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GENERAL SURGERY BOARD REVIEW MANUAL
PUBLISHING STAFF
PRESIDENT, GROUP PUBLISHER
Bruce M. White
EXECUTIVE EDITOR
Debra Dreger
SENIOR EDITOR
Miranda J. Hughes, PhD
ASSISTANT EDITOR
Rita E. Gould
EDITORIAL ASSISTANT
Kara V. Warner
Gastrointestinal Carcinoid
Tumors: Case Studies
Series Editor and Contributing Author:
Christopher R. McHenry, MD, FACS, FACE
Associate Professor of Surgery, Case Western Reserve University School of
Medicine, Director, Division of General Surgery, MetroHealth Medical
Center, Cleveland, OH
Contributing Author:
Elizabeth A. Mittendorf, MD
Staff Surgeon, Malcolm Grow Medical Center, Andrews Air Force Base, MD
EXECUTIVE VICE PRESIDENT
Barbara T. White, MBA
PRODUCTION DIRECTOR
Suzanne S. Banish
PRODUCTION ASSOCIATES
Table of Contents
Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
Tish Berchtold Klus
Mary Beth Cunney
Gastric Carcinoid Tumors . . . . . . . . . . . . . . . . . . . . . . . . 2
PRODUCTION ASSISTANT
Duodenal Carcinoid Tumors . . . . . . . . . . . . . . . . . . . . . . 4
Stacey Caiazzo
ADVERTISING/PROJECT MANAGER
Patricia Payne Castle
Jejunoileal Carcinoid Tumors. . . . . . . . . . . . . . . . . . . . . . 4
Appendiceal Carcinoid Tumors . . . . . . . . . . . . . . . . . . . . 5
Colonic Carcinoid Tumors . . . . . . . . . . . . . . . . . . . . . . . . 6
NOTE FROM THE PUBLISHER:
This publication has been developed without
involvement of or review by the American
Board of Surgery.
Endorsed by the
Association for Hospital
Medical Education
The Association for Hospital Medical Education
endorses HOSPITAL PHYSICIAN for the purpose of presenting the latest developments in
medical education as they affect residency programs and clinical hospital practice.
Rectal Carcinoid Tumors . . . . . . . . . . . . . . . . . . . . . . . . . 6
Carcinoid Syndrome. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Treatment of Advanced and Metastatic
Carcinoid Tumors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Board Review Questions . . . . . . . . . . . . . . . . . . . . . . . . . 9
Detailed Answers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Cover Illustration by Joe Wilder, MD
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General Surgery Volume 7, Part 4 1
®
GENERAL SURGERY BOARD REVIEW MANUAL
Gastrointestinal Carcinoid Tumors:
Case Studies
Series Editor and Contributing Author:
Christopher R. McHenry, MD, FACS, FACE
Contributing Author:
Elizabeth A. Mittendorf, MD
Associate Professor of Surgery
Case Western Reserve University School of Medicine
Director, Division of General Surgery
MetroHealth Medical Center
Cleveland, OH
Staff Surgeon
Malcolm Grow Medical Center
Andrews Air Force Base, MD
I. INTRODUCTION
Carcinoid tumors are a heterogeneous group of neuroendocrine tumors that can arise in any organ originating from the endoderm. They arise from enterochromaffin or enterochromaffin-like cells (in the amine
precursor uptake and decarboxylation system) with the
potential to produce several different biologically active
amines and peptides. Serotonin is the best known of
these biologically active substances. Carcinoid tumors
may also secrete corticotropin, histamine, dopamine, substance P, neurotensin, prostaglandins, and kallikrein.1
The release of vasoactive substances into the systemic circulation is responsible for the development of the carcinoid syndrome, which is a marker of advanced disease
(see Section VIII.).
The incidence of carcinoid tumors is 1 to 2.5 per
100,000 annually; they are most commonly found in the
bronchial tree and the gastrointestinal (GI) tract.1 – 4
Figure 1 depicts the anatomic location of carcinoid tumors as identified in review of the National Cancer
Institute’s Surveillance, Epidemiology, and End Results
(SEER) database, which accumulated data from 1973 to
1991. In the small intestine and appendix, carcinoid
2 Hospital Physician Board Review Manual
tumors account for approximately 33% and 77% of all
tumors, respectively.2,5 In organs such as the colon, stomach, and lung that develop tumors more frequently, carcinoid tumors make up only 1% of tumors.2
Carcinoid tumors have traditionally been classified
according to their presumed derivation from different
embryonic divisions of the GI tract. Foregut carcinoid
tumors originate in the lungs, bronchi, stomach, or duodenum; midgut tumors in the small intestine, appendix,
and proximal large intestine; and hindgut tumors in the
distal colon and rectum.6 The biologic and clinical characteristics vary within these groups. This review will
examine GI carcinoid tumors by location including the
stomach, duodenum, small intestine, appendix, colon,
and rectum. The carcinoid syndrome will also be reviewed. Two case patients are presented to emphasize
clinical features and management issues. Sample board
review questions with detailed answers are provided at
the end of this manual for self-assessment.
