Carcinoid Tumors - Mansosp.mans.edu.eg/.../0708_Carcinoid_Tumors.pdf · Carcinoid Tumors Deﬁnition ... Indeed, the distribution of carcinoids in autopsy TABLE 2. ... Silver staining

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Carcinoid Tumors

efinitionarcinoid tumors are neuroendocrine tumors arising from enterochromaf-n (EC) cells that are distributed throughout the body. EC cells are theost common endocrine cells and are most frequently identified in the

ubmucosa of the intestine and bronchus. Regardless of their primary site,ll carcinoids share histological, immunohistochemical, and ultrastruc-ural features.1 They may be classified based on either their embryologicite of origin or their microscopic features, with the former used moreommonly. These tumors may produce or contain a variety of amines,eptides, tachykinins, and prostaglandins. The term “carcinoid syndrome”s used to describe the complex manifestations produced by the systemicelease of 1 or more of these compounds. The systemic manifestations ofhis syndrome vary, depending on the embryologic origin of the primaryumor and the extent or site of metastatic disease.Carcinoid is the most common endocrine tumor of the gastrointestinal

GI) tract. The term carcinoid has been adopted by clinicians in referenceo a variety of neuroendocrine neoplasms with variable malignantotential. In the future, accurate biological and molecular profiling willllow more precise classification.

istorical BackgroundLandmark observations in the history of carcinoid tumors are listed inable 1. Carcinoid was first characterized in 1888 by Lubarsh, who

dentified multiple tumors in the small bowel in 2 patients at necroscopy.2

leal carcinoid was first described by Ranson in 1890.3 Oberndorfer usedhe term “karzinoide” to describe tumors that demonstrated a morendolent behavior than adenocarcinomas.4 Carcinoids were first recog-ized as endocrine tumors by Gosset and Masson in 1914.5 Massononfirmed this in 1928 after observing that the malignant chromaffin-taining, or Kulchitsky’s cells in carcinoids demonstrated amine precursor
ptake and decarboxylation (APUD) characteristics.6
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In 1974, Pearse proposed that all tumors of the APUD cell seriesotherwise known as neurocristomas, based on their presumptive deriva-ion from neuroectodermal tissue) should preferably be called “apudo-as” because of their common cytochemical (APUD) and ultrastructural

haracteristics that aid in their diagnosis.7,8 However, in recent years, thisoncept of classifying all tumors with neuroendocrine features as aohesive group has been challenged by the recognition that cells ofifferent embryologic origin, such as immunocytes, manifest neuroendo-rine characteristics.9 It is likely that the concept of a “neuroendocrine”ystem will continue to be redefined as the genetic signals for expressionf the neuroendocrine phenotype in tumors such as carcinoids are betternderstood.9

haracteristics of Carcinoid Tumors

lassificationIn 1963, Williams and Sandler10 classified carcinoid tumors based on

heir presumed embryonic site of origin (Tables 2 and 3). This embryo-ogic classification system distinguished between carcinoids arising in theoregut (respiratory tract, stomach, duodenum, biliary tree, pancreas),idgut (small intestine, appendix, right colon, ovary, testis), and hindgut

ABLE 1. Landmark observations in the history of carcinoid tumors

Year Author Contribution

888 Lubarsh2 First characterization of carcinoid890 Ranson3 First description of ileal carcinoid907 Oberndorfer4 First use of term “karzinoide” to describe tumors with

behavior more indolent than adenocarcinomas912 Saltykow225 First description of colon carcinoid914928

Gosset and Masson5

Masson6Carcinoids should be considered endocrine tumorsbased on the observation that the malignantchromaffin, or Kulchitsky, cells in carcinoidsdemonstrated amine uptake and decarboxylationcharacteristics

931 Scholte146 Identification of carcinoid syndrome937 Hamperl226 First description of pulmonary carcinoid952 Biörck152 First description of carcinoid heart disease953 Lembech227 Carcinoids contain serotonin954 Thorson228 Identification of carcinoid syndrome in patient with

liver metastases from intestinal carcinoid955 Page229 Demonstration of elevated urinary 5-HIAA levels in

patients with carcinoid syndrome

-HIAA, 5-Hydroxyindoleacetic acid.

transverse colon, left colon, rectum). Tumors within each subgroup have

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istinct histologic features, metabolism, and secretory products. Conse-uently, investigators have proposed a classification system encompass-ng morphologic, functional, and biologic characteristics including sucheatures as primary site, presumed cell of origin, and histologic features11

Table 2).

pidemiologyThe overall incidence of carcinoid tumors is estimated to be 1 to 2 caseser 100,000 individuals in the United States and is similar in England,cotland, Spain, Italy, and Japan.12-17 This incidence varies with gender,ge, and race. Carcinoids are 8 to 11 times more common thannsulinomas and 7 to 26 times more common than gastrinomas.18-20 Theirndolent nature suggests that the true incidence of carcinoid tumors is

ABLE 2. Characteristics of carcinoid tumors

CharacteristicsEmbryologic site of orgin

Foregut Midgut Hindgut

rgan Trachea, bronchus,lung

Small intestine Colon

Stomach Appendix RectumPancreas Right colonGallbladder, bile duct Ovary, testis

ell(s) of origin Epithelial endocrinecell

Epithelial endocrinecell

Epithelial endocrinecell

ECL cell (stomach) Subepithelial endocrinecell (appendix)

istologySilver staining Argentaffin-negative,

argyrophilicArgentaffin-positive Argentaffin-negative

(75%),argyrophilic(55%)

Neuron-specificenolase

Positive Positive Positive

Chromogranin A Positive Positive Positive (42%)ecretory productsTumor 5-HT Low High NoneSerum 5-HTP, gastrin, ACTH,

GH, histamine5-HT

Urine 5-HIAA High High NormalOther urine 5-HTP, 5-HT, histamine 5-HT None

arcinoid syndrome Occasional, may beatypical

Frequent Rare

ata adapted from references 28, 107, and 230.-HT, 5-Hydroxytryptamine (serotonin); 5-HIAA, 5-hydroxyindoleacetic acid; ECL, entero-hromaffin-like; ACTH, adrenocorticotropic hormone; GH, growth hormone

robably underestimated. Indeed, the distribution of carcinoids in autopsy


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eries is different than that reported in clinical or surgical studies.utopsy series from the Mayo Clinic and from Malmo, Sweden, have

eported that the incidence of carcinoids is closer to 0.65% to 1.2%,ccounting for 28% of all small bowel neoplasms.21,22 At autopsy, 76%f all carcinoids are found in the jejunum and ileum, compared with onlyne quarter of cases in the other series. The distribution of carcinoidumors by site of origin and primary organ in clinical series is listed inable 3. Carcinoids are generally diagnosed in the fifth or sixth decade of

ife, have a higher incidence in African-Americans, and are slightly morerequent in women (55%).12-14 At presentation, 40% to 60% of patientsre asymptomatic.22,23

A recent analysis of 10,878 carcinoid tumors from the Surveillance,pidemiology, and End Result (SEER) Program of the Nationalancer Institute found that 64% of all carcinoid tumors originate in theI tract and 28% originate in the lungs or bronchi (Table 4). This

tudy evaluated data from 1973 to 1999 divided into 2 periods, 1973o 1991 and 1992 to 1999. Within the GI tract, carcinoids of the small

ABLE 3. Distribution of carcinoid tumors, incidence of carcinoid syndrome, and incidence ofetastatic disease by site of origin

SiteDistribution

(%)

Carcinoidsyndrome

(%)

Metastases(%)

oregutEsophagus �1 — 67Stomach 2–6 9.5 7–31Duodenum 2–4 3.4 20Liver �1 — 29Gallbladder �1 5 33–56Pancreas �1 20 20–76Trachea, bronchus, lung 10–30 13 20–27idgutJejunum 1–2 9 35Ileum 10–23 9 35Meckel’s diverticulum �1 — —Appendix 2–44 �1 2–35Right colon 4–6 5 60–71Ovary 1–2 33 6–32Testis �1 50 —

indgutTransverse colon �1 — 30Left colon 2–4 — 30Rectum 9–19 — 3–14

nknown 1–4 — 15–28

ata adapted from references 13, 24, 25, 28, and 37.

ntestine were most common (29%), and were followed in incidence


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y tumors of the rectum (14%), stomach (5%), and appendix (5%).24

hese rates differ from those in an earlier tumor registries, includinghe End Results Group (ERG) and the Third National Cancer SurveyTNCS), which collected data in the United States from 1950 to 1969nd 1969 to 1971, respectively (Table 4). The incidence rates ofastric carcinoid tumors increased from 2% in the ERG and TNCSeports to 4% and 6% in the 2 SEER study periods. Similarly, rates ofmall bowel carcinoid have increased from 19% (ERG) to 29%combined SEER).13,24,25 In contrast, appendiceal carcinoid tumorsomprised 44% (ERG) and 35% (TNCS) of all carcinoid tumors, butnly 7% and 3% in the 2 SEER studies.13,24,25 The overall incidencef carcinoids has increased over the past 30 years.24

These vastly differing incidence rates should be interpreted with someaution, and likely do not reflect as dramatic a decrease in the incidencef appendiceal carcinoid tumors as initially seems apparent. A majoractor in the apparently decreasing incidence of appendiceal carcinoidumors is the fact that the SEER database reported only “malignant”arcinoid tumors, whereas the earlier registries reported carcinoids withoth “benign” and “malignant” features. A decreasing incidence ofncidental appendectomy during surgery for other indications may havelso influenced the recent decrease in the diagnosis of appendicealarcinoid tumors.

istologyCarcinoid tumors arise from endocrine cells associated with epithelial

ABLE 4. Trends in the distribution of carcinoid tumors over a 50-year period*

Carcinoid Site

End ResultsStudy Group(1950–60)N � 1867

(%)

Third NationalCancerSurvey

(1969–70)N � 970 (%)

Surveillance,Epidemiology & End

Results Program (1973–1999) N � 10,878

(%)

rachea, bronchus, lung 10.2 14.1 27.9tomach 2.2 1.9 4.6uodenum 1.8 2.3 2.8ejunum 1.0 2.0 1.8leum 10.8 13.8 14.9ppendix 43.9 35.5 4.8ecum 2.7 3.0 4.1olon 4.7 3.9 8.6ectum 15.4 12.3 13.6

Adapted with permission from Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715arcinoid tumors. Cancer 2003; 97:934–59.

