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GENERAL SURGERY BOARD REVIEW MANUAL

General Surgery Volume 7, Part 4 1

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NOTE FROM THE PUBLISHER:This publication has been developed withoutinvolvement of or review by the AmericanBoard of Surgery.

Gastrointestinal CarcinoidTumors: Case StudiesSeries Editor and Contributing Author: Christopher R. McHenry, MD, FACS, FACEAssociate Professor of Surgery, Case Western Reserve University School ofMedicine, Director, Division of General Surgery, MetroHealth MedicalCenter, Cleveland, OH

Contributing Author: Elizabeth A. Mittendorf, MDStaff Surgeon, Malcolm Grow Medical Center, Andrews Air Force Base, MD

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Gastric Carcinoid Tumors . . . . . . . . . . . . . . . . . . . . . . . . 2

Duodenal Carcinoid Tumors . . . . . . . . . . . . . . . . . . . . . . 4

Jejunoileal Carcinoid Tumors. . . . . . . . . . . . . . . . . . . . . . 4

Appendiceal Carcinoid Tumors . . . . . . . . . . . . . . . . . . . . 5

Colonic Carcinoid Tumors . . . . . . . . . . . . . . . . . . . . . . . . 6

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

Table of Contents

Cover Illustration by Joe Wilder, MD

2 Hospital Physician Board Review Manual

®

I. INTRODUCTION

Carcinoid tumors are a heterogeneous group of neu-roendocrine tumors that can arise in any organ origi-nating from the endoderm. They arise from entero-chromaffin or enterochromaffin-like cells (in the amineprecursor uptake and decarboxylation system) with thepotential to produce several different biologically activeamines and peptides. Serotonin is the best known ofthese biologically active substances. Carcinoid tumorsmay also secrete corticotropin, histamine, dopamine, sub-stance P, neurotensin, prostaglandins, and kallikrein.1

The release of vasoactive substances into the systemic cir-culation is responsible for the development of the carci-noid syndrome, which is a marker of advanced disease(see Section VIII.).

The incidence of carcinoid tumors is 1 to 2.5 per100,000 annually; they are most commonly found in thebronchial tree and the gastrointestinal (GI) tract.1–4

Figure 1 depicts the anatomic location of carcinoid tu-mors as identified in review of the National CancerInstitute’s Surveillance, Epidemiology, and End Results(SEER) database, which accumulated data from 1973 to1991. In the small intestine and appendix, carcinoid

tumors account for approximately 33% and 77% of alltumors, respectively.2,5 In organs such as the colon, stom-ach, and lung that develop tumors more frequently, car-cinoid tumors make up only 1% of tumors.2

Carcinoid tumors have traditionally been classifiedaccording to their presumed derivation from differentembryonic divisions of the GI tract. Foregut carcinoidtumors originate in the lungs, bronchi, stomach, or duo-denum; midgut tumors in the small intestine, appendix,and proximal large intestine; and hindgut tumors in thedistal colon and rectum.6 The biologic and clinical char-acteristics vary within these groups. This review willexamine GI carcinoid tumors by location including thestomach, duodenum, small intestine, appendix, colon,and rectum. The carcinoid syndrome will also be re-viewed. Two case patients are presented to emphasizeclinical features and management issues. Sample boardreview questions with detailed answers are provided atthe 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

GENERAL SURGERY BOARD REVIEW MANUAL

Gastrointestinal Carcinoid Tumors: Case Studies

Series Editor and Contributing Author: Contributing Author: Christopher R. McHenry, MD, FACS, FACE Elizabeth A. Mittendorf, MD

Associate Professor of Surgery Staff SurgeonCase Western Reserve University School of Medicine Malcolm Grow Medical Center

Director, Division of General Surgery Andrews Air Force Base, MDMetroHealth Medical Center

Cleveland, OH


G a s t r o i n t e s t i n a l C a r c i n o i d T u m o r s

6% of all GI carcinoid tumors.7 Gastric carcinoid tu-mors can be divided into 3 groups based on clinical andhistologic characteristics: those associated with chronicatrophic gastritis type A (CAG-A), those associated withthe Zollinger-Ellison syndrome, and those that are spo-radic.