II. GASTRIC CARCINOID TUMORS
Carcinoid tumors of the stomach are uncommon,
accounting for 0.54% of all gastric malignancies and
Gastrointestinal Carcinoid Tumors
ZOLLINGER-ELLISON SYNDROME–ASSOCIATED TUMORS
Tumors associated with Zollinger-Ellison syndrome
account for 5% to 10% of gastric carcinoids.16 Like those
associated with CAG-A, these tumors are probably caused
by gastrin-induced hyperplasia of enterochromaffin-like
cells.16 Of note, they occur almost exclusively with
Zollinger-Ellison syndrome in association with multiple
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CHRONIC ATROPHIC GASTRITIS TYPE A–ASSOCIATED
TUMORS
Tumors associated with CAG-A account for 65% to
75% of gastric carcinoids.1,8 A substantial number of patients with CAG-A–associated carcinoid tumors also have
pernicious anemia.9–11 CAG-A–associated carcinoid tumors are more common in women and usually present
in the sixth or seventh decade.1 Symptoms caused by
hormone overproduction are rare, and the diagnosis is
usually made endoscopically during evaluation for anemia or vague abdominal pain.8,9
These tumors are usually small and multifocal, located in the body or fundus of the stomach.8,9 This location
and multifocal nature are explained by their origin from
enterochromaffin-like cells that exist in the gastric fundus.
Patients with CAG-A usually have hypochlorhydria and
hypergastrinemia; this gastrin hypersecretion has been
postulated to result in hyperplasia of enterochromaffinlike cells. These hyperplastic lesions may then develop
into carcinoid tumors.1,12 This hypothesis is supported by
studies in the ratshowing that carcinoid tumors occurred
when hypergastrinemia was induced by administration of
a proton-pump inhibitor.13
CAG-A–associated carcinoid tumors usually follow a
benign clinical course. Successful treatment by endoscopic resection is possible for lesions less than 1 cm in
diameter. Patients with larger, multiple, or recurrent
tumors may require more extensive surgical resection.
Antrectomy to remove the source of gastrin has been
reported to result in tumor regression in some cases;
however, the long-term benefits are uncertain.10,14,15
Metastatic spread to regional lymph nodes occurs in
less than 10% of cases. Although local recurrences have
been reported, recent series report no deaths from the
disease in treated patients. The 5-year survival rate
approaches 100%.9,14
36
Lu
6% of all GI carcinoid tumors.7 Gastric carcinoid tumors can be divided into 3 groups based on clinical and
histologic characteristics: those associated with chronic
atrophic gastritis type A (CAG-A), those associated with
the Zollinger-Ellison syndrome, and those that are sporadic.
Figure 1. The anatomic distribution for carcinoid tumors.
endocrine neoplasia type 1. It is thought that prolonged
hypergastrinemia in combination with genetic susceptibility is required for the development of these lesions.1,8
The location, treatment, and long-term prognosis of
carcinoid tumors associated with Zollinger-Ellison syndrome are similar to those associated with CAG-A. Removal of the source of gastrin is accomplished by excision of the gastrin-producing tumors.
SPORADIC TUMORS
Sporadic tumors account for 15% to 25% of gastric
carcinoids and are more common in men.1,8,16 These
lesions tend to be larger than 1 cm in diameter, are usually solitary, and are composed of a mixture of endocrine cells. Precursor lesions in the gastric mucosa are
lacking.1,8 Unlike carcinoid tumors associated with
CAG-A and Zollinger-Ellison syndrome, sporadic gastric
carcinoid tumors usually follow a more aggressive course
with lymph node and liver metastases frequently present
at the time of presentation. In a review of gastric carcinoids by Kirshbom and colleagues, distant metastases
were noted at presentation in 60% of patients with sporadic tumors.17 Endocrine symptoms, particularly histamine-mediated flushing, are frequent.10 Other symptoms referable to overproduction of histamine—such as
hypotension, lacrimation, cutaneous edema, and bronchoconstriction—may also be seen. Increased urinary
secretion of methyl-imidazole-acetic acid, the primary
General Surgery Volume 7, Part 4 3
Gastrointestinal Carcinoid Tumors
Figure 2. Computed tomograph of patient 1’s abdomen demonstrating a 2.5-cm solid mass (arrow) just medial to the cecum and
posterior to a distal ileal loop. P = posterior; R = right.
histamine metabolite, can be demonstrated.18 Treatment of these aggressive lesions is usually by gastrectomy.