rgans throughout the body. Enterochromaffin cells, also known as


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ulchitsky’s cells, are the most common endocrine cells and are mostrequently identified in the submucosa of the intestine and bronchus (Fig). Other types of endocrine cells, enterochromaffin-like (ECL) cells inhe stomach, gastrin (G) cells in the antrum of the stomach, somatostatinD) cells in the proximal small intestine, and L cells in the rectum andppendix, can also give rise to tumors. Several proposed classificationchemes distinguish between these tumors on the basis of variousistopathologic features (size, morphologic growth pattern, necrosis, anditotic activity). However, the prognostic usefulness of these classifica-

ion schemes has been difficult to generalize to all neuroendocrine tumors,n part because the clinical setting and management of tumors arising atarious anatomic sites is different.In the lung, a 3-tier classification scheme that correlates well with tumorehavior and patient survival has been proposed.26 “Typical” carcinoidsave a characteristic histologic appearance of monotonous sheets of smallound cells with uniform nuclei and cytoplasm without pleomorphism11

Fig 1). Mitotic figures are rare.11 “Atypical” carcinoids have greateruclear atypia, higher mitotic rates (between 2 and 10 per 10 high powericroscopic fields), and/or necrosis, features all associated with more

ggressive behavior.27 Tumors that show even greater degrees of mitoticctivity, necrosis, or nuclear pleomorphism are classified as high gradeeuroendocrine carcinomas (small cell or large cell, depending on theorphology of the tumor cells) (Fig 1). These tumors typically behave

ery aggressively and will not be considered further in this review.In the GI tract, most endocrine tumors fall into the “typical” carcinoid

ategory, and pathologists cannot distinguish benign from malignantarcinoid tumors based on histologic features alone.28 Therefore, malig-ant behavior can only be confirmed in the presence of invasion oregional or distant metastases. Therefore, the above classification has noteen adopted for general use in the GI tract. The World Healthrganization and American Joint Commission on Cancer recognize the

ategories of carcinoid tumor (also called well-differentiated neuroendo-rine tumor), large cell neuroendocrine carcinoma and small cell carci-oma.29 Colorectal carcinomas with a mixed endocrine/glandular pheno-ype appear to behave similarly to the more common type of colorectalarcinoma and will not be considered further. Gastrointestinal tractarcinoids may also be subclassified histologically based on their site ofrigin (foregut, midgut, and hindgut) into growth patterns: insular (22%),rabecular (18%), undifferentiated (4%), glandular (2%), or mixed43%).30 Foregut carcinoids (stomach and duodenum) have a mixed
attern, including a solid, ribbon-like, trabecular, or acinar appear-

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nce.28,31 Midgut carcinoids (jejunum and ileum) typically have annsular formation of regular tumor cells surrounded by fibrotic stro-a.28,31 Hindgut carcinoids (left colon and rectum) usually have a solid

r trabecular pattern.28,31 Growth patterns may have prognostic signifi-ance. In 1 study, median survival was 4.4 years for a mixed insular pluslandular pattern, 2.9 years for an insular pattern, 2.5 years for arabecular pattern, 2.3 years for a mixed insular plus trabecular pattern,.9 years for a glandular pattern, and 0.5 years for an undifferentiatedattern.32 However, these differences may not be independent of otheractors such as tumor site, size, and stage.Historically, the diagnosis of carcinoid tumors (and confirmation of theeuroendocrine phenotype) was based on silver impregnation stains.33,34

n argentaffin reaction was marked by silver uptake and reduction. An

IG 1. (Continued) Histologic classification of neuroendocrine tumors. (A) Small bowel carcinoidumor (hematoxylin and eosin, �100). Low power view illustrates submucosal location (arrows). (B)Typical” carcinoid tumor (hematoxylin and eosin, �400). This well-differentiated tumor is charac-erized by nested growth pattern and uniform appearance of nuclei. No necrosis or mitotic figures areresent. (C) Pulmonary large cell neuroendocrine carcinoma (hematoxylin and eosin, �400). Thisoorly differentiated tumor demonstrates variability in nuclear size. Mitotic figures are presentarrow). (Color version of figure is available online.)

rgyrophilic carcinoid took up silver but did not reduce it. This classifi-


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ation system has been replaced by identification of the granule-associ-ted proteins chromogranin, synaptophysin, and neuron-specific enolasey immunohistochemistry, which is more specific for neuroendocrineifferentiation.28,33 Ultrastructural features identified under electron mi-roscopy (EM) include membrane-bound, electron-dense neurosecretoryranules.27 However, EM is used less frequently in current practiceecause of the reliability, rapidity, and low cost of immunohistochemis-ry. Table 2 lists histologic characteristics of carcinoid tumors classifiedy site of origin. There is some variation in cell of origin, pattern ofistologic staining, and secretory products contained by the tumor cells.Investigations have not identified consistent predictors of metastaticehavior, such as mitotic rate, cellular atypia, or necrosis, among GIarcinoid tumors. Immunohistochemical staining positive for the prolif-ration marker MIB-1 and p53 may be associated with metastases.35 Highevels of Ki-67 may correlate with worse survival. Future research effortsay identify cell-specific markers predictive of more aggressive behav-

or.

athophysiologyDietary tryptophan is normally oxidized to nicotinic acid, with less than% undergoing 5-hydroxylation into 5-hydroxytryptophan (5-HTP)36

Fig 2). In contrast, most individuals with carcinoid tumors havebnormal metabolism of tryptophan.36 It is hypothesized that in carcinoidumors, up to 60% of dietary tryptophan is shunted to 5-hydroxylationnstead of oxidation, resulting in the synthesis of 5-HTP, 5-hydroxytryp-amine (5-HT, serotonin), and 5-hydroxyindoleacetic acid (5-HIAA).36,37

he bulk of serotonin is metabolized by monoamine oxidase in the liverr aldehyde dehydrogenase in the kidney to 5-HIAA, which is thenxcreted in the urine.1,36 With tryptophan shunted to the tumor instead ofhe brain, nicotinic acid levels are depleted, resulting in pellagra. Pellagras characterized by dermatitis, diarrhea, and dementia.36

Systemic signs or symptoms result from direct secretion of serotoninnd other secretory products into the systemic circulation, usually in theresence of liver metastases or bulky retroperitoneal disease. Serotoninoncentrations within the tumor correlate with the frequency of typicalarcinoid syndrome. Midgut carcinoids have a high serotonin content andre thus associated with a higher incidence of classic carcinoid syn-rome28 (Table 2). Paracrine secretion of serotonin in the intestine mayause diarrhea. In contrast, foregut and hindgut carcinoids maintain lowerotonin levels, and thus these tumors rarely cause the classic symptoms.
oregut carcinoids secrete other biologically active compounds and have

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ore atypical symptoms, such as Cushing’s syndrome (from productionf ACTH) or acromegaly (from production of growth hormone-releasingormone).28,38 Hindgut carcinoids may produce more biologically inertompounds and are seldom if ever associated with hormonal manifesta-ions.39

olecular BiologyCarcinoid tumors have been associated with a variety of genetic

lterations. Multiple endocrine neoplasia type 1 (MEN 1) is an autosomalominant disorder associated with loss of the tumor suppressor geneEN1 on chromosome 11q13 and is typically characterized by tumors of

he parathyroid, pancreas islet cells, and pituitary.40 Carcinoids, particu-arly gastric carcinoids, may occur in 10% of individuals affected with

EN 1.36 Conversely, the MEN1 gene may be involved in tumorigenesisf sporadic carcinoids even in the absence of other MEN 1 manifesta-ions. In 1 study, loss of heterozygosity on chromosome 11 was identifiedn 78% of 46 patients with sporadic carcinoid.41 Furthermore, inactivationf both copies of the MEN1 gene was identified in 44% of sporadic casesf lung carcinoid, suggesting a possible familial etiology to these

Tryptophan

Nicotinic acid

Hydroxylase

5-hydroxytryptophan

Decarboxylase

5-hydroxytryptamine

Monoamine-oxidase(liver)

ldehyde-dehydrogenase(kidney)

5-hydroxyindoleacetic acid

IG 2. Pathway of tryptophan metabolism. Tryptophan normally undergoes oxidation to nicotiniccid. In individuals with carcinoid tumors, tryptophan undergoes 5-hydroxylation to 5-hydroxytryp-

ophan (5-HTP), with subsequent formation of 5-hydroxytryptamine (5-HT, serotonin) and 5-hydroxy-ndoleacetic acid (5-HIAA).

umors.42-44


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For midgut carcinoids, the major areas of chromosomal loss are 18q54%), 9p (15%), 11q (13%), and 16q (12%).45-49 MEN1 mutations havenly occasionally been detected in midgut carcinoids.50 One recent studyapped loss of heterozygosity (LOH) on chromosome 11 using arrayGH and showed that only 1 of 9 midgut neuroendocrine tumors hadOH at 11q13 (MEN1 locus), whereas 3 of 9 had LOH at 11q23.51

Mutations of the p53 tumor suppressor gene have been implicated in theumorigenesis of several malignancies including atypical carcinoids of theung.23,52 Likewise, the bax protein is a main effector of apoptosishrough bax:bax dimerization. Heterodimerization with the p53-regulatedrotein bcl-2 (bax:bcl-2) inactivates apoptosis. In patients with pulmonaryarcinoid, bcl-2 overexpression, bax downregulation, and a bcl-2:baxatio greater than 1 are associated with a worse prognosis.37,53 In gastricarcinoids, bcl-2 expression is greater in metastatic lesions when com-ared with the primary tumor.54

The expression of growth factors such as basic fibroblast growth factorbFGF),55 vascular endothelial growth factor (VEGF),56,57 transformingrowth factor-alpha (TGF-�) and beta (TGF-�),58-60 trefoid peptides,61

nd platelet-derived growth factor (PDGF)55,62 has been demonstrated inI and pulmonary carcinoids. Expression of growth factor receptors

ncluding PDGF receptor (PDGFR)55,62 and epidermal growth factoreceptor (EGFR)59 has also been identified.

iagnosis

arkersThe diagnostic test of choice for suspected carcinoid tumor is theeasurement of urinary levels of the major serotonin metabolite 5-HIAA

n a 24-hour urine sample (normal range 2-8 mg/24 hours). Approxi-ately 50% of patients with carcinoids have elevated levels of urinary