CHRONIC ATROPHIC GASTRITIS TYPE A–ASSOCIATEDTUMORS

Tumors associated with CAG-A account for 65% to75% of gastric carcinoids.1,8 A substantial number of pa-tients with CAG-A–associated carcinoid tumors also havepernicious anemia.9–11 CAG-A–associated carcinoid tu-mors are more common in women and usually presentin the sixth or seventh decade.1 Symptoms caused byhormone overproduction are rare, and the diagnosis isusually made endoscopically during evaluation for ane-mia or vague abdominal pain.8,9

These tumors are usually small and multifocal, locat-ed in the body or fundus of the stomach.8,9 This locationand multifocal nature are explained by their origin from enterochromaffin-like cells that exist in the gastric fundus.Patients with CAG-A usually have hypochlorhydria andhypergastrinemia; this gastrin hypersecretion has beenpostulated to result in hyperplasia of enterochromaffin-like cells. These hyperplastic lesions may then developinto carcinoid tumors.1,12 This hypothesis is supported bystudies in the ratshowing that carcinoid tumors occurredwhen hypergastrinemia was induced by administration ofa proton-pump inhibitor.13

CAG-A–associated carcinoid tumors usually follow abenign clinical course. Successful treatment by endo-scopic resection is possible for lesions less than 1 cm indiameter. Patients with larger, multiple, or recurrenttumors may require more extensive surgical resection.Antrectomy to remove the source of gastrin has beenreported 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 inless than 10% of cases. Although local recurrences havebeen reported, recent series report no deaths from thedisease in treated patients. The 5-year survival rateapproaches 100%.9,14

ZOLLINGER-ELLISON SYNDROME–ASSOCIATED TUMORS

Tumors associated with Zollinger-Ellison syndromeaccount for 5% to 10% of gastric carcinoids.16 Like thoseassociated with CAG-A, these tumors are probably causedby gastrin-induced hyperplasia of enterochromaffin-likecells.16 Of note, they occur almost exclusively withZollinger-Ellison syndrome in association with multiple

endocrine neoplasia type 1. It is thought that prolongedhypergastrinemia in combination with genetic suscepti-bility is required for the development of these lesions.1,8

The location, treatment, and long-term prognosis ofcarcinoid tumors associated with Zollinger-Ellison syn-drome are similar to those associated with CAG-A. Re-moval of the source of gastrin is accomplished by exci-sion of the gastrin-producing tumors.

SPORADIC TUMORS

Sporadic tumors account for 15% to 25% of gastriccarcinoids and are more common in men.1,8,16 Theselesions tend to be larger than 1 cm in diameter, are usu-ally solitary, and are composed of a mixture of endo-crine cells. Precursor lesions in the gastric mucosa arelacking.1,8 Unlike carcinoid tumors associated withCAG-A and Zollinger-Ellison syndrome, sporadic gastriccarcinoid tumors usually follow a more aggressive coursewith lymph node and liver metastases frequently presentat the time of presentation. In a review of gastric carci-noids by Kirshbom and colleagues, distant metastaseswere noted at presentation in 60% of patients with spo-radic tumors.17 Endocrine symptoms, particularly hista-mine-mediated flushing, are frequent.10 Other symp-toms referable to overproduction of histamine—such ashypotension, lacrimation, cutaneous edema, and bron-choconstriction—may also be seen. Increased urinarysecretion of methyl-imidazole-acetic acid, the primary

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Figure 1. The anatomic distribution for carcinoid tumors.



histamine metabolite, can be demonstrated.18 Treat-ment of these aggressive lesions is usually by gastrectomy.The 5-year survival rates are reported to be 52%.1,8

III. DUODENAL CARCINOID TUMORS

Duodenal carcinoids, also of foregut origin, are ex-tremely rare, accounting for only 2% to 3% of GI carci-noids.4,8 They are more common in men and usuallypresent in the sixth decade.19 The most common pre-senting symptoms are abdominal pain and bleeding.Duodenal carcinoid tumors are frequently polypoidlesions identified by flexible endoscopy performed forthe evaluation of upper GI bleeding.2,19 Other symp-toms include obstruction of the common bile ductresulting in jaundice. Approximately 10% are inciden-tally identified.19

Duodenal carcinoids may secrete gastrin, calcitonin,or somatostatin.2,8 Levels of serotonin and its primarymetabolite 5-hydroxyindoleacetic acid (5-HIAA) arelow, and development of the carcinoid syndrome israre.19 Most of these tumors follow a benign course.Although regional lymph node metastases have beenreported, more than 70% of duodenal carcinoid tu-mors are localized at the time of presentation.19 Theyare usually solitary, small, and can be removed endo-scopically. At the time of excision, endoluminal ultra-sonography can be used to assess for the depth of inva-sion.2 Full-thickness wall excision or resection is rarelynecessary.20 Ten-year survival rates are reported to beapproximately 60%.17,19

