The New England Journal of Medicine
`
`Review Article
`
`Medical Progress
`
`C
`
`ARCINOID
`
` T
`
`UMORS
`
`M
`ATTHEW
`
` H. K
`ULKE
`
`, M.D.,
`
`AND
`
` R
`OBERT
`
` J. M
`AYER
`
`, M.D.
`
`C
`
`ARCINOID tumors were first described over
`100 years ago by Lubarsch, who found mul-
`tiple tumors in the distal ileum of two pa-
`tients at autopsy.
` The term
`
`karzinoide was used by
`1
`Oberndorfer in 1907 to describe similar tumors that
`appeared to behave in a more indolent fashion than
` Carcinoid tumors have
`typical adenocarcinomas.
`2
`subsequently been reported in a wide range of or-
`gans but most commonly involve the lungs, bronchi,
`and gastrointestinal tract.
`
`BIOLOGY
`Carcinoid tumors are thought to arise from neu-
`roendocrine cells. They are characterized histologi-
`cally by positive reactions to silver stains and to
`markers of neuroendocrine tissue, including neuron-
`specific enolase, synaptophysin, and chromogranin.
`When viewed through an electron microscope, car-
`cinoid tumors are typically found to contain numer-
`ous membrane-bound neurosecretory granules. These
`granules are composed of a variety of hormones and
`biogenic amines.
`One of the best-characterized of these substances
`is serotonin. Serotonin is synthesized from its pre-
`cursor, 5-hydroxytryptophan, by the enzyme aro-
`matic acid decarboxylase. Serotonin is subsequently
`metabolized by monoamine oxidase to 5-hydroxy-
`indoleacetic acid (5-HIAA), which is excreted in the
`urine. In addition to serotonin, carcinoid tumors
`have been found to secrete corticotropin,
` hista-
`3
` dopamine,
` substance P,
` neurotensin,
` pros-
`mine,
`4
`5
`6
`7
`taglandins,
` and kallikrein.
` The release of serotonin
`8
`9
`and other vasoactive substances into the systemic
`circulation is thought to cause the carcinoid syn-
`drome, the manifestations of which are episodic
`flushing, wheezing, diarrhea, and eventual right-sid-
`ed valvular heart disease.
`10
`
`From the Department of Adult Oncology, Dana–Farber Cancer Insti-
`tute and Harvard Medical School, Boston. Address reprint requests to Dr.
`Kulke at the Dana–Farber Cancer Institute, 44 Binney St., Boston, MA
`02115.
`©1999, Massachusetts Medical Society.
`
`858
`
`·
`
`March 18, 1999
`
`CLASSIFICATION
`Carcinoid tumors have traditionally been classified
`according to their presumed derivation from differ-
`ent embryonic divisions of the gut.
` Foregut carci-
`11
`noid tumors most commonly originate in the lungs,
`bronchi, or stomach; midgut carcinoid tumors in the
`small intestine, appendix, and proximal large bowel;
`and hindgut carcinoid tumors in the distal colon and
`rectum. Within these subgroups, the biologic and
`clinical characteristics of the tumors may vary con-
`siderably (Table 1). Many investigators have there-
`fore adopted a classification system that takes into ac-
`count not only the site of origin but also variations
`in the histologic characteristics of carcinoid tumors.
`12
`Under this revised system, so-called typical tu-
`mors are classified as well-differentiated neuroendo-
`crine tumors. These tumors are characterized by
`small cells containing regular, well-rounded nuclei
`and have five generally accepted growth patterns: in-
`sular, trabecular, glandular, undifferentiated, and
`mixed.
` Tumors with increased nuclear atypia, high-
`13
`er mitotic activity, or areas of necrosis have in the
`past been broadly termed “atypical” or “anaplastic”
`carcinoids. These tumors have more recently been
`classified as either well-differentiated or poorly dif-
`ferentiated neuroendocrine carcinomas (Fig. 1).
`
`INCIDENCE
`The overall incidence of carcinoid tumors in the
`United States has been estimated to be 1 to 2 cases
`per 100,000 people.