-HIAA, whether or not they have carcinoid syndrome. An elevatedrinary 5-HIAA level has a diagnostic sensitivity of 70% and a specificityf 88% to 100%. Levels correlate with tumor burden.63 However, fruitsnd vegetables, including banana, kiwi, avocado, pineapple, plantain,lum, and tomato, and a variety of nuts, including butternuts, mockernut,ecan, sweet pignut, shagbark, and walnut, may increase urinary 5-HIAAevels.37,64 Cough medicine with guaifenesin, acetaminophen, salicylates,nd L-dopa also affect urinary 5-HIAA levels.65

Another tumor marker, chromogranin A (CGA), is a 49-kD proteinontained in the neurosecretory vesicles of neuroendocrine tumor cells. It
s detectable in the plasma of patients with endocrine neoplasms. Because

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t does not rely on serotonin secretion, serum CGA is a more sensitive androadly applicable marker than urinary 5-HIAA.66,67 Serum CGA levelsay be measured not only in patients with metastatic small bowel and

ppendiceal carcinoid tumors, but also in patients with bronchial andectal carcinoid tumors in whom urinary 5-HIAA levels are less likely toe elevated.66,67 Serum CGA levels also correlate with treatment re-ponse, and may also have prognostic value. In 1 series of 71 patientsith metastatic carcinoid tumors, CGA levels of more than 5000 �g/mLere independently associated with poor prognosis.67 Because CGA

evels may also be elevated in other conditions, their specificity forarcinoid is low and they should not solely be used as a diagnostic test.Platelet serotonin levels may be measured by using high-performance

iquid chromatography and gas chromatography-mass spectrometry.ema and colleagues68 reported that platelet serotonin levels are more

ensitive for the detection of carcinoid tumors and are more consistentlylevated than urinary 5-HIAA. This was particularly true in patients withumors producing low levels of serotonin. Furthermore, platelet serotoninevels were not influenced by the consumption of serotonin-rich foods.

iagnostic Imaging and Localizing StudiesBronchial carcinoids may be seen on chest radiographs or computed

omography (CT). Gastric carcinoids may be identified incidentallyuring diagnostic evaluation for anemia or abdominal pain. Gastric,uodenal, and colorectal carcinoids may be visualized on endoscopy orontrast radiographs. Abdominal CT may identify retroperitoneal tumorsnd liver metastases or demonstrate mesenteric calcifications (70%) andbrosis associated with small intestinal carcinoids (Fig 3).

uclear ImagingMore than 80% of carcinoid tumors express membrane-bound receptors

or the peptide somatostatin.69 The somatostatin analogue, DTPA-d-he10-[octreotide], has been used for the detection and treatment ofarcinoids. OctreoScans exploit the expression of somatostatin receptorsy carcinoid tumors for localization. Octreotide radiolabeled with indium-11 binds to somatostatin receptors 2 and 5. OctreoScans have aensitivity of 80% to 90% and may be the initial imaging modality inocalizing lesions in carcinoid patients28,70 (Fig 4). Furthermore, theetection of metastatic lesions with OctreoScans predicts response toherapy with somatostatin analogues.71,72 However, this diagnostic studys not available at all centers.
Nuclear isotope scans using metaiodobenzylguanidine (MIBG) ra-

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iolabeled with iodine-131 or 123 (131I or 123I) identify primary oretastatic tumors if 131I-MIBG is taken up and stored by the tumor in

he cellular neurosecretory granules. This study has a sensitivity of5% to 70% and specificity of 95%.73 131I-MIBG scintigraphy is lessensitive than OctreoScan and is only rarely used for identifyingetastatic lesions.73

ET ScanPositron emission tomography (PET) traditionally exploits the fact that

ancer cells have a higher glycolytic rate than normal cells and 18F-uoro-2-deoxy-D-glucose (FDG) is used most commonly to identify

ncreased uptake by tumors. In carcinoid tumors, an investigational typef PET is based instead on the metabolism of tryptophan and utilizes-HTP-labeled with 11C to localize tumors as small as 0.5 cm.74,75

IG 3. CT Image of carcinoid tumor with mesenteric fibrosis. A carcinoid tumor at the base of the smallowel mesentery (short arrow) is associated with mesenteric fibrosis (long arrow).

urther evaluation of this method of imaging is required.


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linical Features and Management of Specificarcinoid Tumors

eneral CommentsThe clinical presentation of carcinoid tumors varies depending on the

ite of origin, physical characteristics, and the release of hormonallyctive compounds produced and stored by the tumor. The variousiologically active amines, peptides, tachykinins, and other compoundstored and secreted by carcinoid tumors are listed in Table 5. In general,ost carcinoids are small, asymptomatic indolent tumors. In symptomatic

atients, the clinical diagnosis is frequently made on the basis ofymptoms of flushing and diarrhea.76

The site of origin impacts the pattern of presentation. Foregut carcinoidsave a more atypical presentation due to their secretion of peptideormones other than serotonin, including gastrin, adrenocortotropicormone (ACTH), or growth hormone (GH). Midgut carcinoids containigh levels of serotonin, but are symptomatic only in the setting ofetastatic or bulky retroperitoneal disease. Hindgut carcinoids are clini-

ally silent until in an advanced state. They are rarely hormonally active,ven in the setting of metastatic disease. The most common symptom isleeding.Specific clinical features will be considered by site in the followingiscussion. Figures 5, 6, and 7 depict algorithms for management ofocalized disease, advanced disease, and carcinoid syndrome, respec-ively. The management of patients with specific presentations is sum-arized in Table 6.On gross or endoscopic examination, tumors appear as tan, yellow, orray intramural or submucosal nodules. Gastric and small bowel carci-oids may present with multifocal primary disease in up to 28% ofases.77 Furthermore, 17% to 53% may have synchronous nonendocrinerimary malignancies.78,79 These second malignancies are most com-only gastrointestinal (43%) or gynecologic (20%) in origin; pulmonary,

rologic, hematologic, and neurologic malignancies have also beenescribed.80

The presence of metastatic disease, frequently seen in symptomatic

™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™™IG 4. OctreoScan and CT localization of carcinoid tumor metastatic to the liver. (A) OctreoScandentifies radioactive tracer within the liver (arrow). (B) Corresponding CT image shows liver
etastases (arrow).

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atients, correlates with the size of the primary lesion and with theocation. The metastatic risk for carcinoid tumors is least for appendicealumors and greatest for rectal primaries, as discussed herein. The risk isowest for subcentimeter tumors and rises with increased size, regardlessf the site. The most common metastatic site is the liver, followed by lungnd bone.

ronchopulmonary Carcinoid TumorsCarcinoid tumors of the bronchopulmonary tree account for 2% ofrimary lung tumors.81 “Typical” carcinoids, or well-differentiated pul-onary neuroendocrine tumors, are identified in the fifth decade of

ife.82-84 Because of their perihilar location, these tumors present with

ABLE 5. Biologically active compounds secreted by carcinoid tumors

Amines 5-HT5-HIAA5-HTPCatecholaminesDopamineHistamine

Peptides ACTHCalcitoninChromograninsCRHGastrinGH-RHGlucagonGrowth hormonehCGahCGbInsulinMotilinPancreatic polypeptideNeuron-specific enolaseNeurotensinSynaptophysinVIP

Tachykinins KallikreinNeurokininsNeuropeptide KSubstance P

Other Prostaglandins

-HT, 5-Hydroxytryptamine (serotonin); 5-HIAA, 5-hydroxyindoleacetic acid; 5-HTP, 5-hy-roxytryptophan; ACTH, adrenocorticotrophic hormone; CRH, corticotrophin-releasingormone; GH-RH, growth hormone-releasing hormone; hCG, human chorionic gonadotro-in; VIP, vasoactive intestinal protein.

ecurrent obstructive pneumonia, cough, chest pain, or hemoptysis.82


Malignant Carcinoid Tumor

Localized Disease

Lung Stomach Small Bowel Appendix Colon Rectum

Typicalcarcinoid

Atypicalcarcinoid

Wedge resection/ segmentectomy

Segmentectomy

< 1 cm > 2 cm Pernicious anemia /atrophic gastritis

Sporadic form

Local /endoscopic

excision

Partialgastrectomy

Antrectomy Partialgastrectomy

Bowel resection with widemesenteric resection

< 2 cm > 2 cm Lymph node /mesoappendix

involved

Appendectomy Rightcolectomy

Colectomy

< 1 cm 1-2 cm > 2 cm

Localexcision

LAR / APR

LAR / APR /local

excision

FIG 5. Algorithm for management of malignant carcinoid tumors with localized disease. LAR � low anterior resection; APR � abdominal perineal resection.

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Advanced Disease

Hepatic metastases,No extrahepatic disease

Extrahepatic disease

Limited disease Extensive disease

Resectable

Hepatic arteryembolization /

occlusion

Ablation IFN Somatostatinanalogues

Chemotherapy

Unresectable

IFN Somatostatinanalogues

ChemotherapyResection ±preoperativehepatic arteryembolization

Hepatic arteryembolization /

occlusion

Ablation

Liver transplantation

FIG 6. Algorithm for management of malignant carcinoid tumors with advanced disease. IFN � interferon.

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Carcinoid Syndrome

Flushing Diarrhea Bronchospasm Heart disease

Avoidprecipitants

Antidiarrheal medications Bronchodilators Diuretics

5HT3 antagonists

Hepatic arteryembolization / occlusion

Somatostatin analogues Somatostatin analogues

Valve replacement

IFN,chemotherapy

FIG 7. Algorithm for management of malignant carcinoid tumors with carcinoid syndrome. Adapted with permission from Jensen RT, Doherty GM. Carcinoid tumorsand the carcinoid syndrome. IFN � interferon. In: DeVita VTJ, Hellman S, Rosenberg SA, editors. Cancer: Principles and Practice of Oncology. Philadelphia, PA:Lippincott Williams & Wilkins; 2001; pp 813-33.