IV. JEJUNOILEAL CARCINOID TUMORS

CASE PATIENT 1

Patient 1 is a 49-year-old healthy man who presentswith a 7-day history of persistent sharp right-sided peri-umbilical pain and a 3-day history of loose bowel move-ments. He denies fever, nausea, vomiting, or weight loss.A computed tomographic (CT) scan shows a 2.5-cmmass posterior to a distal ileal loop that is suspicious fortumor (Figure 2). Patient 1 undergoes an exploratorylaparotomy, and a 0.6-cm whitish discoloration is identi-fied in the serosal surface of the distal ileum. A 3.5-cmmass corresponding to the lesion seen on CT is identifiedwithin the mesenteric fat of the distal ileum. The patientundergoes en bloc resection of an 8-cm segment of ileumcontaining the primary tumor and the adjacent mesen-tery containing the metastatic nodal disease (Figure 3).No hepatic metastases are identified. Final pathology re-veals a 1.9-cm carcinoid tumor with extension throughthe serosa and into the mesenteric fat with 2 of 5 lymphnodes involved with metastatic carcinoid tumor. Post-operatively, the patient’s diarrhea resolves, and he deniesany other symptoms consistent with carcinoid syndrome.Patient 1 is then followed for 3 years without evidence ofrecurrent disease.

Figure 3. Resected ileum from patient 1. This 8-cm segment ofileum contains a 0.6-cm whitish discoloration (black arrow) and a3.5-cm mass (white arrows) in the mesenteric fat correspondingto the mass seen on computed tomography in Figure 2.

Figure 2. Computed tomograph of patient 1’s abdomen demon-strating a 2.5-cm solid mass (arrow) just medial to the cecum andposterior to a distal ileal loop. P = posterior; R = right.

DISCUSSION

The jejunum and ileum are the most common sitesfor GI carcinoid tumors, accounting for approximately30% of all tumors.4 They are thought to arise from serotonin-producing intraepithelial endocrine cells. Fociof hyperplastic intraepithelial endocrine cells have beenreported, but the cause of this hyperplasia is unknown.1

These tumors are found with increasing frequency fromthe jejunum to the ileum, with most occurring in the dis-tal one third of the small bowel. Small bowel carcinoidsare multiple in 29% to 41% of patients and are associat-ed with an adenocarcinoma elsewhere in the GI tract in 8% to 29% of patients.4,21–23 This distribution under-scores the importance of a thorough exploration of theentire small and large intestine at the time of surgicaltherapy. Modlin and colleagues analyzed the SEER datawhere 13% of all carcinoid tumors were associated withother noncarcinoid tumors.4 They suggested regular sur-veillance of the colon and rectum, small intestine, andlung in all patients as well as regular surveillance of thecervix and ovaries in women diagnosed with a carcinoidtumor in the small intestine, appendix, or colon.4 Theseassociated noncarcinoid tumors may present as a meta-chronous lesion in up to 10% of patients.3

Presentation

In general, patients with a small bowel carcinoidtumor present with vague complaints; standard imagingtechniques, such as computed tomography and smallbowel contrast studies, are of limited value in identify-ing the primary tumor. The diagnosis of small bowelcarcinoid is therefore difficult to make preoperative-ly.1,24 Most patients with small bowel carcinoids presentin the sixth or seventh decade, typically with abdominalpain. The pain is often intermittent and colicky in na-ture and is associated with a small bowel obstruction.This obstruction most commonly results from bowelinvolvement in a dense, fibrotic, desmoplastic reactionthat causes shortening of the mesentery with resultantbowel kinking, angulation, and subsequent obstruc-tion. The size of the primary tumor or peritoneal carci-nomatosis may also cause obstruction. If not the resultof obstruction, the pain may be caused by ischemia,which results from vascular compromise secondary tolarge bulky mesenteric nodal disease or from serotonin-induced elastic microvascular sclerosis.25 Approximately5% to 7% of patients with small bowel carcinoids willpresent with carcinoid syndrome. GI blood loss is anuncommon presenting complaint or clinical feature ofsmall bowel carcinoids. In contrast, GI blood loss is thecause for investigation in gastric, colonic, and rectal car-cinoids in 38%, 33% and 40% of cases, respectively.3