The 5-year survival rates are reported to be 52%.1,8
Figure 3. Resected ileum from patient 1. This 8-cm segment of
ileum contains a 0.6-cm whitish discoloration (black arrow) and a
3.5-cm mass (white arrows) in the mesenteric fat corresponding
to the mass seen on computed tomography in Figure 2.
III. DUODENAL CARCINOID TUMORS
IV. JEJUNOILEAL CARCINOID TUMORS
Duodenal carcinoids, also of foregut origin, are extremely rare, accounting for only 2% to 3% of GI carcinoids.4,8 They are more common in men and usually
present in the sixth decade.19 The most common presenting symptoms are abdominal pain and bleeding.
Duodenal carcinoid tumors are frequently polypoid
lesions identified by flexible endoscopy performed for
the evaluation of upper GI bleeding.2,19 Other symptoms include obstruction of the common bile duct
resulting in jaundice. Approximately 10% are incidentally identified.19
Duodenal carcinoids may secrete gastrin, calcitonin,
or somatostatin.2,8 Levels of serotonin and its primary
metabolite 5-hydroxyindoleacetic acid (5-HIAA) are
low, and development of the carcinoid syndrome is
rare.19 Most of these tumors follow a benign course.
Although regional lymph node metastases have been
reported, more than 70% of duodenal carcinoid tumors are localized at the time of presentation.19 They
are usually solitary, small, and can be removed endoscopically. At the time of excision, endoluminal ultrasonography can be used to assess for the depth of invasion.2 Full-thickness wall excision or resection is rarely
necessary.20 Ten-year survival rates are reported to be
approximately 60%.17,19
4 Hospital Physician Board Review Manual
CASE PATIENT 1
Patient 1 is a 49-year-old healthy man who presents
with a 7-day history of persistent sharp right-sided periumbilical pain and a 3-day history of loose bowel movements. He denies fever, nausea, vomiting, or weight loss.
A computed tomographic (CT) scan shows a 2.5-cm
mass posterior to a distal ileal loop that is suspicious for
tumor (Figure 2). Patient 1 undergoes an exploratory
laparotomy, and a 0.6-cm whitish discoloration is identified in the serosal surface of the distal ileum. A 3.5-cm
mass corresponding to the lesion seen on CT is identified
within the mesenteric fat of the distal ileum. The patient
undergoes en bloc resection of an 8-cm segment of ileum
containing the primary tumor and the adjacent mesentery containing the metastatic nodal disease (Figure 3).
No hepatic metastases are identified. Final pathology reveals a 1.9-cm carcinoid tumor with extension through
the serosa and into the mesenteric fat with 2 of 5 lymph
nodes involved with metastatic carcinoid tumor. Postoperatively, the patient’s diarrhea resolves, and he denies
any other symptoms consistent with carcinoid syndrome.
Patient 1 is then followed for 3 years without evidence of
recurrent disease.
Gastrointestinal Carcinoid Tumors
DISCUSSION
The jejunum and ileum are the most common sites
for GI carcinoid tumors, accounting for approximately
30% of all tumors.4 They are thought to arise from
serotonin-producing intraepithelial endocrine cells. Foci
of hyperplastic intraepithelial endocrine cells have been
reported, but the cause of this hyperplasia is unknown.1
These tumors are found with increasing frequency from
the jejunum to the ileum, with most occurring in the distal one third of the small bowel. Small bowel carcinoids
are multiple in 29% to 41% of patients and are associated with an adenocarcinoma elsewhere in the GI tract
in 8% to 29% of patients.4,21–23 This distribution underscores the importance of a thorough exploration of the
entire small and large intestine at the time of surgical
therapy. Modlin and colleagues analyzed the SEER data
where 13% of all carcinoid tumors were associated with
other noncarcinoid tumors.4 They suggested regular surveillance of the colon and rectum, small intestine, and
lung in all patients as well as regular surveillance of the
cervix and ovaries in women diagnosed with a carcinoid
tumor in the small intestine, appendix, or colon.4 These
associated noncarcinoid tumors may present as a metachronous lesion in up to 10% of patients.3
Presentation
In general, patients with a small bowel carcinoid
tumor present with vague complaints; standard imaging
techniques, such as computed tomography and small
bowel contrast studies, are of limited value in identifying the primary tumor. The diagnosis of small bowel
carcinoid is therefore difficult to make preoperatively.1,24 Most patients with small bowel carcinoids present
in the sixth or seventh decade, typically with abdominal
pain. The pain is often intermittent and colicky in nature and is associated with a small bowel obstruction.