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ABLE 6. Management by site, size, and presence or absence of carcinoid syndrome

Site SizeCarcinoidsyndrome

Extent of resection

ung, bronchus Any, typical �,� Wedge or segmental resectionAny, atypical �,� Consider more extensive

resectiontomach �1 cm �,� Local, endoscopic excision

�2 cm or recurrent �,� Partial or subtotal gastrectomyPernicious anemia, atrophic

gastritis�,� Antrectomy

Sporadic group �,� Gastrectomymall intestine Any size �,� Bowel resection with wide

mesenteric resectionppendix �1 cm �,� Appendectomy

�1 cm, base of appendix �,� Cecectomy1–2 cm �,� Appendectomy or right

colectomy with widemesenteric resection

�2 cm �,� Right colectomy with widemesenteric resection

Involved vessels,mesoappendix, or nodes(any size)

�,� Right colectomy with widemesenteric resection

olon Any size �,� Colectomy with widemesenteric resection

ectum �1 cm �,� Wide local excision1–2 cm �,� LAR/APR (for invasion of

muscularis propria)�2 cm �,� Wide local excision, sphincter

preservation (controversial)iver metastasis �50% hepatic involvement �,� Hepatic resection, ablation

�50% hepatic involvement � Hepatic artery embolization,IFN, chemotherapy, orclinical trials

�50% hepatic involvement � Hepatic artery embolization,IFN, chemotherapy, orclinical trials � long-actingsomatostatin analogue

xtrahepaticmetastasis

High volume � IFN, chemotherapy, clinicaltrials

High volume � Above � long-actingsomatostatin analogue

dvanced disease,any site

Low volume, negativeOctreoScan

� Observation

Low volume, positiveOctreoScan

� Long-acting somatostatinanalogue

Any volume or progressivedisease

� Long-acting somatostatinanalogue, IFN, clinical trials

AR, Low anterior resection; APR, abdominoperineal resection; IFN, interferon.


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ive- and 10-year survival rates of 60% to 100% and 40% to 100%,espectively, have been reported.85 Pulmonary carcinoids may releaseorticotropin, resulting in Cushing’s syndrome in 2% of patients; in fact,% of patients presenting with Cushing’s syndrome have a pulmonaryarcinoid tumor.86,87 These tumors may also release GH-releasing hor-one (GH-RH), resulting in acromegaly.88 Carcinoid syndrome is ob-

erved in less than 5% of cases.82 Metastases, usually to mediastinalymph nodes, liver, bone, or skin, have been identified in fewer than 15%f cases.27,82,83

“Atypical” carcinoids, accounting for one third of bronchopulmonaryarcinoids, commonly present in the sixth decade of life.89-91 Histologi-ally, they have more nuclear atypia and mitotic figures. Unlike typicalarcinoids, atypical tumors are larger and located more peripherally.90,91

hese tumors are more aggressive, with lymph node metastases identifiedn 30% to 50% of cases.Localized pulmonary carcinoid tumors may be treated with conserva-

ive wedge or segmental resection82,90 (see Fig 5, Table 6). Atypicalarcinoids require more extensive resection, including lobectomy.90

In patients with bronchopulmonary carcinoid tumors, age, tumorize, and extent of lymph node involvement have been identified asrognostic factors.37 Studies have reported 5-year overall survivalates of more than 90% for typical carcinoids and 40% to 60% fortypical carcinoids.82-84,90,91 The 5-year overall survival rates forronchopulmonary carcinoid tumors with localized disease, regionalpread, and distant metastases are 81%, 77%, and 26%, respectively24

Table 7).

astric Carcinoid TumorsGastric carcinoids account for fewer than 1% of all gastric neo-lasms.13,25 They may be found incidentally at endoscopy or may presentith abdominal pain, gastrointestinal bleeding, or anemia.28 Gastric

arcinoids originate from the histamine-producing enterochromaffin-likeells.92 Gastrin may be mitogenic for these cells.92 Patients often lackarietal cells and have achlorydria and hypergastrinemia.92

Based on their clinical or histological features gastric carcinoids may belassified into 3 groups: those associated with chronic atrophic gastritisype A (CAG-A), those associated Zollinger-Ellison syndrome, andporadic gastric carcinoids. Characteristics of these distinct subtypes areisted in Table 8. Approximately 75% of cases are associated withAG-A (Fig 8), one half of which are also associated with pernicious
nemia.92-95 These tumors usually are less than 1 cm in size, arise in the

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undus and body of the stomach, and predominate in women. Theyypically are detected in the sixth or seventh decade of life, and areultifocal in more than 50% of cases. Ten percent of cases haveetastases.93,95,96

Gastric carcinoids are associated with Zollinger-Ellison syndrome in% to 10% of cases, usually in conjunction with MEN 1. These tumorsre less than 1.5 cm in diameter, have an equal gender distribution, andetastasize in 25% of cases.94

ABLE 7. Five-year overall survival*

SiteLocalized

(%)

Regionalmetastases

(%)

Distantmetastases

(%)

Unstaged(%)

Allstages

(%)

rachea, bronchus, lung 81 77 26 48 74tomach 69 38 21 65 63iver NA 16 NA 20 18allbladder 76 33 NA NA 59ancreas 64 NA 41 NA 38mall bowel 60 73 50 32 61ppendix 81 88 10 67 71ight colon 79 78 44 NA 61eft colon 80 50 NA 100 68ectum 90 49 26 87 87nus 100 NA NA NA 100ther GI NA NA NA 50 16vary 95 NA 13 NA 66estis 100 NA NA NA 100ll sites 78 72 39 48 67

A, Not available; GI, gastrointestinal.Adapted with permission from Modlin IM, Lye KD, Kidd M. A 5-decade analysis of 13,715arcinoid tumors. Cancer 2003; 97:934–59.

ABLE 8. Subtypes of gastric carcinoid tumor

Frequency(%)

Genderdistribution

Size FeaturesMetastatic

rate (%)

hronic atrophicgastritis type A

75 F � M �1 cm Absence of parietalcells,achlorhydria,hypergastrinemia,multifocal

10

ollinger-Ellisonsyndrome

5–10 F � M 1.5 cm MEN 1 25

poradic 15–20 F � M �1 cm Atypical carcinoidsyndrome

54–66

, Female; M, male; MEN 1, multiple endocrine neoplasia type 1.

The remaining 15% to 20% of patients have sporadic gastric carcinoid.


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hese sporadic cases have a histamine-mediated atypical carcinoidyndrome manifested as flushing and erythema, pruritis, conjunctivaluffusion, facial edema, and urticaria. The tumors are typically larger thancm in size at diagnosis and predominate in men. They have a higheretastatic potential (54% to 66%) and a less favorable prognosis than the

ther 2 groups.96,97

Tumors smaller than 1 cm in size may be treated with a limited orndoscopic resection with close endoscopic surveillance93 (see Fig 2).arger or recurrent tumors usually require more extensive resection.atients with pernicious anemia or atrophic gastritis should undergo anntrectomy to remove the gastrin stimulus; regression of the lesions issually observed. Because of the aggressive nature of sporadic gastricarcinoids, affected patients may benefit from more radical resection,

IG 8. Gastric carcinoid tumor. The submucosal gastric carcinoid tumor (arrow) is associated withhronic atrophic gastritis in the overlying mucosa (hematoxylin and eosin, �400). Reprinted withermission from Kulke MH, Mayer RJ. Carcinoid tumors. N Engl J Med 1999;340:858-68. (Colorersion of figure is available online.)

ncluding gastrectomy. The 5-year overall survival rates for gastric


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arcinoid tumors with localized disease, regional spread, and distantetastases are 69%, 38%, and 21%, respectively24 (see Table 7).

mall Bowel Carcinoid TumorsCarcinoid tumors account for 29.6% to 42.3% of all primary neoplasmsf the small bowel based on data from 4 population-based studies (Table).98-101 Their distribution is different from that of the more commonmall bowel adenocarcinoma. Carcinoid tumors are rarely found in theuodenum, representing 3.4% to 11.9% of all duodenal neoplasms and

ABLE 9. Distribution of carcinoid tumors across the small bowel

Study

Totalsmallbowel

cancers*

Carcinoid by small bowel subsite (%)Total

carcinoidDuodenum Jejunum Ileum NOS

os Angeles County100 N � 1190 N � 5031972–1985

% of small bowelsubsite

8.3 20.2 67.2 51.1

% of total smallbowel cancers

1.8 3.6 25.8 11.0 42.3

EER registries101 N � 1832 N � 5421973–1982


5.2 9.3 54.6 31.1


1.0 2.0 19.7 6.9 29.6

ancer registries ofBritishColumbia,Alberta,Saskatchewan,and Manitoba99

N � 1244 N � 334

1975–1989% of small bowel

subsite3.4 10.1 56.9 25.3


0.7 1.7 15.8 8.6 26.8

tah Cancer Registry N � 328 N � 1361966–199098


11.9 30.9 58.9 42.5


1.5 5.2 19.2 15.6 41.5

OS, not otherwise specified.Includes adenocarcinoma, carcinoid, sarcoma, and lymphoma.

.7% to 1.8% of all primary small bowel neoplasms.98-101 Carcinoid


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umors are similarly rare in the jejunum, accounting for 9.3% to 30.9% ofll jejunal neoplasms and 1.7% to 5.2% of all primary small boweleoplasms.98-101 However, these tumors are much more commonlydentified in the ileum, and in fact are the most common ileal neoplasm,enerally in the terminal 60 cm (Fig 9).101 Ileal carcinoid tumorsepresent 54.6% to 67.2% of all ileal tumors and 15.8% to 25.8% of allrimary small bowel neoplasms.98-101 Tumors are often multicentric, asrst described by Lubarsch,2 occasionally presenting as clusters of lesionstudding the mucosa.22

Small bowel carcinoids typically present in the sixth or seventh decadef life with symptoms similar to other small bowel tumors: bowelbstruction, abdominal pain, diarrhea, and gastrointestinal bleeding.23

dvanced disease may induce a characteristic, idiopathic desmoplasticeaction, resulting in mesenteric (Fig 3) or retroperitoneal fibrosis (Fig

IG 9. Small bowel carcinoid tumor. The tumor (arrow) is solid and yellow in color, and predominantlyubmucosal. Infiltration of the muscularis (bottom) is present. (Color version of figure is availablenline.)