Diagnosis and Treatment

Because early stage disease has a lack of distinctivesymptoms, patients tend to present with later stage dis-ease, which decreases survival. In a review of 184 patientswith small bowel carcinoids, Onaitis and colleagues foundthat 42 (22%) had localized disease, 37 (20%) had re-gional lymph node metastases, and 105 (57%) had dis-tant metastases at the time of diagnosis.19 The likelihoodof metastases is generally thought to depend on the sizeof the primary lesion. Tumors smaller than 1 cm in diam-eter have a 20% to 30% incidence of nodal and hepaticmetastases. Tumors between 1 and 2 cm have a 60% to80% incidence of nodal metastases and a 20% incidenceof hepatic metastases. Tumors larger than 2 cm in diame-ter have a greater than 80% incidence of nodal metastasesand a 40% to 50% incidence of hepatic metastases.25,26

The presence of metastatic disease affects the 5-year sur-vival of patients with small bowel carcinoids, which is 50%to 68% overall.3,4,8,24 In patients with localized disease, the5-year survival rate is 75%. With spread to regional lymphnodes, the 5-year survival is 59% to 65% and with distantmetastases, the 5-year survival is 20% to 36%.1,24 Studieshave shown that jejunoileal carcinoids have the worstprognosis,3 which has been attributed to their moreaggressive behavior with an increased incidence of meta-static disease and to diagnostic delay caused by the lack ofdistinctive symptoms.

Surgical management of patients with small bowelcarcinoids involves extended resection including theprimary tumor and the mesentery with relevant lymphnode drainage. Even in the presence of distant metas-tases, resection can help ameliorate endocrine symp-toms.2,27

V. APPENDICEAL CARCINOID TUMORS

GENERAL PRINCIPLES

The appendix is the second most common site ofinvolvement in the GI tract, accounting for 26% of GI car-cinoid tumors.1,4 Carcinoid tumors are the most commonmalignant tumor of the appendix. In contrast to other GIcarcinoids that are of mucosal origin, appendiceal carci-noids arise from subepithelial neuroendocrine cells pres-ent in the lamina propria and submucosa of the wall ofthe appendix.28 These subepithelial neuroendocrine cellsare more numerous at the tip of the appendix, which isconsistent with the observation that 70% to 80% ofappendiceal carcinoids occur in this location.29 The den-sity of subepithelial neuroendocrine cells has been foundto be low in infancy, increasing with age and peaking in



the third decade, after which it slowly declines. Severalauthors have suggested that this may explain why appen-diceal carcinoids present at a relatively early age com-pared with carcinoids at other sites. They have postulatedthat appendiceal carcinoids may regress with age as thesubepithelial neuroendocrine cells regress.30,31

DIAGNOSIS AND TREATMENT

Appendiceal carcinoid tumors are usually diagnosedin the fourth or fifth decade. Review of the SEER datarevealed an average age of 42.2 years at the time of diag-nosis for appendiceal carcinoids versus 62.9 years for allother GI carcinoid tumors.29 In addition to the higherdensity of subepithelial neuroendocrine cells, the earli-er age of diagnosis of appendiceal carcinoid likely re-flects the fact that appendectomies are most frequentlyperformed in young adults.1 Appendiceal carcinoids aremore common in women, probably because of a higherrate of incidental appendectomy.32 In 50% to 60% ofpatients, appendiceal carcinoids are found incidentallywhereas the other 40% to 50% present with acuteappendicitis.3,8

As previously observed, most appendiceal carcinoidsoccur at the tip of the appendix. Less often, they pre-sent 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 indiameter, 4% to 27% are 1 to 2 cm, and 2% to 17% arelarger than 2 cm.30,32 Tumor size has been correlatedwith metastatic potential. Tumors less than 1 cm nevermetastasize, and tumors between 1 and 2 cm rarely me-tastasize (0% to 11%). Tumors larger than 2 cm areassociated with regional or distant metastases 30% to60% of the time.29 These data have implications for thesurgical management of these tumors. In general, tu-mors less than 1 cm in diameter are treated with ap-pendectomy alone, whereas tumors greater than 2 cmin diameter are treated with right hemicolectomy.