This obstruction most commonly results from bowel
involvement in a dense, fibrotic, desmoplastic reaction
that causes shortening of the mesentery with resultant
bowel kinking, angulation, and subsequent obstruction. The size of the primary tumor or peritoneal carcinomatosis may also cause obstruction. If not the result
of obstruction, the pain may be caused by ischemia,
which results from vascular compromise secondary to
large bulky mesenteric nodal disease or from serotonininduced elastic microvascular sclerosis.25 Approximately
5% to 7% of patients with small bowel carcinoids will
present with carcinoid syndrome. GI blood loss is an
uncommon presenting complaint or clinical feature of
small bowel carcinoids. In contrast, GI blood loss is the
cause for investigation in gastric, colonic, and rectal carcinoids in 38%, 33% and 40% of cases, respectively.3
Diagnosis and Treatment
Because early stage disease has a lack of distinctive
symptoms, patients tend to present with later stage disease, which decreases survival. In a review of 184 patients
with small bowel carcinoids, Onaitis and colleagues found
that 42 (22%) had localized disease, 37 (20%) had regional lymph node metastases, and 105 (57%) had distant metastases at the time of diagnosis.19 The likelihood
of metastases is generally thought to depend on the size
of the primary lesion. Tumors smaller than 1 cm in diameter have a 20% to 30% incidence of nodal and hepatic
metastases. Tumors between 1 and 2 cm have a 60% to
80% incidence of nodal metastases and a 20% incidence
of hepatic metastases. Tumors larger than 2 cm in diameter have a greater than 80% incidence of nodal metastases
and a 40% to 50% incidence of hepatic metastases.25,26
The presence of metastatic disease affects the 5-year survival of patients with small bowel carcinoids, which is 50%
to 68% overall.3,4,8,24 In patients with localized disease, the
5-year survival rate is 75%. With spread to regional lymph
nodes, the 5-year survival is 59% to 65% and with distant
metastases, the 5-year survival is 20% to 36%.1,24 Studies
have shown that jejunoileal carcinoids have the worst
prognosis,3 which has been attributed to their more
aggressive behavior with an increased incidence of metastatic disease and to diagnostic delay caused by the lack of
distinctive symptoms.
Surgical management of patients with small bowel
carcinoids involves extended resection including the
primary tumor and the mesentery with relevant lymph
node drainage. Even in the presence of distant metastases, resection can help ameliorate endocrine symptoms.2,27
V. APPENDICEAL CARCINOID TUMORS
GENERAL PRINCIPLES
The appendix is the second most common site of
involvement in the GI tract, accounting for 26% of GI carcinoid tumors.1,4 Carcinoid tumors are the most common
malignant tumor of the appendix. In contrast to other GI
carcinoids that are of mucosal origin, appendiceal carcinoids arise from subepithelial neuroendocrine cells present in the lamina propria and submucosa of the wall of
the appendix.28 These subepithelial neuroendocrine cells
are more numerous at the tip of the appendix, which is
consistent with the observation that 70% to 80% of
appendiceal carcinoids occur in this location.29 The density of subepithelial neuroendocrine cells has been found
to be low in infancy, increasing with age and peaking in
General Surgery Volume 7, Part 4 5
Gastrointestinal Carcinoid Tumors
the third decade, after which it slowly declines. Several
authors have suggested that this may explain why appendiceal carcinoids present at a relatively early age compared with carcinoids at other sites. They have postulated
that appendiceal carcinoids may regress with age as the
subepithelial neuroendocrine cells regress.30,31
DIAGNOSIS AND TREATMENT
Appendiceal carcinoid tumors are usually diagnosed
in the fourth or fifth decade. Review of the SEER data
revealed an average age of 42.2 years at the time of diagnosis for appendiceal carcinoids versus 62.9 years for all
other GI carcinoid tumors.29 In addition to the higher
density of subepithelial neuroendocrine cells, the earlier age of diagnosis of appendiceal carcinoid likely reflects the fact that appendectomies are most frequently
performed in young adults.1 Appendiceal carcinoids are
more common in women, probably because of a higher
rate of incidental appendectomy.32 In 50% to 60% of
patients, appendiceal carcinoids are found incidentally
whereas the other 40% to 50% present with acute
appendicitis.3,8
As previously observed, most appendiceal carcinoids
occur at the tip of the appendix. Less often, they present within the body (5% to 21%), base (7% to 10%),
or diffusely (1.5% to 3.5%). At the time of diagnosis,
60% to 76% of these carcinoids are less than 1 cm in
diameter, 4% to 27% are 1 to 2 cm, and 2% to 17% are
larger than 2 cm.30,32 Tumor size has been correlated
with metastatic potential. Tumors less than 1 cm never
metastasize, and tumors between 1 and 2 cm rarely metastasize (0% to 11%). Tumors larger than 2 cm are
associated with regional or distant metastases 30% to
60% of the time.29 These data have implications for the
surgical management of these tumors. In general, tumors less than 1 cm in diameter are treated with appendectomy alone, whereas tumors greater than 2 cm
in diameter are treated with right hemicolectomy.