0). Contraction of the fibrotic scar tissue results in an accordion-like


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uckling of the bowel wall.22 This may potentially cause bowel obstruc-ion or mesenteric ischemia.22 Although the biological mechanism ofbrosis remains unknown, growth factors are now being evaluated asotential etiologic agents behind carcinoid-associated fibrosis.102 Candi-ate agents include platelet-derived growth factor (PDGF), insulin-likerowth factors I and II (IGF-I and II), epidermal growth factor (EGF), andhe transforming growth factor-alpha and beta (TGF-�, TGF-�) familiesf peptides. Regional lymph nodes and the liver are the most common sitef disease spread, and the majority of patients present with metastaticisease. Carcinoid syndrome is present in up to 10% of all small bowelarcinoid cases.22

Small bowel carcinoids have a greater propensity to metastasize than dohose at other sites such as the appendix. Therefore, small bowelarcinoids should be treated with bowel resection with wide en blocesenteric resection, in an effort to remove any potentially involved

egional nodes for better local control103 (Fig 5, Table 6). Since the

IG 10. Retroperitoneal fibrosis. A retroperitoneal metastatic carcinoid tumor deposit (arrow) isssociated with a local desmoplastic reaction resulting in fibrosis of the retroperitoneum. (Colorersion of figure is available online.)

ncidence of multicentric disease is 20% to 40% and of a second primary


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alignancy is 20% to 30%, the entire bowel should be inspected.104

imited resections may be necessary for palliation for obstruction oresenteric ischemia due to mesenteric fibrosis, even in the presence ofetastatic disease.22

The risk of regional and distant dissemination of primary carcinoids ofhe small bowel, appendix, colon, and rectum correlates with size (Table). Survival correlates with the stage of disease at presentation. Accordingo the SEER data from the National Cancer Institute, the 5-year overallurvival rates for small bowel carcinoid tumors with localized disease,egional spread, and distant metastases are 60%, 73%, and 50%, respec-ively24 (Table 7).

ppendiceal Carcinoid TumorsCarcinoid tumors are the most common tumors of the appendix.105

ppendiceal carcinoids are generally incidental findings during appen-ectomy, identified once in every 200 to 300 cases.106 They are mostften diagnosed at a relatively young age, in the fourth or fifth decade ofife.13 Appendiceal carcinoids are more common in women, a finding thatannot be explained solely by the higher rate of incidental appendecto-ies in women undergoing cholecystectomy or obstetric and gynecologic

rocedures. Only 10% of appendiceal carcinoid tumors are symptomatic,argely because approximately 75% are located in the distal one third ofhe appendix where they are less likely to cause obstruction.The algorithm for the management of appendiceal carcinoids is shown

n Fig 5 and Table 6. Those smaller than 1 cm in size may be treated byppendectomy.106 Subcentimeter appendiceal carcinoids at the base of theppendix may require a cecectomy. Management of appendiceal carci-oid tumors between 1 and 2 cm in size is more controversial. In general,umors 2 cm or smaller in size may be managed with appendectomylone, although some would argue that in a young, otherwise healthyatient, a right colectomy should be performed. Moertel and col-eagues106 recommended simple appendectomy in patients with appen-iceal carcinoid tumors 2 cm or smaller in size, even in young patients inxcellent condition, because the additive risk associated with rightemicolectomy exceeded the risk of death from metastatic appendicealarcinoid. Treatment of tumors 1 to 2 cm in size may be individualizedased on tumor location and patient-specific factors. Those larger than 2m in size are best treated with a right colectomy, given the greater riskf lymph node metastases and observation of local recurrences afterimple appendectomy.106,107 The presence of mesoappendiceal invasion
s considered an indication for hemicolectomy, although no local recur-

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ences have been reported in these cases after simple appendec-omy.108,109 Patients with nodal involvement should also undergo rightolectomy. Multicentricity, common at other sites, is uncommon (4.2%)ith appendiceal carcinoid tumors.105

Size is the best predictor of prognosis. Only 5% of appendicealarcinoid tumors are larger than 2 cm in size, but 33% of these haveetastasized at presentation.105,106,110 The risk of regional and distant

pread based on size is shown in Table 10. The 5-year overall survivalates for patients with localized disease, regional metastases, and distantetastases are 81%, 88%, and 10%, respectively24 (see Table 7).Subbuswamy and colleagues first described a new variant type of

ppendiceal epithelial tumor.111 Variably called goblet cell carcinoid,ucinous carcinoid, adenocarcinoid, intermediate type of carcinoid, crypt

ell carcinoma, or amphicrine neoplasia, this tumor may be asymptom-tic, resemble acute appendicitis, or present as a Krukenberg’s tumor oridespread peritoneal disease.112 Goblet cell carcinoids are more aggres-

ive than typical appendiceal carcinoids; nearly 20% of patients haveetastatic disease at presentation.112 Indeed, a large proportion of these

umors behave as adenocarcinomas and are best considered malignantumors with bidirectional endocrine and glandular differentiation. Predic-ors of more aggressive behavior and metastatic spread include anncreased number of Paneth cells, increased amount of mucin secretion,nd the presence of pancreatic polypeptide.112 Tumors with cecal in-olvement or high histologic grade confirmed after initial appendectomyhould undergo completion right colectomy due to the known risk forntraperitoneal seeding before lymph node involvement.112 Female pa-ients are at risk for developing ovarian metastases and should be treated

ABLE 10. Risk of regional and distant dissemination based on size

Site of primary lesion<1 cm

(%)

Size1–2 cm

(%)

>2 cm(%)

isk for regional spread by siteSmall bowel 40 60 85Appendix �0.1 �2 50Right colon 40 60 85

isk for distant spread by siteSmall bowel 15–25 58–80 86–95Appendix 2 33Rectum 5 5–30 �70

ata from references 15, 28, 76, 107, and 116–118.

ith bilateral salpingo-oophorectomy.112 Peritoneal cytoreductive sur-


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ery with intraperitoneal hyperthermic chemoperfusion may improveurvival in cases with advanced peritoneal dissemination.112 In patientsith metastatic disease, chemotherapy with 5-fluorouracil (5-FU) and

eucovorin is offered.

olonic Carcinoid TumorsCarcinoids make up less than 1% of primary colonic tumors.13 Patients

ypically present in the seventh decade.113 Symptoms, such as pain,norexia, or weight loss, are usually only present with advanced dis-ase.113 Carcinoid syndrome is present in fewer than 5% of cases.Approximately two thirds of the tumors are in the cecum or right

olon.113,114 The average tumor diameter at presentation is 5 cm. Twohirds of patients present with regional or distant metastatic disease.113,114

econd primary malignancies, usually in GI or genitourinary organs, aredentified 25% to 40% of the time.113 Treatment for colon carcinoidumor is generally a radical colectomy with en bloc mesenteric resectionFig 5, Table 6). The 5-year overall survival rates for patients withocalized disease, regional metastases, and distant metastases are listed inable 7.13

ectal Carcinoid TumorsCarcinoid tumors account for 1% to 2% of all rectal tumors.13 They

re usually asymptomatic and present in the sixth decade of life.arcinoids are detected incidentally in 1 of every 2500 proctoscopies,

ocated on the anterior or lateral rectal walls between 4 and 13 cmbove the dentate line (Fig 11).15,115 Symptoms, when present, includeectal bleeding, pain, or constipation.27,115 Carcinoid syndrome is onlyanifested rarely.15

The algorithm for the management of rectal carcinoid tumors is shownn Fig 2. Tumors smaller than 1 cm, which account for two thirds ofesions, may be managed with wide local excision alone. Management ofectal carcinoids between 1 and 2 cm in size is somewhat controversial.ndoscopic ultrasound is frequently used in these cases to assess thextent of local invasion. Those with involvement of the muscularisropria, symptoms at diagnosis, or ulceration generally have a worserognosis and should undergo full thickness excision via low anterioresection (LAR) or abdominoperineal resection (APR).115,116 Thosearger than 2 cm in size have traditionally been treated with a LAR orPR, but they are at such a high risk of distant metastasis (Table 10) that

adical local resection offers little if any survival benefit over local
xcision alone.117-119 Thus, wide local excision with every attempt at

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phincter preservation may be more appropriate in many cases; anndividualized approach should be used to decide the course of treatment.Common sites of metastases are lymph nodes and liver. Metastases are

ommonly present with tumors larger than 2 cm in size, but in less than% of patients with tumors smaller than 1 cm in size.116 Synchronousarcinoid primary tumors are identified in 0% to 3% of cases, and secondrimary malignancies occur in 7% to 32% of cases.104 The 5-year overallurvival rates for patients with localized disease, regional metastases, andistant metastases are 90%, 49%, and 26%, respectively24 (Table 7).

rimary Carcinoids at Other SitesThymic carcinoids present as anterior mediastinal masses. In a prospec-

ive analysis, thymic carcinoids were identified in 8% of patients withEN 1 and were associated strongly with the concomitant presence of

IG 11. Rectal carcinoid. This submucosal rectal carcinoid tumor (arrow) was identified incidentallyn sigmoidoscopy and was removed by endoscopic snare. Photograph courtesy of Linda S. Lee, MD,epartment of Medicine, Gastroenterology and Hepatology Division, Brigham and Women’sospital, Boston. (Color version of figure is available online.)

astric carcinoid.120 Thymic carcinoids are hormonally inactive, but are


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ery aggressive, with more than 50% recurring locally.120 Gibril andolleagues120 from the National Institutes of Health recommended areventive cervical thymectomy at the time of parathyroidectomy inndividuals with MEN 1.Pancreatic carcinoids may occur sporadically or in MEN 1 and vonippel Lindau kindreds, but not in neurofibromatosis 1 families.1 These

umors usually arise in pancreatic islets, and symptoms depend on theormones released. Tumors located in the head, neck, or uncinate processf the pancreas may be resected with a pancreaticoduodenectomy. Thosen the body or tail of the pancreas may require a distal pancreatectomy,ith or without a splenectomy.Ovarian carcinoids have been reported. Overproduction of peptide YY may

ead to symptoms of constipation.121 Carcinoid syndrome has been reportedn 29% to 33% of patients with primary ovarian carcinoid tumors, even in thebsence of hepatic metastases.122,123 Ovarian and testicular carcinoids maye detected as masses on physical examination or ultrasound.

arcinoid Metastases to the Liver

IG 12. Carcinoid tumor metastatic to the liver. Contrast-enhanced abdominal CT illustrates theeterogeneous appearance of bilobar liver metastases from a small bowel carcinoid tumor.

Metastatic disease is present in 90% of symptomatic patients (Fig 12).