Treatment of tumors between 1 and 2 cm in diame-ter is more controversial and should be individualizedbased on tumor characteristics. A right hemicolectomyshould be performed when there is angio-invasion orsubserosal lymphatic invasion, involvement of the meso-appendix, or lymph node metastases.21,32,33 A right hemi-colectomy is also indicated to avoid residual tumor orrecurrence for carcinoid tumors at the base of the ap-pendix or with involvement of the surgical margin orcecum.25,33 Associated, noncarcinoid tumors are seen in15% 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 allother carcinoid tumors of the GI tract.29 The better prog-

nosis for appendiceal tumors may reflect the earlier iden-tification of carcinoid tumors of the appendix. Accord-ing to the SEER data, 64.6% of appendiceal carcinoidswere localized at the time of diagnosis. The 5-year sur-vival rate is 94% for localized tumors, 84.6% for regionalinvasion, and 33.7% for distant metastases.29

VI. COLONIC CARCINOID TUMORS

Colonic carcinoids are uncommon tumors account-ing for less than 1% of all colonic tumors and approxi-mately 5% of GI carcinoids.1,8 Like small bowel carci-noids, colonic carcinoids arise from serotonin-producingepithelial endocrine cells. These tumors decrease in fre-quency from the right colon to the left colon; most arefound in the cecum.1,2,19

Colonic carcinoids present most commonly in theseventh decade, and most patients are symptomatic.Presenting signs and symptoms include pain, anorexia,weight loss, and GI bleeding. Colonic obstruction hasalso been reported.19 Patients presenting with these com-plaints often undergo colonoscopic evaluation or a con-trast study that can diagnose a lesion. CT scans can beuseful for assessing the presence of metastatic disease.21

At the time of diagnosis, the average tumor size is 5 cmin diameter, and more than 66% of patients have nodalor distant metastases present at diagnosis.34,35 Despite thepresence of hepatic metastases, less than 5% presentwith hormonal symptoms.1,21,35 Between 25% and 40%of patients have a second, noncarcinoid malignancy.21,34

Surgical therapy for colonic carcinoids involves re-section of the affected segment of the colon and its lym-phatic drainage, which is the same as for adenocarcino-ma of the colon. Like carcinoids at other locationswithin the GI tract, 5-year survival is determined by theextent of disease at the time of diagnosis. The 5-year survival rates are 70% for patients with local dis-ease, 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 historypertinent for hypertension and non–insulin-dependentdiabetes mellitus who presents with a 2-week history ofrectal bleeding. Colonoscopy is performed and identi-fies a 3-cm lesion approximately 9 cm from the analverge. Biopsy is consistent with a carcinoid tumor. A CT



scan shows multiple liver metastases (Figure 4). Thepatient denies symptoms suggestive of carcinoid syn-drome. He undergoes a low anterior resection of therectum. The final pathology reveals a carcinoid tumorwith ulceration and necrosis. Metastases are present in35 out of 40 lymph nodes. Because patient 2 is asympto-matic, no adjuvant therapy is recommended.

DISCUSSION

Rectal carcinoids account for between 1% and 2% ofall rectal tumors and 12.6% of all GI carcinoids.1,4 Un-like carcinoids of the small bowel or colon, rectal carci-noids contain glucagon and glicentin-related peptidesrather than serotonin.36 These tumors are known to behormonally inactive even when extensive liver metas-tases are present.37

Most rectal carcinoids are diagnosed in the sixthdecade. Approximately 50% are asymptomatic and arefound on routine proctoscopic or endoscopic examina-tion.38 Rectal bleeding, constipation, and pain are themost frequent complaints in symptomatic patients.3,21,38

Like other carcinoids, the size of the primary lesiondetermines the incidence of metastases. For lesions lessthan 1 cm in diameter, the incidence of metastatic spreadis 3%. For 1 to 2 cm lesions, the rate of metastases is 11%;for lesions greater than 2 cm in diameter, the rate is74%.39 Of rectal carcinoids, 66% are less than 1 cm at pre-sentation; most lesions are localized. The 5-year survivalrate for these lesions is 81%. For those with involvementof regional lymph nodes, the 5-year survival is 47%; forthose with distant metastases, the 5-year survival is 18%.4

TREATMENT

The size of the lesion helps determine the appropri-ate surgical therapy for patients with rectal carcinoids.For lesions less than 1 cm in diameter, it is generallyaccepted that local excision is sufficient. For lesionslarger than 2 cm in diameter, low anterior resection orabdominoperineal resection has been the traditionaltreatment.1 The management of lesions 1 to 2 cm indiameter is more controversial. Most of these lesionscan be treated by local excision. Some authors have sug-gested that the presence of muscular invasion, symp-toms at the time of diagnosis, or mucosal ulceration arepoor prognostic factors and warrant more extensivesurgery.38,39 This treatment strategy has been chal-lenged by Sauven and colleagues,40 who found no sur-vival advantage with a more radical approach in patientswith advanced locoregional disease. They advocatedlocal excision alone provided that the entire tumorcould be removed.40 This less aggressive approach hasnot been substantiated by others, and most surgeons

continue to recommend standard rectal resection forlarge, advanced lesions.21 In the case of disseminateddisease, it should be remembered that, even in the pres-ence of extensive hepatic metastases, these tumors arehormonally inactive. Therefore, local measures aloneshould be applied to palliate symptoms such as bleed-ing or obstruction.24

VIII. CARCINOID SYNDROME

GENERAL PRINCIPLES

Carcinoid syndrome is manifested by a spectrum ofsymptoms that occur when a tumor excretes excess quan-tities of hormonal mediators into the circulation. Thesyndrome is characterized by flushing, diarrhea, valvularheart disease, and bronchoconstriction.41 Asthma attackscaused by bronchoconstriction are uncommon.

