence of
liver metastasis.

Common symptoms and signs include cutaneous flushing

(80%), diarrhea (76%), hepatomegaly (71%), cardiac lesions,
most commonly right heart valvular disease (41% to 70%), and
asthma (25%). Cutaneous flushing in the carcinoid syndrome
may be of four varieties:
1. Diffuse erythematous, which is short-lived and normally
affects the face, neck, and upper chest
2. Violaceous, which is similar to a diffuse erythematous flush
except that the attacks may be longer and patients may
develop a permanent cyanotic flush, with watery eyes and
injected conjunctivae
3. Prolonged flushes, which may last up to 2 to 3 days and
involve the entire body, and may be associated with profuse
lacrimation, hypotension, and facial edema and
4. A bright-red patchy flushing, typically seen with gastric
carcinoids
The diarrhea associated with carcinoid syndrome is episodic (usually occurring after meals), watery, and often explosive. Increased circulating serotonin levels are thought to be the
cause of the diarrhea because the serotonin antagonist methysergide effectively controls the symptom. Cardiac lesions of carcinoid tumors mainly involve the right side of the heart and are
usually limited to the tricuspid and pulmonary valves. The
three most common cardiac lesions are pulmonary stenosis
(90%), tricuspid insufficiency (47%), and tricuspid stenosis
(42%). Asthmatic attacks are usually observed during the flushing symptom, and serotonin and bradykinin have been implicated in this symptom. Malabsorption and pellagra (dementia,
dermatitis, and diarrhea) are occasionally present and are
thought to be caused by excessive diversion of dietary
tryptophan.
Diagnosis The elevation of various humoral factors forms the
basis for diagnostic tests in patients with carcinoid tumors and
the carcinoid syndrome. Carcinoid tumors produce serotonin,

Small Intestine Chapter 50 1261

SECTION X ABDOMEN

which is then metabolized in the liver and the lung to the pharmacologically inactive 5-hydroxyindoleacetic acid (5-HIAA).
Elevated urinary levels of 5-HIAA measured over 24 hours with
high-performance liquid chromatography are highly specific,
although not sensitive. A potentially useful marker of neuroendocrine tumors is the plasma concentration of chromogranin A,
a protein made in the secretory granules, which is elevated in
more than 80% of patients with carcinoid tumors. Although
recent reports have proposed chromogranin A levels to be the
test of choice for the diagnosis of carcinoid, the lack of specificity
for this test limits its usefulness as a sole marker. It appears that
the combination of 24-hour urine 5-HIAA and serum chromogranin A levels provides the best biochemical diagnostic accuracy. In terms of surveillance after resection or as a marker to
monitor response to therapy, chromogranin A levels have proven
efficacy over urine 5-HIAA levels. Plasma serotonin, substance
P, neurotensin, neurokinin A, and neuropeptide K levels can be
measured, but these peptides may not be elevated in all patients.
Provocative tests using pentagastrin, calcium, or epinephrine
may be used to reproduce the symptoms of carcinoid tumors.
The administration of pentagastrin is the safest, most reliable,
and most frequently used; however, with the accuracy of current
diagnostic tests, there are relatively few indications today for
provocative tests.
Carcinoid tumors of the small intestine are rarely diagnosed preoperatively. Barium radiographic studies of the small
bowel may exhibit multiple filling defects as a result of kinking
and fibrosis of the bowel (Fig. 50-31). There are a number of
imaging techniques used to diagnose the extent and spread of
carcinoid tumors. As CT technology has continued to progress,
CT scanning has become the imaging modality of choice for
identifying the site of disease and the presence of lymphatic or
hematogenous metastases. CT angiography may be useful in
cases associated with a large mesenteric process to identify
encasement and pseudoaneurysm formation, typical of a malignant process in the mesentery. A novel imaging study that takes
advantage of the fact that many of these tumors possess somatostatin receptors is somatostatin receptor scintigraphy using
111
In-labeled pentetreotide. This scintigraphic localization study
has shown encouraging results, with a higher reported sensitivity than conventional imaging techniques, such as CT, for
delineating and localizing carcinoid tumors. In particular,
somatostatin receptor scintigraphy is the test of choice to identify extra-abdominal metastatic disease or in cases in which the
primary cannot be appreciated on CT scan. Although CT scanning and somatostatin receptor scintigraphy (SRS) are the predominant modalities for carcinoid tumor localization and
staging, MRI is emerging as a potential adjunct to these current
imaging techniques. When directly compared with CT or SRS,
MRI has shown enhanced sensitivity for hepatic metastases
evaluation. Unfortunately, MRI has not improved the ability to
identify extrahepatic disease and remains constrained by institutional expertise. 18F-fluorodeoxyglucose positron emission
tomography (FDG-PET) scanning, although important in the
evaluation of other malignancies, has not proven beneficial for
carcinoids. However, the addition of newer isotopes such as
11
C5-HTP and 18F-L-dihydroxyphenylalanine (18F-DOPA)
has dramatically improved the sensitivity of PET for neuroendocrine malignancies and, when fused with conventional CT
scanning, may ultimately outperform the current accepted
imaging modalities.31