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f liver metastases are suspected, an abdominal CT should be obtained.arcinoid metastases to the liver are often hypervascular after thedministration of intravenous contrast, so images should be obtainedefore and after contrast injection.124,125

The clinical course of patients with metastatic carcinoid disease variesonsiderably. Patients may remain asymptomatic for years. An elevatedlasma chromogranin A level is an independent predictor of poorrognosis.67 Management of carcinoid metastases to the liver depends onhe extent of disease and the magnitude of the symptoms. Treatmentlgorithms are outlined in Fig 6.Surgical Strategies. In the setting of metastatic disease, asymptomaticrimary carcinoid tumors do not need to be resected. However, palliativeesection or debulking of the primary disease may be indicated in patientsith obstruction or severe desmoplastic reactions.126

Limited metastatic liver disease may be treated with hepatic resec-ion, providing both long-term symptomatic relief and prolongedurvival.127-129 Ablative therapies (radiofrequency ablation, cryoabla-ion, ethanol injection) are an alternative when resection is noteasible. Que and colleagues129 reported that patients with neuroen-ocrine tumor metastases to the liver undergoing hepatectomy had a-year overall survival rate of 73%. However, relapses were commonfter an intended curative resection, and the morbidity and mortalityates were 24% and 2.7%, respectively.Liver transplantation for most metastatic malignancies has commonly

esulted in early tumor recurrences.37 The results with neuroendocrineumors have been more promising. Results from a multicenter study fromrance demonstrated a 5-year overall survival rate of 69%.130 Major

ransplant-related complications were reported in 53% of cases. Althoughong-term survival results are encouraging, liver transplantation as aiable treatment modality for metastatic carcinoid is limited by donorrgan availability.Hepatic Artery Occlusion. The role for hepatic artery occlusion in the

reatment of metastatic disease is expanding. Vascular occlusion takesdvantage of the fact that the liver has a dual blood supply. Metastases tohe liver primarily derive their blood supply from the hepatic arteryirculation, whereas hepatocytes are sustained by additional blood supplyrom the portal venous circulation. Thus, vascular occlusion of the hepaticrtery, via ligation or embolization, selectively devascularizes tumorells.131-136 Although early attempts at hepatic artery ligation resulted in
uccessful selective tumor necrosis, responses were short-lived as a result

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f reactive angiogenesis and the development of collateral circulation.137

herefore, surgical ligation of hepatic arteries is now rarely performed.Trials investigating hepatic artery occlusion by embolization with

gents such as gelatin powder, polyvinyl alcohol, and coils, so-calledbland embolization,” have demonstrated biochemical response ratesusually �50% reduction in urinary 5-HIAA levels) of 13% to 52% andumor response rates (by imaging criteria) of 37% to 38%131,135,138

Table 11). Chemoembolization with agents such as 5-fluorouracil,

ABLE 11. Efficacy of embolization-based therapy in advanced carcinoid*

Treatment(s)No. of

patients

Biochemicalresponse

rate(%)

Tumorresponse

rate(%)

Responseby trialcriteria

(%)

Embolizationagent

Reference

mbolization 12 NA NA NA Gelatin powder 13323 52 NA 87 Gelatin powder,

polyvinylalcohol, coils

131

29 41 38 52 Gelatin powder 13817 NA 33 NA Cisplatin

microcapsules140

mbolization v.ligation

8 13 38 38 Gelatin powder 135

19 37 37 42mbolization �doxorubicin

18 57 33 NA Gelatin powder 136

23 91 35 NA Gelatin powder 14415 69 78 79 Gelatin powder 143

mbolization �IFN-�

17 47 53 NA Gelatin powder 196

mbolization �octreotide �fluorouracil/cizpiztin/mitomycin C

10 NA 60 60 Gelatin powder,bovinecollagenfibers

139

mbolization �octreotide �fluorouracil/cizpiztin/mitomycinC/doxorubicin

15 NA 8 77 Polyvinylalcohol

141

mbolization �fluorouracil/cizpiztin

16 75 25 NA Gelfoampowder

142

A, not reported; IFN, interferon.Adapted with permission from Schnirer II, Yao JC, Ajani JA. Carcinoid—a comprehensiveeview. Acta Oncol 2003; 42:672–92.

ecarbazine, doxorubicin, cisplatin, mitomycin C, or streptozocin com-


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ined with bland embolization resulted in biochemical response rates of7% to 91% and tumor response rates of 8% to 60%.136,139-144 Theddition of chemoembolization did not result in responses superior tohose from bland embolization alone.This technique provides effective palliation, although sometimes of

hort duration. However, treatment-related toxicities are significant. Apostembolization syndrome,” consisting of high fevers, severe pain,ausea, fatigue, and a transient transaminitis, is common. A massiveelease of hormones may trigger a carcinoid crisis (see below). Grade/4 toxicities include gastrointestinal bleeding, sepsis, ischemic ne-rosis of the gallbladder and small bowel, gastric and duodenal ulcers,ortal vein thrombosis, renal failure, hepatorenal syndrome, andrrhythmias.133,136,138-144 Treatment-related deaths have been causedy sclerosing cholangitis (2, both from bovine collagen fiber emboli-ation), sepsis (2), hepatic abscess, and hepatorenal syndrome2).133,138-140

urvivalIn a study of 188 cases of GI carcinoid tumors, McDermott and

olleagues145 identified age less than 50 years, female gender, site ofrimary tumor (appendix � small bowel � colorectal � pancreas), depthf invasion, tumor size (1 cm � 1.1-2.0 cm � 2.1 cm), and absence ofodal or liver metastases as prognostically favorable variables on univar-ate analysis. On multivariate analysis, the only independent predictor ofeath due to the disease was the presence of metastases.145 Gender was anndependent predictor of death due to any cause.Five-year overall survival data from the SEER database are presented inable 7.24 The 5-year overall survival rate for all carcinoid tumors,

egardless of the site, was 67%.24 The SEER data detail survival ratesased on the specific organ site of origin and on extent of disease atresentation (localized disease, regional metastases, distant metastases).n general, the stage of disease correlated with the survival rate. The besturvival rates (all stages) were identified for patients with rectal (88%),ppendiceal (71%), and bronchopulmonary (74%) carcinoids.24 Theoorest survival rates (all stages) were noted for patients with hepatic18%) and pancreatic (38%) carcinoids.24

Re-analysis of the SEER data using the histological classificationescribed by Williams and Sandler10 revealed 5-year overall survivalates of 70% for foregut carcinoids (GI and bronchopulmonary sites),
1% for midgut carcinoids (small bowel, appendix, with and without

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olon), 88% for hindgut carcinoids (rectum only), and 79% for hindgutarcinoid (combining colon and rectum).24

arcinoid Syndrome

eneral CommentsCarcinoid syndrome, the hormonal manifestation of carcinoid tumors,as first described by Scholte in 1931.146 It is present in only 10% to 18%f localized cases and 40% to 50% of patients with more advancedisease.36,147 The presence of carcinoid syndrome is associated with poorurvival.37

Symptoms develop when the secretory products released from theumors gain direct access to the systemic circulation, bypassing metabo-ism in the liver. The situations in which such a circumstance mayevelop include the presence of liver metastases, retroperitoneal diseaseith drainage into paravertebral veins, or primary sites of disease outside

he GI tract. Midgut carcinoids account for 90% of cases of carcinoidyndrome.Symptoms of carcinoid syndrome were originally attributed to elevated

evels of serotonin secreted by the tumor.148 In a review of 748 cases ofarcinoid syndrome, 92% had increased serotonin activity,149 but inarious studies 12% to 26% of patients with elevated serotonin levels hado symptoms of carcinoid syndrome.148

Typical symptoms and the presumed etiologic agents are listed in Table2. Treatment algorithms for several of the symptoms associated witharcinoid crisis are illustrated in Fig 7. Typical symptoms includeramatic purple flushing of the upper body, watery diarrhea, facial edema,weating, bronchospasm, dyspnea, abdominal pain, and hypotension.ymptoms may last from a few minutes to several days and may be

imited to 1 part of the body or be more diffuse.37

Flushing, the most common symptom, is identified in 85% to 90% ofases of carcinoid syndrome.37,107 Episodes of flushing are often associ-ted with an uncomfortable feeling of warmth and occasionally withacrimation, pruritis, palpitations, facial or salivary gland edema, diarrhea,nd hypotension.28,37 Several variations of cutaneous flushing have beenescribed.37,126 The diffuse erythematous variant is characterized byhort-lived flushing of the face, neck, and upper chest. Violaceousushing is similar to diffuse erythematous flushing, but with longeruration and a possible permanent cyanotic flush, watery eyes, andnjected conjunctiva. Prolonged flushing may last up to 3 days, with
nvolvement of the whole body. It is also characterized by lacrimation,

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ypotension, and facial edema. Finally, gastric carcinoids may bessociated with a distinct pattern of flushing with bright red patches.lushing associated with bronchial carcinoids may last longer and haveore pronounced symptoms.28 Precipitating factors include stress, alco-

ol, or particular foods such as blue cheese or chocolate.38 Flushing haseen attributed to the systemic release of various tachykinins, serotonin,rostaglandin, and substance P and may be controlled by somatostatinnalogues but not by serotonin antagonists.37,39,107 The exact cause,owever, remains unclear.Diarrhea may be watery or frothy, or may resemble steatorrhea in up to7% of patients.38 Secretory diarrhea occurs with flushing in 85% ofases.38 The frequency of bowel movements ranges from 2 to 30 per

ABLE 12. Clinical features of carcinoid syndrome*

SymptomFrequency

(%)SecretoryProduct

Other cause

lushing 85–90 BradykininKallikrein5-HTProstaglandinSubstance P

ecretory diarrhea 70 Gastrin5-HTVIPProstaglandin

bdominal pain 35 Obstruction, ischemia,hepatomegaly

eart disease 30 (right), 10(left)

5-HT

Substance Pelangiectasia (face) 25 VIP

SerotoninBradykininProstaglandin

ronchospasm 15 BradykininHistamineProstaglandin5-HT

ellagra 5 Niacin deficiencylucose intolerance — 5-HTrthropathy — 5-HTypotension — 5-HT

dditional data from references 36, 37, 77, 107, 151, and 162.-HT, 5-Hydroxytryptamine (serotonin); VIP, vasoactive intestinal peptide.Adapted with permission from Schnirer II, Yao JC, Ajani JA. Carcinoid—a comprehensiveeview. Acta Oncol 2003; 42:672–92.

ay.28 The total bulk from steatorrhea is greater than 15 g per day in 46%


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f patients.28 The diarrhea may be mediated by gastrin, serotonin,asoactive intestinal peptide (VIP), or prostaglandin.37,107 Serotoninppears to have a causative role; treatment with the serotonin antagonistethysergide reduces the frequency of diarrhea.150 Diarrhea may also

epresent part of the spectrum of pellagra, along with dermatitis andementia.Repeated attacks of carcinoid syndrome may result in telangectasia andermanent skin discoloration. Facial telangiectasias, present in 25% ofatients with carcinoid syndrome, likely arises from systemic absorptionf VIP, serotonin, bradykinin, or prostaglandin.37,107 Bronchospasm,dentified in 15% of patients, usually results from release of bradykinin,istamine, prostaglandin, or serotonin.151