Carcinoid syndrome is present in only 10% of pa-tients with GI carcinoid tumors. More than 75% of pa-tients with the carcinoid syndrome have the primarytumor in the small intestine, usually the ileum.19,41 Car-cinoid syndrome is a marker of advanced disease and isusually seen with extensive metastatic tumor depositsin the liver. In patients with liver metastases, the metab-olism of hormonal mediators is impaired by a reduc-tion in functional liver tissue. In addition, the metasta-tic foci in the liver can release nondetoxified mediatorsdirectly into the systemic circulation.41 Although carci-noid syndrome occurs in patients with GI carcinoidtumors that have metastasized to the liver, it may occurin the absence of hepatic metastases in patients withcarcinoid tumors that have direct access to the systemic



Figure 4. A computed tomographic image from patient 2 show-ing liver metastases from a primary rectal carcinoid tumor.

circulation, such as ovarian, testicular, and bronchialcarcinoids.25

The precise mediator responsible for the carcinoidsyndrome is not known. It was previously thought thatserotonin was solely responsible for the flushing anddiarrhea; however, investigators have been unable toshow consistent increases in serotonin levels in these pa-tients. The role of other mediators has not been conclu-sively established. It is likely that the vasomotor sequelaeof the syndrome are related to the synergistic effects ofseveral agents, most likely serotonin and bradykinin.42

The most reliable way to confirm the clinical diagnosisof carcinoid syndrome is to document an elevated levelof urinary 5-HIAA, a serotonin metabolite.32 A 24-hoururinary 5-HIAA level greater than 9 mg is abnormal.Most patients with carcinoid syndrome excrete greaterthan 50 to 100 mg of 5-HIAA daily.41

SYMPTOMS

Flushing, the hallmark of the syndrome, occurs in75% to 90% of patients with carcinoid syndrome. Sev-eral different forms of flushing have been describeddepending on the site of the primary tumor. Diffuseerythematous flushing, the most common form, affectsthe face, neck, and upper chest and lasts for approxi-mately 2 to 10 minutes. It is associated with midgut car-cinoids21 and can be provoked by various stimuli, suchas foods and/or alcohol, or by emotional or physicalstress.42 Violaceous flushing is a second type, similar inpresentation to the diffuse erythematous type exceptthat the attacks may last longer and patients occasional-ly develop a permanent cyanotic flush with facial telan-giectasias and watery eyes. This type is usually associatedwith foregut tumors. Bright red, patchy flushing is theresult of increased histamine and is seen with gastriccarcinoids. Prolonged flushing, the final subtype, maylast up to 3 days, and may involve the entire body. Thistype of flushing is seen with bronchial carcinoids.21

Diarrhea occurs in 75% of patients with carcinoid syn-drome. 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 sero-tonin on the bowel; methysergide or cyproheptadine(serotonin antagonists) are frequently effective in con-trolling this symptom.21,43

Cardiac lesions occur in approximately 33% of pa-tients with carcinoid syndrome. These lesions are usuallynot present initially but develop over time. The right sideof the heart is usually affected with plaque-like thicken-ings developing on the endocardium of the atrium, ven-tricle, and the undersides of the tricuspid and pulmonicvalves. As the valves become thickened, they become less

mobile, resulting in pulmonary stenosis, tricuspid steno-sis, and tricuspid insufficiency.41 Although left-sided le-sions have been described, the left side of the heart is usu-ally unaffected because serotonin, the proposed mediator,is metabolized in the lung.41 Bronchoconstriction causingasthma attacks is uncommon.