` Because many carcinoid tu-
`14,15
`mors are indolent, their true incidence may be high-
`er. A Swedish study in which the frequency of carci-
`noid tumors was calculated on the basis of both
`surgical specimens and autopsies in a single geo-
`graphic location reported the incidence to be 8.4
`cases per 100,000 people.
`16
`An analysis of 2837 cases in the United States,
`based on data from the End Results Group (1950–
`1969) and the Third National Cancer Survey (1969–
`1971), found that the appendix was the most com-
`mon site of carcinoid tumors, followed by the rectum,
`ileum, lungs and bronchi, and stomach.
` A recent
`14
`analysis of 5468 cases identified by the Surveillance,
`Epidemiology, and End Results (SEER) Program of
`the National Cancer Institute between 1973 and 1991
`found an increase in the proportion of pulmonary and
`gastric carcinoids and a decrease in the proportion
`of appendiceal carcinoids (Table 2).
` These changes
`15
`in relative incidence may be due in part to variations
`in the detection and reporting of carcinoid tumors.
`Benign-appearing carcinoid tumors, for example, were
`not recorded in the SEER data base until 1986.
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org at REPRINTS DESK INC on December 15, 2015. For personal use only. No other uses without permission.
`
` Copyright © 1999 Massachusetts Medical Society. All rights reserved.
`
`NOVARTIS EXHIBIT 2020
`Par v. Novartis, IPR 2016-01479
`Page 1 of 11
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`MEDICAL PROGRESS
`
`UMORS
`
`T
`
`ABLE
`
` 1.
`
` C
`
`LASSIFICATION
`
`
`
`OF
`
` C
`
`ARCINOID
`
` T
`
`.
`
`S
`ITE
`
`
`
`AND
`
` S
`UBTYPE
`
`P
`RESUMED
`
` C
`ELL
`
`
`
`OF
`
` O
`RIGIN
`
`H
`ISTOLOGIC
`
` F
`EATURES
`
`C
`LINICAL
`
` C
`HARACTERISTICS
`
`Lungs and bronchi
`Well-differentiated neuroendocrine
`tumor (typical carcinoid)
`
`Well-differentiated neuroendocrine
`carcinoma (atypical carcinoid)
`Stomach*
`CAG-A–associated carcinoid tumor
`
`Epithelial endocrine cell
`
`Minor cellular atypia, rare mitoses
`
`Epithelial endocrine cell
`
`Cellular atypia, increased mitoses,
`areas of necrosis
`
`Enterochromaffin-like cell
`
`Well differentiated, noninvasive
`
`Carcinoid tumor associated with Zol-
`linger–Ellison syndrome or MEN-1
`
`Enterochromaffin-like cell
`
`Well differentiated, noninvasive
`
`Sporadic carcinoid tumor
`
`Enterochromaffin-like cell
`
`Small bowel
`
`Appendix
`
`Colon
`
`Rectum
`
`Epithelial endocrine cell
`
`Subepithelial endocrine cell
`
`Epithelial endocrine cell
`
`Epithelial endocrine cell
`
`Well differentiated, but often
`invasive
`
`Usually well differentiated; con-
`tains serotonin and substance P
`
`Usually well differentiated; con-
`tains serotonin and substance P
`Usually well differentiated; con-
`tains serotonin and substance P
`Usually well differentiated; con-
`tains glicentin and glucagon
`
`*CAG-A denotes chronic atrophic gastritis type A, and MEN-1 multiple endocrine neoplasia type 1.
`
`Usually indolent; may secrete
`corticotropin; rarely secretes
`serotonin
`Usually aggressive, with high in-
`cidence of metastases
`
`Indolent; often multiple; not
`associated with carcinoid
`syndrome
`Indolent; may be multiple; not
`associated with carcinoid
`syndrome
`May be aggressive, with high in-
`cidence of metastases; associ-
`ated with atypical carcinoid
`syndrome
`Often multiple, usually in ileum;
`associated with carcinoid
`syndrome
`Usually indolent
`
`Usually right-sided; often pre-
`sents at late stage
`Carcinoid syndrome rare
`
`PULMONARY CARCINOID TUMORS
`Pulmonary carcinoids make up approximately 2 per-
`cent of primary lung tumors.