Systemic release of serotonin may also be responsible for carcinoideart disease (discussed in detail follows), glucose intolerance, arthrop-thy, and hypotension.37,107 Cardiac symptoms arise from associatedndocardial fibrosis, resulting in tricuspid regurgitation or pulmonictenosis, which in turn cause right-sided heart failure.Pellagra is present in 5% of cases of carcinoid syndrome and is due toiacin deficiency secondary to abnormal tryptophan metabolism. Torevent pellagra, dietary supplements should include nicotinamide.

arcinoid Heart DiseaseCarcinoid heart disease was first described by Biörck and colleagues in952.152 Two thirds of patients with carcinoid syndrome have carcinoideart disease. Carcinoid heart disease usually involves the right side of theeart.153 Fibrous thickening of the endocardium often causes fixation ofhe valves, most commonly leading to tricuspid regurgitation, but also toulmonary stenosis, tricuspid stenosis, and pulmonary regurgitation153

Fig 13). The fibrous deposits are usually on the ventricular side of thericuspid valve and the associated chordae. Left-sided carcinoid heartisease is reported in fewer than 10% of patients.154,155

The pathologic mechanism behind the development of this heart diseaseemains uncertain. The preponderance of right-sided lesions suggests thatausal factors may be released into the hepatic veins from the liveretastases. The endocardial fibrosis may be induced by continuously high

oncentrations of circulating amines. Patients with carcinoid syndromend carcinoid heart disease have high serum levels of serotonin, but whatole this hormone plays is unknown.153-155 It has also been associatedith high levels of urinary 5-HIAA and plasma neurokinin A and

ubstance P.154,155

Identical valvular lesions are present in patients exposed to fenfluramine


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nd dexfenfluramine, appetite suppressant drugs that interfere witherotonin metabolism.156-159 Further insight into the mechanism behindarcinoid heart disease may come from the study of valvular diseasettributed to these anorectic agents.27

A treatment algorithm for the management of carcinoid heart disease ishown in Fig 4. Initial attempts at control involve diuretics and soma-ostatin analogues (discussed in detail below). Treatment resulting inecreased urinary 5-HIAA excretion does not result in the regression ofhe cardiac lesions.154 Valve replacement leads to a substantial improve-

ent in symptoms, but is associated with significant perioperativeorbidity and mortality in patients with symptomatic carcinoid heart

isease.160,161

arcinoid CrisisCarcinoid crisis is a life-threatening form of carcinoid syndrome

riggered by specific events such as anesthesia, surgery, or chemotherapy.hese precipitating events presumably stimulate release of an over-

IG 13. Carcinoid heart disease. Thickened, fibrotic pulmonic valve associated with carcinoid heartisease. Photograph courtesy of James R. Stone, MD, PhD, Department of Pathology, Massachusettseneral Hospital, Boston. Reprinted with permission from Kulke MH, Mayer RJ. Carcinoid tumors.Engl J Med 1999;340:858-68. (Color version of figure is available online.)

helming amount of biologically active compounds, such as cat-


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cholamines. Specific symptoms include flushing, diarrhea, tachycardia,rrhythmias, hypertension or hypotension, bronchospasm, and alteredental status.162 Symptoms are generally refractory to fluid resuscitation

nd administration of vasopressors.Carcinoid crisis may be precipitated by anesthesia, with intraoperative

omplications occurring in 11% of patients.126 Intraoperatively, theerotonergic blocking agent octreotide should be readily available.163

uring a carcinoid crisis, 50 mg of octreotide may be administeredntravenously. Blood pressure may change rapidly, requiring close mon-toring. Even with octreotide, bronchospasm may occur, necessitatingreatment with bronchodilators. Histamine (H1- and H2-) receptor block-rs reduce histamine release from gastric carcinoid tumors.1 Patients witharcinoid heart disease are at risk for developing arrhythmias. Regionalnesthesia and specific pharmacologic agents such as morphine, suxam-thonium, beta-blockers, tubocurarine, halothane, and atracurium shoulde avoided.104

anagement of Unresectable DiseaseThe role for surgery in advanced disease is unclear. If complete

xtirpation is possible, resection may be attempted in an effort to achieverolonged disease-free survival and symptomatic relief. Palliative resec-ion may be necessary for symptoms such as obstruction. Debulkingrocedures for symptomatic disease poorly controlled with octreotide orepatic artery occlusion may be considered on a case-by-case basis.When resection is not possible, other treatment options are available.n algorithm for treatment of advanced, unresectable disease is illustrated

n Fig 6. In a comprehensive review of carcinoid tumors, Schnirer andolleagues have pooled and examined the results of various trials, asummarized here.37 In these studies, a positive biochemical response wasefined as a 50% or greater reduction in an elevated biomarker, usuallyrinary 5-HIAA. Tumor response rates were measured on cross-sectionalmaging studies (CT or MRI).

omatostatin Receptor-Directed Hormonal TherapySomatostatin is a 14-amino acid peptide that binds to a family of 5embrane-bound, G protein-coupled receptors.164 Somatostatin regulates

xocrine and endocrine secretion and exerts a cytostatic effect on tumorells, among other functions.72,165-167 Receptors for somatostatin arexpressed on more than 80% of carcinoid tumors.69 In carcinoid tumors,omatostatin inhibits symptoms such as flushing and diarrhea.168,169 Its
linical utility is limited by its short half-life (2 to 4 minutes).

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Octreotide is an 8-amino acid somatostatin analogue with a longeralf-life of 90 to 120 minutes. It is effective in controlling the symptomsf carcinoid syndrome. Octreotide at doses of 50 to 500 �g administeredubcutaneously every 8 hours is effective in completely or partlyesolving flushing in 85% of patients and diarrhea in 74% of patients.170

rinary 5-HIAA levels were decreased in 72% of patients.171 Presently,onger acting somatostatin analogues are available. Lanreotide172 may bedministered every 10 to 14 days and intramuscular depot octreotide173

ay be administered monthly once reaching a steady state in 8 to 12eeks.Clinical trials have demonstrated that somatostatin analogues may have

ntitumor effects in addition to their efficacy in controlling symptoms.iochemical response rates of 27% to 72% have been observed, but tumor

esponse rates, based on CT or MRI studies, range from only 0% to 9%Table 13).171,172,174-179 In patients with confirmed disease progression,he institution of octreotide therapy resulted in tumor stabilization in 50%o 55% of patients.174,178,180 Schnirer and colleagues pooled the dataogether from several studies and identified only 3 partial responses (2%)n 182 evaluable patients treated with analogues (Table 13).37 Rareeported side effects include cardiac arrhythmias and conduction abnor-alities, cholelithiasis, hypothyroidism, hypo- or hyperglycemia, and

teatorrhea.37

Radiolabeled somatostatin analogues have also been used therapeuti-ally.181-189 Scintigraphy with indium-111 (111In)-labeled octreotide haseen used commonly to localize previously undetected primary oretastatic neuroendocrine tumors. At higher doses, 111In-labeled oct-

eotide has been evaluated as a potential novel therapeutic; unfortunately,bjective response rates with this agent have been low.190 More encour-ging results have been obtained with octreotide coupled to yttrium-90, aigh-energy beta particle emitter. In early phase II trials, objectiveadiologic responses have been noted in up to 23% of patients withetastatic neuroendocrine tumors.189,191 The longer term utility of this

gent, however, appears to be limited by both renal and hematologicoxicities.192 Most recently, octreotide labeled with lutetium-177 (177Lu),low energy beta particle emitter, has been evaluated in a phase I studyith encouraging results. In 1 series, 131 patients with somatostatin

eceptor-positive advanced neuroendocrine tumors received 177Lu-oct-eotate administered every 6 to 10 weeks, to a final intended dose of 600o 800 mCi.184 There were 35 objective responses (27%), 3 of which wereomplete.
MIBG, a compound similar to norepinephrine, accumulates in the

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ABLE 13. Efficacy of biologically active agents in advanced carcinoid*

Agent(s)No. of

patients

Biochemicalresponse

rate(%)

Tumorresponse

rate(%)


(%)

References

ctreotide 25 72 0 72 17119 63 0 0 17623 27 9 28 17720 NA 0 0 17824 45 0 NA 21955 37 2 NA 17564 33 0 0 174

anreotide 13 58 5 8 23139 42 0 0 232

anreotide-SR 10 NA 0 0 17211In-Pentetreotide 9 NA 0 NA 233uman leukocyte IFN 36 53 11 19 234

13 7 7 15 23510 50 20 50 2107 29 14 14 236

ooled data 40 12 37FN-� 27 39 20 NA 237

10 40 10 40 23820 50 0 50 23918 NA 0 0 24010 17 0 10 180

111 42 16 NA 24116 66 25 25 24214 50 0 NA 24320 60 11 NA 24412 25 17 NA 21934 24 12 NA 24522 59 18 59 24625 28 0 NA 1969 NA NA 22 247

ooled data 40 12 37FN-� � IFN-� 12 0 0 8 248ctreotide � IFN-� 24 77 0 NA 249

19 72 0 NA 1759 75 0 NA 195

amoxifen 16 0 0 0 19731I-MIBG 98 37 15 NA 19331I-MIBG v. 30 7 0 NA 250unlabelled MIBG 20 5 0 NA

A, not reported; SR, sustained-release; 111In-pentetreotide, indium-111-pentetreotide;FN, interferon; 131I-MIBG, iodine-131-metaiodobenzylguanidine.Adapted with permission from Schnirer II, Yao JC, Ajani JA. Carcinoid—a comprehensive
eview. Acta Oncol 2003; 42:672–92.