Treatment of tumors between 1 and 2 cm in diameter is more controversial and should be individualized
based on tumor characteristics. A right hemicolectomy
should be performed when there is angio-invasion or
subserosal lymphatic invasion, involvement of the mesoappendix, or lymph node metastases.21,32,33 A right hemicolectomy is also indicated to avoid residual tumor or
recurrence for carcinoid tumors at the base of the appendix or with involvement of the surgical margin or
cecum.25,33 Associated, noncarcinoid tumors are seen in
15% of patients with carcinoid tumors of the appendix.29
Carcinoid tumors of the appendix have an overall
5-year survival rate of 85.9% compared with 54% for all
other carcinoid tumors of the GI tract.29 The better prog-
6 Hospital Physician Board Review Manual
nosis for appendiceal tumors may reflect the earlier identification of carcinoid tumors of the appendix. According to the SEER data, 64.6% of appendiceal carcinoids
were localized at the time of diagnosis. The 5-year survival rate is 94% for localized tumors, 84.6% for regional
invasion, and 33.7% for distant metastases.29
VI. COLONIC CARCINOID TUMORS
Colonic carcinoids are uncommon tumors accounting for less than 1% of all colonic tumors and approximately 5% of GI carcinoids.1,8 Like small bowel carcinoids, colonic carcinoids arise from serotonin-producing
epithelial endocrine cells. These tumors decrease in frequency from the right colon to the left colon; most are
found in the cecum.1,2,19
Colonic carcinoids present most commonly in the
seventh decade, and most patients are symptomatic.
Presenting signs and symptoms include pain, anorexia,
weight loss, and GI bleeding. Colonic obstruction has
also been reported.19 Patients presenting with these complaints often undergo colonoscopic evaluation or a contrast study that can diagnose a lesion. CT scans can be
useful for assessing the presence of metastatic disease.21
At the time of diagnosis, the average tumor size is 5 cm
in diameter, and more than 66% of patients have nodal
or distant metastases present at diagnosis.34,35 Despite the
presence of hepatic metastases, less than 5% present
with hormonal symptoms.1,21,35 Between 25% and 40%
of patients have a second, noncarcinoid malignancy.21,34
Surgical therapy for colonic carcinoids involves resection of the affected segment of the colon and its lymphatic drainage, which is the same as for adenocarcinoma of the colon. Like carcinoids at other locations
within the GI tract, 5-year survival is determined by the
extent of disease at the time of diagnosis. The
5-year survival rates are 70% for patients with local disease, 44% for those with regional metastases, and 20%
for those with distant metastases.4
VII. RECTAL CARCINOID TUMORS
CASE PATIENT 2
Patient 2 is a 78-year-old man with a medical history
pertinent for hypertension and non–insulin-dependent
diabetes mellitus who presents with a 2-week history of
rectal bleeding. Colonoscopy is performed and identifies a 3-cm lesion approximately 9 cm from the anal
verge. Biopsy is consistent with a carcinoid tumor. A CT
Gastrointestinal Carcinoid Tumors
scan shows multiple liver metastases (Figure 4). The
patient denies symptoms suggestive of carcinoid syndrome. He undergoes a low anterior resection of the
rectum. The final pathology reveals a carcinoid tumor
with ulceration and necrosis. Metastases are present in
35 out of 40 lymph nodes. Because patient 2 is asymptomatic, no adjuvant therapy is recommended.
DISCUSSION
Rectal carcinoids account for between 1% and 2% of
all rectal tumors and 12.6% of all GI carcinoids.1,4 Unlike carcinoids of the small bowel or colon, rectal carcinoids contain glucagon and glicentin-related peptides
rather than serotonin.36 These tumors are known to be
hormonally inactive even when extensive liver metastases are present.37
Most rectal carcinoids are diagnosed in the sixth
decade. Approximately 50% are asymptomatic and are
found on routine proctoscopic or endoscopic examination.38 Rectal bleeding, constipation, and pain are the
most frequent complaints in symptomatic patients.3,21,38
Like other carcinoids, the size of the primary lesion
determines the incidence of metastases. For lesions less
than 1 cm in diameter, the incidence of metastatic spread
is 3%. For 1 to 2 cm lesions, the rate of metastases is 11%;
for lesions greater than 2 cm in diameter, the rate is
74%.39 Of rectal carcinoids, 66% are less than 1 cm at presentation; most lesions are localized. The 5-year survival
rate for these lesions is 81%. For those with involvement
of regional lymph nodes, the 5-year survival is 47%; for
those with distant metastases, the 5-year survival is 18%.4
TREATMENT
The size of the lesion helps determine the appropriate surgical therapy for patients with rectal carcinoids.