` They are thought
`17,18
`to arise from neuroendocrine Kulchitsky’s cells lo-
`cated in the bronchial mucosa.
` Pulmonary carci-
`19,20
`noids can be classified along a spectrum of pulmo-
`nary neuroendocrine tumors, of which small-cell lung
`cancer is the most malignant.
`21
`Patients with typical pulmonary carcinoids (i.e.,
`well-differentiated pulmonary neuroendocrine tu-
`mors) usually present in the fifth decade of life.
`18,22,23
`The majority of the tumors are perihilar in location,
`and patients often present with recurrent pneumo-
`nia, cough, hemoptysis, or chest pain.
` These tumors
`23
`may also have a variety of neuroendocrine manifes-
`tations. Ectopic secretion of corticotropin from pul-
`monary carcinoid tumors accounts for 1 percent of
`all cases of Cushing’s syndrome.
` Acromegaly due to
`3
`ectopic secretion of growth hormone–releasing fac-
`tor has also been reported.
` The carcinoid syn-
`24
`drome occurs in less than 5 percent of cases.
`23,25-27
`Well-differentiated pulmonary neuroendocrine tu-
`mors are usually indolent, with metastases reported
`in less than 15 percent of cases.
` When they
`22,23,26,28
`do occur, metastases usually develop in mediastinal
`lymph nodes, liver, bone, or skin. The presence of
`lymph-node metastases and the presence of symp-
`toms at the time of diagnosis are adverse prognostic
`factors.
` Most studies have found five-year survival
`17
`rates of more than 90 percent.
`17,18,22,23,25-29
`
`Approximately one third of pulmonary carcinoids
`have atypical histologic features and are more accu-
`rately classified as well-differentiated pulmonary neu-
`roendocrine carcinomas.
` Atypical carcinoids oc-
`17,26
`cur in older patients, most commonly in the sixth
`decade of life.
` They tend to be larger than well-
`29,30
`differentiated neuroendocrine tumors and occur more
`commonly in the peripheral lung fields.
` Atypical
`29,30
`carcinoids have an aggressive clinical course, metas-
`tasizing to mediastinal lymph nodes in 30 to 50 per-
`cent of cases.
` The five-year survival rate is be-
`25,29,30
`tween 40 and 60 percent.
`17,25-27,30
`Conservative resection, consisting of wedge or
`segmental resection, is currently the preferred form
`of treatment for localized pulmonary carcinoid tu-
`mors.
` Such procedures have resulted in low rates
`31
`of recurrence and excellent long-term survival.
`27,32,33
`The adequacy of conservative resection in patients
`with atypical carcinoids has been questioned, and
`several authors have advocated more extensive surgi-
`cal procedures for these patients.
` Endoscopic re-
`27,30
`moval or laser photoablation may result in successful
`palliation of symptoms but is not recommended as
`definitive therapy.
`28
`
`GASTRIC CARCINOID TUMORS
`Gastric carcinoid tumors make up less than 1 per-
`cent of gastric neoplasms.
` They can be separated
`14,15
`into three distinct groups on the basis of both clin-
`ical and histologic characteristics: those associated
`
`Volume 340 Number 11
`
`·
`
`859
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org at REPRINTS DESK INC on December 15, 2015. For personal use only. No other uses without permission.
`
` Copyright © 1999 Massachusetts Medical Society. All rights reserved.
`
`NOVARTIS EXHIBIT 2020
`Par v. Novartis, IPR 2016-01479
`Page 2 of 11
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`
`The New England Journal of Medicine
`
`A
`
`C
`
`B
`
`D
`
`Figure 1.
` Classification of Neuroendocrine Tumors.