FIGURE 50-31 Barium radiograph of a carcinoid tumor of the terminal ileum demonstrates fibrosis with multiple filling defects and highgrade partial obstruction (arrows). (Courtesy Dr. Melvyn H. Schreiber,
The University of Texas Medical Branch, Galveston, Tex.)

Treatment
Surgical Therapy The treatment of patients with small bowel

carcinoid tumors is based on tumor size and site and presence

or absence of metastatic disease.30 For primary tumors smaller
than 1cm in diameter without evidence of regional lymph node
metastasis, a segmental intestinal resection is adequate. For
patients with lesions larger than 1cm, with multiple tumors, or
with regional lymph node metastasis, regardless of the size of the
primary tumor, wide excision of bowel and mesentery is required.
Lesions of the terminal ileum are best treated by right hemicolectomy. Small duodenal tumors can be excised locally; however,
more extensive lesions may require pancreaticoduodenectomy.
In addition to treatment of the primary tumor, it is important
that the abdomen be thoroughly explored for multicentric
lesions. In cases in which the mesenteric disease appears to
involve a large portion of the mesentery, dissection of the tumor
off the mesenteric vessels, with preservation of the blood supply
to unaffected bowel, is appropriate, albeit technically demanding. Not only does removal of the mesenteric disease provide a

1262 SECTION X ABDOMEN

significant survival advantage, but also mesenteric debulking
ensures the most durable palliation for the patient.
Caution should be exerted in the anesthetic management
of patients with carcinoid tumors because anesthesia may precipitate a carcinoid crisis characterized by hypotension, bronchospasm, flushing, and tachycardia predisposing to arrhythmias.
The treatment of carcinoid crisis is IV octreotide given as a bolus
of 50 to 100g, which may be continued as an infusion at
50g/hour. In addition, IV antihistamine and hydrocortisone
may be of some benefit.
In patients with carcinoid tumors and widespread metastatic disease, surgery is still indicated. In contrast to metastases
from other tumors, there is a definite role for surgical debulking,
which often provides beneficial symptomatic relief. In patients
with limited hepatic involvement, metastasectomy has been
shown to provide the most durable survival benefit when compared with other treatment modalities. Unfortunately, most
patients are not candidates for liver resection because of extensive disease; recurrence after metastasectomy occurs in up to
75% of patients. In these cases, transarterial chemoembolization
or radioembolization has been shown to provide liver-directed
control of disease. Furthermore, resection of the primary tumor,
with or without mesenteric resection, has been shown to improve
survival and slow progression of hepatic metastases in patients
with unresectable disease. Although there have been some small
series of hepatic transplantation for extensive liver metastases
from carcinoid, unacceptably high recurrence rates limit this
approach.
Medical Therapy Medical therapy for patients with malignant
carcinoid syndrome is primarily directed toward the relief of
symptoms caused by the excess production of humoral factors.30
Various long-acting analogues of somatostatin, such as octreotide (Sandostatin) or the slow-release formulation (Sandostatin
LAR), relieve symptoms of the carcinoid syndrome (e.g., diarrhea, flushing) in most patients. In addition to the relief of
symptoms using octreotide, tumor regression has been reported
in some patients. A randomized controlled trial of 85 patients
with unresectable metastatic midgut carcinoid compared treatment with Sandostatin LAR to placebo.32 A significant improvement in progression-free survival was seen and was most
pronounced in patients with a resected primary tumor and/or
low hepatic burden.
Recently, second-generation right hemicolectomy somatostatin analogues have been developed to address the limitations of the current regimens. Pasireotide represents an important
advance in current biologic therapy. With its broad somatostatin
receptor inhibition and up to 40-fold increase in binding affinity, as compared with current somatostatin analogues, pasireotide my have a role as primary therapy or salvage therapy for
patients who fail treatment on first-generation somatostatin
therapy.33 Interferon- (IFN-) has also been shown to provide
symptomatic relief in patients with carcinoid syndrome. A clinical trial that evaluated the use of IFN- in more than 100
patients with carcinoid syndrome identified decreases in urinary
5-HIAA levels in 42% of patients and tumor regression in 15%.
However, the increased incidence of side effects (e.g., fever,
fatigue, anorexia, weight loss) precludes the widespread use of
this drug.
Serotonin receptor antagonists have been used with limited
success. Methysergide is no longer used because of the increased