For lesions less than 1 cm in diameter, it is generally
accepted that local excision is sufficient. For lesions
larger than 2 cm in diameter, low anterior resection or
abdominoperineal resection has been the traditional
treatment.1 The management of lesions 1 to 2 cm in
diameter is more controversial. Most of these lesions
can be treated by local excision. Some authors have suggested that the presence of muscular invasion, symptoms at the time of diagnosis, or mucosal ulceration are
poor prognostic factors and warrant more extensive
surgery.38,39 This treatment strategy has been challenged by Sauven and colleagues,40 who found no survival advantage with a more radical approach in patients
with advanced locoregional disease. They advocated
local excision alone provided that the entire tumor
could be removed.40 This less aggressive approach has
not been substantiated by others, and most surgeons
Figure 4. A computed tomographic image from patient 2 showing liver metastases from a primary rectal carcinoid tumor.
continue to recommend standard rectal resection for
large, advanced lesions.21 In the case of disseminated
disease, it should be remembered that, even in the presence of extensive hepatic metastases, these tumors are
hormonally inactive. Therefore, local measures alone
should be applied to palliate symptoms such as bleeding or obstruction.24
VIII. CARCINOID SYNDROME
GENERAL PRINCIPLES
Carcinoid syndrome is manifested by a spectrum of
symptoms that occur when a tumor excretes excess quantities of hormonal mediators into the circulation. The
syndrome is characterized by flushing, diarrhea, valvular
heart disease, and bronchoconstriction.41 Asthma attacks
caused by bronchoconstriction are uncommon.
Carcinoid syndrome is present in only 10% of patients with GI carcinoid tumors. More than 75% of patients with the carcinoid syndrome have the primary
tumor in the small intestine, usually the ileum.19,41 Carcinoid syndrome is a marker of advanced disease and is
usually seen with extensive metastatic tumor deposits
in the liver. In patients with liver metastases, the metabolism of hormonal mediators is impaired by a reduction in functional liver tissue. In addition, the metastatic foci in the liver can release nondetoxified mediators
directly into the systemic circulation.41 Although carcinoid syndrome occurs in patients with GI carcinoid
tumors that have metastasized to the liver, it may occur
in the absence of hepatic metastases in patients with
carcinoid tumors that have direct access to the systemic
General Surgery Volume 7, Part 4 7
Gastrointestinal Carcinoid Tumors
circulation, such as ovarian, testicular, and bronchial
carcinoids.25
The precise mediator responsible for the carcinoid
syndrome is not known. It was previously thought that
serotonin was solely responsible for the flushing and
diarrhea; however, investigators have been unable to
show consistent increases in serotonin levels in these patients. The role of other mediators has not been conclusively established. It is likely that the vasomotor sequelae
of the syndrome are related to the synergistic effects of
several agents, most likely serotonin and bradykinin.42
The most reliable way to confirm the clinical diagnosis
of carcinoid syndrome is to document an elevated level
of urinary 5-HIAA, a serotonin metabolite.32 A 24-hour
urinary 5-HIAA level greater than 9 mg is abnormal.
Most patients with carcinoid syndrome excrete greater
than 50 to 100 mg of 5-HIAA daily.41
SYMPTOMS
Flushing, the hallmark of the syndrome, occurs in
75% to 90% of patients with carcinoid syndrome. Several different forms of flushing have been described
depending on the site of the primary tumor. Diffuse
erythematous flushing, the most common form, affects
the face, neck, and upper chest and lasts for approximately 2 to 10 minutes. It is associated with midgut carcinoids21 and can be provoked by various stimuli, such
as foods and/or alcohol, or by emotional or physical
stress.42 Violaceous flushing is a second type, similar in
presentation to the diffuse erythematous type except
that the attacks may last longer and patients occasionally develop a permanent cyanotic flush with facial telangiectasias and watery eyes. This type is usually associated
with foregut tumors. Bright red, patchy flushing is the
result of increased histamine and is seen with gastric
carcinoids. Prolonged flushing, the final subtype, may
last up to 3 days, and may involve the entire body. This
type of flushing is seen with bronchial carcinoids.21
Diarrhea occurs in 75% of patients with carcinoid syndrome. It is episodic, watery, and may be voluminous,
which can contribute to fluid and electrolyte imbalances.
The diarrhea is thought to be due to the effects of serotonin on the bowel; methysergide or cyproheptadine
(serotonin antagonists) are frequently effective in controlling this symptom.21,43
Cardiac lesions occur in approximately 33% of patients with carcinoid syndrome. These lesions are usually
not present initially but develop over time. The right side
of the heart is usually affected with plaque-like thickenings developing on the endocardium of the atrium, ventricle, and the undersides of the tricuspid and pulmonic
valves. As the valves become thickened, they become less
8 Hospital Physician Board Review Manual
mobile, resulting in pulmonary stenosis, tricuspid stenosis, and tricuspid insufficiency.41 Although left-sided lesions have been described, the left side of the heart is usually unaffected because serotonin, the proposed mediator,
is metabolized in the lung.41 Bronchoconstriction causing
asthma attacks is uncommon.