CARCINOID CRISIS

Carcinoid crisis is an uncommon, potentially life-threatening manifestation of the carcinoid syndrome. Itis characterized by flushing, severe diarrhea, and cen-tral nervous system symptoms, ranging from lighthead-edness to somnolence or coma. Patients can experienceconcomitant cardiovascular symptoms, including tachy-cardia, arrhythmias, and blood pressure lability. Thecarcinoid crisis is an emergency requiring aggressivepharmacologic intervention (see Section IX.).41

IX. TREATMENT OF ADVANCED ANDMETASTATIC CARCINOID TUMORS

When treating patients with advanced and/ormetastatic carcinoid tumors, it should be recognized thatthese tumors are often very indolent and that patientsfrequently live with their disease without difficulties formany years. For asymptomatic patients, the best treat-ment is no treatment at all. In symptomatic patients,octreotide, a long-acting somatostatin analogue, hasbeen found to be the most effective pharmacologic ther-apy. Octreotide works by binding to somatostatin recep-tors which are expressed on more than 80% of carcinoidtumors.44 In an initial study using octreotide, 88% ofpatients experienced improvement of their symptomsand 72% had decreased urinary 5-HIAA excretion.45

Later data from this same group suggested that octre-otide may result in disease stabilization or even tumorregression.46 Octreotide can also be life saving in patientswith the carcinoid crisis.

In general, chemotherapy for metastatic carcinoidsyndrome has been shown to be of limited benefit.Single or multiple drug regimens using doxorubicin,5-fluorouracil, and streptozocin have been found to bethe most effective, with responses occurring in 20% to30% of patients. For most patients, however, the medi-an duration of response is short.42 Data suggest thatchemotherapy may be more effective when combinedwith permanent hepatic artery ligation.47

Surgical resection of liver metastases has been shownto result in long-term relief of symptoms and improvedsurvival in selected patients. In patients with disease con-fined to one lobe, a wedge resection or lobectomy is



indicated. In patients with diffuse hepatic metastases,tumor debulking can be considered because it has beenshown to control symptoms of the carcinoid syndromeand to reduce urinary 5-HIAA levels.2 In patients withunresectable hepatic metastases, hepatic-artery occlu-sion or chemoembolization is an alternative. Thesemodalities are based on the principle that tumorsreceive most of their blood supply from the hepaticartery, in contrast to hepatocytes, which are able toreceive blood from the portal venous circulation.Unfortunately, the duration of response after hepatic-artery occlusion is short, with tumor regression or de-creased levels of urinary 5-HIAA lasting for less than1 year.1 Currently, the role of liver transplantation is un-clear. Only a few patients with metastatic carcinoid havehad transplantation; in early series, there was significantperioperative mortality and high rates of recurrence.48

In patients with carcinoid syndrome undergoingoperative intervention, the perioperative period offersmany potential triggers of mediator release that couldprecipitate a carcinoid crisis. These triggers includeprepping of the abdomen, manipulation of the tumor,catecholamine release from sympathetic nervous sys-tem stimulation, use of medications that either pro-mote histamine release or stimulate and inhibit theautonomic nervous system, hypotension, hypercapnia,and hypothermia.41 Patients well controlled on a regi-men of octreotide should continue with their medica-tion. If not currently on octreotide, patients should begiven 50 to 500 µg subcutaneously every 8 hours for the24 hours before surgery to inhibit mediator release. If apatient develops the carcinoid crisis, the best treatmentis tumor removal or intravenous octreotide. Symptomsof cardiovascular collapse should be managed with stan-dard inotropic and vasopressor agents.41

X. SUMMARY

GI carcinoids are uncommon tumors that arise mostfrequently in the small bowel, appendix, and rectum.The location has important implications for thetumor’s behavior and stage at presentation. Ileal andcolonic carcinoid tumors have the highest rate of metas-tases at diagnosis and the lowest survival rates. Append-iceal and rectal carcinoid tumors are unlikely to havemetastasized by the time of diagnosis and, as a result,tumors in these locations are associated with the bestsurvival rates.

Surgical therapy for carcinoid tumors should bebased primarily on the tumor’s location and stage atpresentation. Less radical procedures can be used to

treat early, localized lesions, whereas more aggressiveprocedures may be undertaken for patients with locallyadvanced or metastatic disease.