`Panel A shows well-differentiated ileal carcinoid tumor (hematoxylin and eosin, ¬400). Panel B shows gastric carcinoid tumor with
`staining for chromogranin (chromogranin immunoperoxidase, ¬100). Panel C shows well-differentiated pulmonary neuroendocrine
`carcinoma (atypical carcinoid) with nuclear atypia and mitosis (arrow) (hematoxylin and eosin, ¬200). Panel D shows poorly differ-
`entiated pulmonary neuroendocrine carcinoma with numerous mitoses (arrows) (hematoxylin and eosin, ¬200). Photographs cour-
`tesy of Jonathan N. Glickman, M.D., Ph.D., Department of Pathology, Brigham and Women’s Hospital, Boston.
`
`with chronic atrophic gastritis type A (CAG-A), those
`associated with the Zollinger–Ellison syndrome, and
`sporadic gastric carcinoid tumors.
`Up to 75 percent of gastric carcinoid tumors are as-
`sociated with CAG-A (Fig. 2).
` More than half of
`34-39
`patients with CAG-A–associated carcinoids also have
`pernicious anemia.
` Patients with CAG-A–asso-
`37,39,40
`ciated carcinoids typically present in the sixth or sev-
`enth decade of life. The tumors are more common in
`women than in men.
` They are usually identified
`34,38,39
`endoscopically during diagnostic evaluation for ane-
`mia or abdominal pain.
` They often measure less
`38,39
`than 1 cm in diameter and are almost always located
`in the body or fundus of the stomach.
`34,39
`CAG-A–associated carcinoids are multifocal in
`over 50 percent of cases.
` Their multifocal nature is
`34
`explained by their presumed origin from entero-
`
`chromaffin-like cells in the gastric fundus. Patients
`with CAG-A usually have hypochlorhydria and hy-
`pergastrinemia. Gastrin hypersecretion has been pos-
`tulated to result in hyperplasia of enterochromaf-
`fin-like cells. Indeed, CAG-A–associated carcinoids
`are almost invariably surrounded by areas of entero-
`chromaffin-like cell hyperplasia.
` These hyperplas-
`34,36
`tic lesions may develop into carcinoid tumors.
`41,42
`This etiologic hypothesis is supported by studies
`in rats, in which hypergastrinemia induced by thera-
`py with the proton-pump inhibitor omeprazole in-
`duced the formation of carcinoid tumors.
` How-
`43
`ever, proton-pump inhibitors have not yet been
`associated with the formation of carcinoid tumors in
`humans.
`44,45
`CAG-A–associated carcinoids are usually indo-
`lent, metastasizing in less than 10 percent of cas-
`
`860
`
`·
`
`March 18, 1999
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org at REPRINTS DESK INC on December 15, 2015. For personal use only. No other uses without permission.
`
` Copyright © 1999 Massachusetts Medical Society. All rights reserved.
`
`NOVARTIS EXHIBIT 2020
`Par v. Novartis, IPR 2016-01479
`Page 3 of 11
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`MEDICAL PROGRESS
`
` 2.
`T
`ABLE
`R
`
`EPORTED
`
`
` T
` C
`
` L
` A
`UMORS
`ARCINOID
`OF
`OCATION
`NATOMICAL
`
` U
` S
`
` 1950
` 1991.*
`THE
`NITED
`IN
`TATES
`BETWEEN
`AND
`
`S
`ITE
`
`
`
`OF
`
` C
`ARCINOID
`
`ERG
`(1950–1969)
`
`TNCS
`(1969–1971)
`
`SEER
`(1973–1991)
`
`percentage of all tumors detected
`
`Lungs, bronchi, and trachea
`Stomach
`Duodenum
`Jejunum
`Ileum
`Appendix
`Cecum
`Colon
`Rectum
`Other
`
`10.2
`2.2
`1.8
`1.0
`10.8
`43.9
`2.7
`4.7
`15.4
`7.3
`
`14.1
`2.0
`2.3
`2.0
`13.8
`35.5
`3.0
`3.9
`12.3
`11.1
`
`32.7
`3.8
`2.1
`2.3
`17.6
`7.6
`5.0
`6.3
`10.1
`12.5
`
` ERG denotes the End Re-
`*Data are adapted from Modlin and Sandor.
`15
`sults Group, TNCS the Third National Cancer Survey, and SEER the Sur-
`veillance, Epidemiology, and End Results Program of the National Cancer
`Institute.