CARCINOID CRISIS
Carcinoid crisis is an uncommon, potentially lifethreatening manifestation of the carcinoid syndrome. It
is characterized by flushing, severe diarrhea, and central nervous system symptoms, ranging from lightheadedness to somnolence or coma. Patients can experience
concomitant cardiovascular symptoms, including tachycardia, arrhythmias, and blood pressure lability. The
carcinoid crisis is an emergency requiring aggressive
pharmacologic intervention (see Section IX.).41
IX. TREATMENT OF ADVANCED AND
METASTATIC CARCINOID TUMORS
When treating patients with advanced and/or
metastatic carcinoid tumors, it should be recognized that
these tumors are often very indolent and that patients
frequently live with their disease without difficulties for
many years. For asymptomatic patients, the best treatment is no treatment at all. In symptomatic patients,
octreotide, a long-acting somatostatin analogue, has
been found to be the most effective pharmacologic therapy. Octreotide works by binding to somatostatin receptors which are expressed on more than 80% of carcinoid
tumors.44 In an initial study using octreotide, 88% of
patients experienced improvement of their symptoms
and 72% had decreased urinary 5-HIAA excretion.45
Later data from this same group suggested that octreotide may result in disease stabilization or even tumor
regression.46 Octreotide can also be life saving in patients
with the carcinoid crisis.
In general, chemotherapy for metastatic carcinoid
syndrome has been shown to be of limited benefit.
Single or multiple drug regimens using doxorubicin,
5-fluorouracil, and streptozocin have been found to be
the most effective, with responses occurring in 20% to
30% of patients. For most patients, however, the median duration of response is short.42 Data suggest that
chemotherapy may be more effective when combined
with permanent hepatic artery ligation.47
Surgical resection of liver metastases has been shown
to result in long-term relief of symptoms and improved
survival in selected patients. In patients with disease confined to one lobe, a wedge resection or lobectomy is
Gastrointestinal Carcinoid Tumors
indicated. In patients with diffuse hepatic metastases,
tumor debulking can be considered because it has been
shown to control symptoms of the carcinoid syndrome
and to reduce urinary 5-HIAA levels.2 In patients with
unresectable hepatic metastases, hepatic-artery occlusion or chemoembolization is an alternative. These
modalities are based on the principle that tumors
receive most of their blood supply from the hepatic
artery, in contrast to hepatocytes, which are able to
receive blood from the portal venous circulation.
Unfortunately, the duration of response after hepaticartery occlusion is short, with tumor regression or decreased levels of urinary 5-HIAA lasting for less than
1 year.1 Currently, the role of liver transplantation is unclear. Only a few patients with metastatic carcinoid have
had transplantation; in early series, there was significant
perioperative mortality and high rates of recurrence.48
In patients with carcinoid syndrome undergoing
operative intervention, the perioperative period offers
many potential triggers of mediator release that could
precipitate a carcinoid crisis. These triggers include
prepping of the abdomen, manipulation of the tumor,
catecholamine release from sympathetic nervous system stimulation, use of medications that either promote histamine release or stimulate and inhibit the
autonomic nervous system, hypotension, hypercapnia,
and hypothermia.41 Patients well controlled on a regimen of octreotide should continue with their medication. If not currently on octreotide, patients should be
given 50 to 500 µg subcutaneously every 8 hours for the
24 hours before surgery to inhibit mediator release. If a
patient develops the carcinoid crisis, the best treatment
is tumor removal or intravenous octreotide. Symptoms
of cardiovascular collapse should be managed with standard inotropic and vasopressor agents.41
treat early, localized lesions, whereas more aggressive
procedures may be undertaken for patients with locally
advanced or metastatic disease.
Advanced lesions with bulky hepatic metastases can
result in the development of carcinoid syndrome, which
is marked by flushing, diarrhea, and right-sided cardiac
lesions. Frequently, symptoms are mild and require no
therapy. Patients with disabling symptoms can be treated
with octreotide. Chemotherapy is of limited benefit. In
appropriate patients, surgical resection of hepatic lesions
may provide long-term relief of symptoms and improve
survival. Hepatic artery occlusion or chemoembolization
are other alternatives in selected patients.
BOARD REVIEW QUESTIONS
Choose the single best answer for each question.
1.
A 63-year-old healthy woman with no pertinent
medical history underwent an upper gastrointestinal (GI) endoscopy for evaluation of vague epigastric pain and anemia. She was found to have a 4-cm
mass in the body of the stomach. Her family history is unremarkable. Biopsy revealed a carcinoid tumor. Treatment should consist of which of the following?
A) Observation
B) A proton pump inhibitor
C) Antrectomy
D) Subtotal gastrectomy
E) Endoscopic resection
2.
In contrast to other GI carcinoid tumors, which of
the following is TRUE for carcinoid tumors of the
appendix?