incidence of retroperitoneal fibrosis. Ketanserin and cyproheptadine have been shown to provide some control of symptoms
and other antagonists, such as ondansetron, may be even more
effective.
Given the slow-growing nature of carcinoid, cytotoxic chemotherapy has had only limited success. The role of chemotherapy is confined predominantly to patients with metastatic
disease who are symptomatic, unresponsive to other therapies,
or have high tumor proliferation rates. The most frequent combination used is streptozotocin plus 5-fluorouracil or cyclophosphamide, which may result in some tumor regression in up to
one third of the patients. The duration of response, however, is
short-lived. The use of cisplatin and etoposide has shown some
promise only in patients with well-differentiated carcinoids.
Results using dacarbazine (DTIC) are conflicting.
In summary, the treatment of metastatic carcinoid tumors
requires a multidisciplinary approach and combined modalities
may be the best option, including surgical debulking, hepatic
artery embolization or chemoembolization, and medical therapy.
In addition, newer and more targeted therapies are being developed that may be useful in the future. Targeted therapy has
progressed down four separate pathways. Given the hypervascular nature of carcinoids, antiangiogenesis therapy (e.g., bevacizumab) is being investigated in combination with cytotoxic and
somatostatin therapy.34 Based on the benefit of sunitinib seen in
pancreatic neuroendocrine tumors, tyrosine kinase inhibitors
have been evaluated as systemic therapy and as a liver-directed
chemoembolization strategy for carcinoids as well. The PI3KAKT-mTOR pathway has also recently emerged as a potential
target for systemic therapy. Agents such as everolimus, an
mTOR inhibitor, although initially developed as immunosuppressant therapy, have redefined themselves as potent antitumor
agents and remain under active investigation for carcinoid
disease. Perhaps the most promising targeted therapy to date is
radiolabeled somatostatin analogue therapy. In a series of over
500 patients with gastrointestinal neuroendocrine tumors
including carcinoid, [177Lu-DOTA0,Tyr3]octreotate was well tolerated and provided significant improvements in response rates
and overall survival when compared with historical controls.35
Prognosis Carcinoid tumors have the best prognosis of all small
bowel tumors, whether the disease is localized or metastatic.
Resection of a carcinoid tumor localized to its primary site
approaches a 100% survival rate. Five-year survival rates are
approximately 65% in patients with regional disease and 25%
to 35% in those with distant metastasis. When widespread metastatic disease precludes cure, extensive resection for palliation is
indicated. In fact, long-term palliation often can be obtained
because these tumors are relatively slow-growing. A number of
factors have been evaluated in an attempt to identify patients
with carcinoid tumors who have a poor prognosis. Probably the
most useful factor identified is an elevated level of chromogranin
A, which was found to be an independent predictor of an
adverse prognosis.
Adenocarcinomas

Adenocarcinomas traditionally have constituted approximately

50% of the malignant tumors of the small bowel in most
reported series, although the incidence has plateaued in recent
years.29 The peak incidence is in the seventh decade of life, and
most series show a slight male predominance. Most of these