`
` Although local recurrences have been report-
`es.
`34,37
`ed, most recent series have reported no deaths from
`the disease in treated patients.
` Lesions less
`34,35,39
`than 1 cm in diameter have been successfully treated
`with endoscopic resection followed by close endo-
`scopic surveillance.
` Patients with larger, mul-
`37,39,46-48
`tiple, or recurrent tumors have generally undergone
`more extensive surgical resection. Antrectomy may
`result in the normalization of serum gastrin levels
`and has been reported to result in tumor regression
`in selected cases.
` The long-term benefits of
`37,46,49,50
`antrectomy, however, are uncertain.
`Between 5 and 10 percent of gastric carcinoids are
`associated with the Zollinger–Ellison syndrome.
`34
`Like carcinoids associated with CAG-A, carcinoids
`associated with the Zollinger–Ellison syndrome are
`thought to arise from enterochromaffin-like cells
`in patients with hypergastremia and are associated
`with hyperplasia of surrounding enterochromaffin-
`like cells.
` Carcinoids associated with the Zollin-
`34
`ger–Ellison syndrome occur almost exclusively in pa-
`tients with multiple endocrine neoplasia type 1,
`an autosomal dominant genetic disorder associated
`
`MEN1, a putative tumor-suppressor
`with the loss of
`gene located on chromosome 11q13. The disease is
`characterized by tumors of the pituitary gland, pan-
`creatic islet cells, and parathyroid glands.
` Allelic
`51,52
`loss on chromosome 11q13 has been reported in
`carcinoid tumors associated with the Zollinger–Elli-
`son syndrome, suggesting that loss of function of
`the
`
`MEN1 gene is required for progression to true
`neoplasia.
` The treatment and long-term prognosis
`53
`of carcinoids associated with the Zollinger–Ellison
`syndrome are similar to those of CAG-A–associated
`carcinoids.
`34
`
`Figure 2.
` Gastric Carcinoid Tumor.
`Gastric carcinoid tumor is present in a typical submucosal lo-
`cation (arrow). The mucosa reveals changes associated with
`chronic atrophic gastritis (hematoxylin and eosin, ¬40). Photo-
`graph courtesy of Jonathan N. Glickman, M.D., Ph.D., Depart-
`ment of Pathology, Brigham and Women’s Hospital, Boston.
`
`Between 15 and 25 percent of gastric carcinoids are
`sporadic.
` In contrast to CAG-A–associated carci-
`34
`noids, these lesions are more frequent in men than
`in women, are usually solitary, and arise in normal-
`appearing mucosa.
` They are usually more than 1 cm
`34
`in diameter, and although they appear histologically
`to be enterochromaffin-like cell tumors, they may also
`contain other cell types.
` Sporadic carcinoid tu-
`34,37
`mors have been associated with an atypical carcinoid
`syndrome that is manifested primarily by flushing and
`is thought to be mediated by histamine.
` The major-
`37
`ity of sporadic carcinoid tumors are metastatic at the
`time of presentation, and the disease is often fatal.
`34
`Because of the aggressive nature of these lesions, most
`are treated with radical gastrectomy.
`
`CARCINOID TUMORS OF THE SMALL
`INTESTINE
`Small-bowel carcinoid tumors make up approxi-
`mately one third of small-bowel tumors in surgical
`
`Volume 340 Number 11
`
`·
`
`861
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org at REPRINTS DESK INC on December 15, 2015. For personal use only. No other uses without permission.
`
` Copyright © 1999 Massachusetts Medical Society. All rights reserved.
`
`NOVARTIS EXHIBIT 2020
`Par v. Novartis, IPR 2016-01479
`Page 4 of 11
`
`

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`The New England Journal of Medicine
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`
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`
` They are most frequently located in the dis-
`series.