A) Originate from subepithelial neuroendocrine
cells
B) Most often occur in older patients
C) Have a worse prognosis
D) Do not occur in association with a second
noncarcinoid tumor
E) May produce carcinoid syndrome in the
absence of hepatic metastases
3.
Carcinoid tumors arising from which site are known
to be hormonally inactive even when extensive liver
metastases are present?
A) Stomach
B) Jejunoileum
C) Appendix
D) Colon
E) Rectum
X. SUMMARY
GI carcinoids are uncommon tumors that arise most
frequently in the small bowel, appendix, and rectum.
The location has important implications for the
tumor’s behavior and stage at presentation. Ileal and
colonic carcinoid tumors have the highest rate of metastases at diagnosis and the lowest survival rates. Appendiceal and rectal carcinoid tumors are unlikely to have
metastasized by the time of diagnosis and, as a result,
tumors in these locations are associated with the best
survival rates.
Surgical therapy for carcinoid tumors should be
based primarily on the tumor’s location and stage at
presentation. Less radical procedures can be used to
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Gastrointestinal Carcinoid Tumors
4.
Carcinoid syndrome is most likely to occur with a
carcinoid tumor of which of the following?
A) Stomach
B) Duodenum
C) Ileum
D) Appendix
E) Rectum
5.
While the abdomen is being prepped in the operating room, a patient with carcinoid syndrome
develops carcinoid crisis characterized by diffuse
erythematous flushing, tachycardia, and hypotension. The most appropriate therapeutic intervention includes standard inotropic and vasopressor
agents as well as administration of which of the following?
A) Methysergide
B) Benadryl
C) Octreotide
D) Dantrolene
E) Cyproheptadine
DETAILED ANSWERS
1. (D) Subtotal gastrectomy. This patient has a sporadic
gastric carcinoid tumor. These lesions tend to be
larger than 1 cm in diameter and are usually solitary.
Unlike carcinoid tumors associated with chronic
atrophic gastritis type A (CAG-A) or Zollinger-Ellison
syndrome, sporadic gastric carcinoid tumors usually
follow a more aggressive course with lymph node and
liver metastases frequently found at presentation.
Treatment of these aggressive lesions is usually by gastrectomy. In contrast, successful treatment of carcinoid tumors associated with CAG-A usually follows a
benign clinical course. Endoscopic resection is
indicated for lesions less than 1 cm in diameter.
Antrectomy to remove the source of gastrin has also
been reported to result in tumor regression in some
cases. The treatment of carcinoid tumors associated
with Zollinger-Ellison syndrome is similar to the treatment of carcinoid tumors in patients with chronic
atrophic gastritis.
2. (A) Originate from subepithelial neuroendocrine
cells. In contrast to other GI carcinoids that are of
mucosal origin, appendiceal carcinoids arise from
subepithelial neuroendocrine cells present in the
lamina propria and submucosa of the wall of the
appendix. Patients affected by appendiceal carcinoid
tumors are younger (average age, 42 years) at the
time of diagnosis versus patients with all other GI carcinoid tumors (average age, 63 years). Associated
10 Hospital Physician Board Review Manual
noncarcinoid tumors are seen in 15% of patients
with carcinoid tumors of the appendix. Carcinoid
syndrome occurs in patients with carcinoid tumors
in the appendix that have metastasized to the liver.
Carcinoid syndrome may occur in patients without
hepatic metastases but who have carcinoid tumors
with direct access to the systemic circulation (eg, tumors of the ovary, testicle, or bronchus).
3. (E) Rectum. Carcinoid tumors of the rectum are
known to be hormonally inactive even when extensive liver metastases are present. This observation has
important therapeutic implications. Patients with
widespread liver metastases that are hormonally inactive may require no treatment at all.
4. (C) Ileum. Carcinoid syndrome is present in 10% of
patients with GI carcinoid tumors. More than 75% of
patients with carcinoid syndrome will have the primary tumor in the small intestine, usually the ileum.
Carcinoid syndrome is a marker of advanced disease
usually seen with extensive metastatic tumor deposits
in the liver.
5. (C) Octreotide. In patients with carcinoid syndrome
undergoing operative intervention, many things during the perioperative period may trigger mediator
release and precipitate a carcinoid crisis. These triggers include prepping of the abdomen; manipulation
of the tumor; catecholamine release from sympathetic nervous system stimulation; the use of medications
that either promote histamine release or stimulate
and inhibit the autonomic nervous system; hypotension; hypercapnia; and hypothermia. Patients with
carcinoid syndrome should be well controlled on a
regimen of octreotide before surgery. If a patient
develops the carcinoid crisis, the best treatment is
administration of intravenous octreotide followed by
tumor removal. Symptoms of cardiovascular collapse
are managed with standard inotropic and vasopressor
agents.
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12 Hospital Physician Board Review Manual