Advanced lesions with bulky hepatic metastases canresult in the development of carcinoid syndrome, whichis marked by flushing, diarrhea, and right-sided cardiaclesions. Frequently, symptoms are mild and require notherapy. Patients with disabling symptoms can be treatedwith octreotide. Chemotherapy is of limited benefit. Inappropriate patients, surgical resection of hepatic lesionsmay provide long-term relief of symptoms and improvesurvival. Hepatic artery occlusion or chemoembolizationare 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 pertinentmedical history underwent an upper gastrointesti-nal (GI) endoscopy for evaluation of vague epigas-tric pain and anemia. She was found to have a 4-cmmass in the body of the stomach. Her family histo-ry is unremarkable. Biopsy revealed a carcinoid tu-mor. Treatment should consist of which of the fol-lowing?A) ObservationB) A proton pump inhibitorC) AntrectomyD) Subtotal gastrectomyE) Endoscopic resection

2. In contrast to other GI carcinoid tumors, which ofthe following is TRUE for carcinoid tumors of theappendix?A) Originate from subepithelial neuroendocrine

cellsB) Most often occur in older patientsC) Have a worse prognosisD) Do not occur in association with a second

noncarcinoid tumorE) May produce carcinoid syndrome in the

absence of hepatic metastases

3. Carcinoid tumors arising from which site are knownto be hormonally inactive even when extensive livermetastases are present?A) StomachB) JejunoileumC) AppendixD) ColonE) Rectum





4. Carcinoid syndrome is most likely to occur with acarcinoid tumor of which of the following?A) StomachB) DuodenumC) IleumD) AppendixE) Rectum

5. While the abdomen is being prepped in the oper-ating room, a patient with carcinoid syndromedevelops carcinoid crisis characterized by diffuseerythematous flushing, tachycardia, and hypoten-sion. The most appropriate therapeutic interven-tion includes standard inotropic and vasopressoragents as well as administration of which of the fol-lowing?A) MethysergideB) BenadrylC) OctreotideD) DantroleneE) Cyproheptadine

DETAILED ANSWERS

1. (D) Subtotal gastrectomy. This patient has a sporadicgastric carcinoid tumor. These lesions tend to belarger than 1 cm in diameter and are usually solitary.Unlike carcinoid tumors associated with chronicatrophic gastritis type A (CAG-A) or Zollinger-Ellisonsyndrome, sporadic gastric carcinoid tumors usuallyfollow a more aggressive course with lymph node andliver metastases frequently found at presentation.Treatment of these aggressive lesions is usually by gas-trectomy. In contrast, successful treatment of carci-noid tumors associated with CAG-A usually follows abenign clinical course. Endoscopic resection isindicated for lesions less than 1 cm in diameter.Antrectomy to remove the source of gastrin has alsobeen reported to result in tumor regression in somecases. The treatment of carcinoid tumors associatedwith Zollinger-Ellison syndrome is similar to the treat-ment of carcinoid tumors in patients with chronicatrophic gastritis.

2. (A) Originate from subepithelial neuroendocrinecells. In contrast to other GI carcinoids that are ofmucosal origin, appendiceal carcinoids arise fromsubepithelial neuroendocrine cells present in thelamina propria and submucosa of the wall of theappendix. Patients affected by appendiceal carcinoidtumors are younger (average age, 42 years) at thetime of diagnosis versus patients with all other GI car-cinoid tumors (average age, 63 years). Associated

noncarcinoid tumors are seen in 15% of patientswith carcinoid tumors of the appendix. Carcinoidsyndrome occurs in patients with carcinoid tumorsin the appendix that have metastasized to the liver.Carcinoid syndrome may occur in patients withouthepatic metastases but who have carcinoid tumorswith direct access to the systemic circulation (eg, tu-mors of the ovary, testicle, or bronchus).

3. (E) Rectum. Carcinoid tumors of the rectum areknown to be hormonally inactive even when exten-sive liver metastases are present. This observation hasimportant therapeutic implications. Patients withwidespread liver metastases that are hormonally in-active may require no treatment at all.

4. (C) Ileum. Carcinoid syndrome is present in 10% ofpatients with GI carcinoid tumors. More than 75% ofpatients with carcinoid syndrome will have the pri-mary tumor in the small intestine, usually the ileum.Carcinoid syndrome is a marker of advanced diseaseusually seen with extensive metastatic tumor depositsin the liver.

5. (C) Octreotide. In patients with carcinoid syndromeundergoing operative intervention, many things dur-ing the perioperative period may trigger mediatorrelease and precipitate a carcinoid crisis. These trig-gers include prepping of the abdomen; manipulationof the tumor; catecholamine release from sympathet-ic nervous system stimulation; the use of medicationsthat either promote histamine release or stimulateand inhibit the autonomic nervous system; hypoten-sion; hypercapnia; and hypothermia. Patients withcarcinoid syndrome should be well controlled on aregimen of octreotide before surgery. If a patientdevelops the carcinoid crisis, the best treatment isadministration of intravenous octreotide followed bytumor removal. Symptoms of cardiovascular collapseare managed with standard inotropic and vasopressoragents.

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