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ecretory granules of neuroendocrine cells. This characteristic has beenxploited in localizing studies with radiolabeled 131I-MIBG. Similarly,31I-MIBG may be employed for therapeutic local tumor irradiation,lthough not all patients with metastatic carcinoid take up MIBG.193,194

n 1 retrospective study, biochemical (5-HIAA) responses were observedn 37% of carcinoid patients treated with MIBG, and 15% had radio-raphic responses to therapy.193 Radiographic response did not, however,orrelate with improved survival.

nterferonAlthough the mechanism of action of interferon (IFN) is not completelynderstood, it has been used in protocol-based treatments of carcinoid.FN-alpha (�) and gamma (�) and human leukocyte IFN have beentudied in trials. Results reported from various trials are summarized inable 13. Data from these trials were pooled by Schnirer and col-

eagues.37 Studies with IFN-� have reported biochemical and tumoresponse rates of 40% and 12%, respectively. Similarly, trials with humaneukocyte IFN demonstrated biochemical and tumor response rates of0% and 12%, respectively. No responses were detected in a trialombining IFN-� and IFN-�.Three studies treated patients unresponsive to octreotide alone (and in 1

tudy, unresponsive to IFN-� as well). Patients were treated withctreotide and IFN-� in combination, with biochemical responses ob-erved in 72% to 77% of patients. However, no objective tumoregression was reported.175,179,195

A trial comparing IFN-� and embolization with gelatin powder versusFN-� alone resulted in significantly higher biochemical (47% vs 28%)nd tumor response rates (53% vs 0%) for the former group.196

IFN therapy is associated with significant toxicities including fever,norexia, weight loss, severe depression, fatigue, alopecia, and myelo-uppression. The high incidence of these toxicities and the low rate ofumor responses have limited the routine use of IFN in treatmentrotocols for metastatic carcinoid.

ther Hormonal TherapyNo effects were observed with tamoxifen.197

hemotherapyTrials with cytotoxic chemotherapy, as single agents or in combination,ave been reported. Results are listed in Table 14. Single agent chemo-
herapy trials with 5-fluorouracil,198,199 doxorubicin,198-200 dacarba-

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Agent(s)No. of

patients

Biochemicalresponse

rate(%)

Tumorresponse

rate(%)


(%)

References

ingle agent chemotherapyActinomycin-D 17 6 6 6 201Carboplatin 20 0 0 0 206Cisplatin 15 7 7 7 205Cyclophosphamide NA 0 0 0 96Dacarbazine 15 NA NA 13 198, 199

15 7 13 13 20156 NA NA 16 2027 NA 29 29 203

18 NA NA 17 251Docetaxel 21 31 0 NA 208Doxorubicin 15 NA NA 13 198, 199

81 NA NA 21 200Etoposide 17 NA 12 12 207Fluorouracil 19 NA NA 26 198, 199Gemcitibine 18 0 0 0 217Melphalan 7 NA NA 0 198, 199Paclitaxel 14 NA 7 NA 216Streptozocin 6 NA NA 17 198, 199

7 14 0 14 204ombination chemotherapyFluorouracil � streptozocin 80 NA NA 21 200

24 8 0 8 20410 0 0 0 210

Fluorouracil � streptozocin 42 40 21 33 96v.

Streptozocin �cyclophosphamide

48 24 24 26

Fluorouracil �cyclophosphamide �doxorubicin v.

8 NA NA 38 211

Fluorouracil � mitomycin C� doxorubicin � methyl-CCNU

9 NA NA 22

Fluorouracil � streptozocin� doxorubicin �cyclophosphamide

65 NA NA 29 209

Etoposide � cisplatin 13 0 0 0 212Fluorouracil � doxorubicin

� cisplatin15 NA 14 14 213

Fluorouracil � dacarbazine� epirubicin

20 NA 10 10 214

Fluorouracil � dacarbazine� leucovorin

9 17 11 11 215

ombination biochemotherapyStreptozocin � doxorubicin 11 0 0 0 219

� IFN-�


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ine,198,199,201-203 streptozocin,198,199,204 actinomycin D,201 cisplatin,205

arboplatin,206 cyclophosphamide,96 etoposide,207 melphalan,198,199 andocetaxel208 have demonstrated only minimal efficacy against carcinoidumors. Response rates by trial criteria (either tumor regression orecrease in urinary 5-HIAA) were 0% to 31%.Combination chemotherapy has been evaluated in clinical trials. The

egimen of 5-fluorouracil and streptozocin has been studied in severalrials. The Eastern Cooperative Oncology Group (ECOG) randomized18 patients to fluorouracil and streptozocin versus streptozocin andyclophosphamide.96 Response rates were 33% versus 26%. The differ-nce in survival was not significant, and both regimens were associatedith considerable toxicity. A second ECOG trial randomized 161 patients

o fluorouracil and streptozocin (with a longer interval between treat-ents) versus single agent doxorubicin. With the increased treatment

nterval, the response rate for fluorouracil and streptozocin was only 22%ompared with 21% for doxorubicin.200 A third trial, from the Southwestncology Group, evaluated the 4 drug combination of fluorouracil,oxorubicin, cyclophosphamide, and streptozocin in 56 patients.209 Theesponse rate of 31% was not felt to be superior to that of fluorouracil andtreptozocin. Additional studies of fluorouracil and streptozocin haveailed to demonstrate better response rates.204,210

Other regimens have evaluated fluorouracil, doxorubicin, and cyclo-hosphamide versus fluorouracil, doxorubicin, mitomycin C, and methyl-CNU211; etoposide and cisplatin212; fluorouracil, doxorubicin, andisplatin213; dacarbazine, fluorouracil, and epirubicin214; and dacarba-ine, fluorouracil, and leucovorin.215 None of these regimens haveemonstrated a response rate of greater than 15% (see Table 14).Newer chemotherapeutic agents have, to date, proved relatively inactive

ABLE 14. Continued

Agent(s)No. of

patients

Biochemicalresponse

rate(%)

Tumorresponse

rate(%)


(%)

References

Fluorouracil � IFN-� 14 25 7 7 218argeted therapyBevacizumab 18 NA 17 NA 222Sunitinib 39 NA 5 NA 223

A, not reported; IFN, interferon.Adapted with permission from Schnirer II, Yao JC, Ajani JA. Carcinoid—a comprehensiveeview. Acta Oncol 2003; 42:672–92.

n neuroendocrine tumors. High dose paclitaxel, administered with


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ranulocyte-colony stimulating factor, was evaluated in 24 patients withetastatic carcinoid and islet cell tumors.216 Significant hematologic

oxicity was observed, and the objective radiologic response rate was only%. Treatment with docetaxel was associated with biochemical responsesut no radiologic responses in a recent phase II trial of 21 patients witharcinoid tumors.208 No responses were observed in 19 neuroendocrineumor patients treated with gemcitabine.217

Finally, 2 small trials have examined the role of biochemotherapy,ombining IFN-� with either fluorouracil218 or streptozocin and doxoru-icin.219 Combination therapy did not result in improved response rates.Studies have demonstrated that patients with poorly differentiatedeuroendocrine tumors are more responsive to cytotoxic chemotherapyhan those with well-differentiated tumors. In an initial study, a combi-ation of cisplatin and etoposide commonly used for small cell lungancer was associated with an overall tumor response rate of 67% in 18atients with “anaplastic” neuroendocrine tumors (presumably analogouso poorly differentiated neuroendocrine tumors), but had little activity inore well-differentiated tumor subtypes.212 In a subsequent study of 36

atients with advanced neuroendocrine tumors, treatment with cisplatinnd etoposide was associated with an overall radiologic response rate of6% and a median survival time of 19 months.220 All patients enrolled inhis study had either poorly differentiated histology or a rapidly progress-ng clinical course, suggesting that few, if any, of these patients had morelassic, indolent carcinoid or pancreatic endocrine tumors.In summary, currently available biologic therapies and chemotherapy

egimens have minimal cytoreductive effects. Further investigation isngoing.

argeted TherapyThalidomide. Thalidomide is postulated to have antiangiogenic activity

hrough its ability to interfere with the VEGF and bFGF pathways, andas associated with apparent disease stabilization in a small phase II

tudy of patients with metastatic neuroendocrine tumors. Thalidomideas combined with temozolomide, an oral analogue of dacarbazine, in ahase II study of 30 patients with metastatic neuroendocrine tumors. In areliminary analysis of 25 evaluable patients, 36% had experiencedecreases in chromogranin A levels of more than 50%, and 20% hadxperienced objective radiologic tumor responses.221 The relative contri-utions of thalidomide and temozolomide to the antitumor activity
bserved in this study, however, are uncertain.

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Bevacizumab. Bevacizumab is a humanized monoclonal antibodyargeting vascular endothelial growth factor (VEGF). In a phase II trial,4 patients with advanced or metastatic carcinoid tumors on a stable dosef octreotide were randomly assigned to bevacizumab or pegylated IFN-2b.222 In a preliminary report of 35 patients completing 18 weeks of

herapy, treatment with bevacizumab was associated with a sustainedecrease in tumor perfusion by functional CT; furthermore, 3 of 18atients treated with bevacizumab experienced radiographic partial re-ponses. After 18 weeks, 95% of patients treated with bevacizumabemained progression-free compared with only 67% of patients treatedith IFN.Sunitinib (SU11248). Sunitinib (SU11248, Sutent) is an orally active,ultitargeted tyrosine kinase inhibitor that specifically inhibits the VEGF

eceptor (VEGFR), the platelet-derived growth factor receptor (PDGFR),nd c-kit. The antitumor efficacy of sunitinib was suggested in areliminary report of a phase II study in which patients with unresectableeuroendocrine tumors received sunitinib administered daily for 4 ofvery 6 weeks). Among 39 patients with carcinoid tumors, there were 2artial responses (5%) and prolonged periods of stable disease in 3692%).223

xternal-Beam Radiation TherapyExternal-beam radiation therapy has not demonstrated any efficacy in

stablishing local control. However, it may be used for palliation foretastases to the brain, bone, and spinal cord (for cord compression).224

onclusionThe term carcinoid has been adopted by clinicians in reference to aariety of neuroendocrine neoplasms with variable malignant potential.ccurate biological and molecular profiling will allow more precise

lassification.The overall incidence of carcinoid tumors has increased over the last 3ecades. Although tumor size and site of origin are well-known determi-ants of clinical behavior, investigations have not identified otheronsistent predictors of metastatic behavior, such as mitotic rate, cellulartypia, or necrosis. Future research efforts may identify cell-specificarkers predictive of more aggressive behavior.Surgery remains the principal therapy for localized disease, but its role

n advanced disease remains unclear. For patients with advanced disease,he somatostatin analogue octreotide is a well-tolerated treatment effec-
ive in controlling symptoms. It also has antitumoral effects demonstrated

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y a reduction in urinary 5-HIAA levels in various studies. At present,ctreotide is the most commonly employed adjuvant therapy. Currentlyvailable single agent and combination chemotherapy regimens have noteen particularly efficacious. Future studies should investigate therapiesargeting growth factors expressed by carcinoid tumors.

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