`54
`tal ileum and are often multicentric, occasionally ap-
`pearing as dozens of lesions lining the small bowel.55
`Small-bowel carcinoids are thought to arise from se-
`rotonin-producing intraepithelial endocrine cells. Foci
`of hyperplastic intraepithelial endocrine cells have
`been reported in association with ileal carcinoid tu-
`mors; however, the cause of this hyperplasia remains
`unknown.56,57
`Patients with small-bowel carcinoids generally
`present in the sixth or seventh decade of life, most
`commonly with abdominal pain or small-bowel ob-
`struction. Because standard imaging techniques, such
`as computed tomography (CT) and small-bowel
`barium contrast studies, rarely identify the primary
`tumor, the preoperative diagnosis of small-bowel car-
`cinoid is difficult.58 Patients frequently have vague
`abdominal symptoms for several years before diag-
`nosis.55,58
`The majority of patients with small-bowel carci-
`noids present with metastases to the lymph nodes or
`the liver, and 5 to 7 percent present with the carci-
`noid syndrome.55,59 Tumor size is an unreliable pre-
`dictor of metastatic disease, and metastases have
`been reported even from tumors measuring less than
`0.5 cm in diameter.58 Long-term survival correlates
`closely with the stage of the disease at presentation.
`The five-year survival rate is 65 percent among pa-
`tients with localized or regional disease and 36 per-
`cent among those with distant metastases.15
`Small-bowel resection, together with resection of
`the associated mesentery, is the treatment of choice
`for small-bowel carcinoids.60 These tumors are fre-
`quently associated with “buckling” of the intestine
`as a result of extensive mesenteric fibrosis.55 Occa-
`sionally, mesenteric ischemia due to either fibrosis or
`an associated mesenteric angiopathy may occur.61 Re-
`section is therefore undertaken for palliative purpos-
`es, even in patients with known metastatic disease.
`
`APPENDICEAL CARCINOID TUMORS
`Carcinoid tumors are the most common cancers
`of the appendix.62 In contrast to carcinoids of the
`small intestine, appendiceal carcinoids are thought
`to arise from subepithelial endocrine cells present in
`the lamina propria and submucosa of the appendix
`wall.63,64 They are most often diagnosed in the
`fourth or fifth decade of life.15 The relatively young
`age at which appendiceal carcinoids are detected may
`in part be due to the fact that appendectomies are
`performed most often in young adults, and the true
`median age for the development of these often asymp-
`tomatic tumors may therefore be greater. Some au-
`thors have postulated, however, that appendiceal car-
`cinoids may regress with age.62,64 Such regression
`would parallel the behavior of appendiceal subepi-
`thelial endocrine cells, which are most numerous in
`young people.65
`
`862
`
`·
`
`March 18, 1999
`
`Appendiceal carcinoids are more common in wom-
`en than in men.15 Their greater frequency in women
`has been attributed to an increased rate of incidental
`appendectomy in women undergoing cholecystecto-
`my or such operations as hysterectomy, oophorecto-
`my, and cesarean section.62 Recently, however, inci-
`dental appendectomy has become less common, and
`most appendiceal carcinoids are found during sur-
`gery for acute appendicitis.66 In the SEER data base,
`the frequency of noncarcinoid appendiceal tumors
`among men and women is similar, further suggest-
`ing that the higher rate of appendiceal carcinoids in
`women may not be due solely to higher rates of ap-
`pendectomy.15 In addition, the preponderance of girls
`among children with appendiceal carcinoids cannot
`be explained by differences in appendectomy rates.67-69
`Less than 10 percent of appendiceal carcinoids
`cause symptoms,70 because approximately 75 percent
`are located in the distal third of the appendix, where
`they are unlikely to cause obstruction. Most of the
`remainder are located in the middle third, and less
`than 10 percent at the base.62
`The size of the tumor is the best predictor of prog-
`nosis in patients with appendiceal carcinoid tumors.
`Over 95 percent of appendiceal carcinoids are less
`than 2 cm in diameter.62,71 Although metastases from
`tumors of this size have been reported, they are rare
`and are usually diagnosed at the time of presenta-
`tion.71-76 In contrast, approximately one third of pa-
`tients with tumors more than 2 cm in diameter have
`either nodal or distant metastases.70 As with small-
`bowel carcinoids, there can be distant metastases to
`the liver, and the carcinoid syndrome has been report-
`ed in patients with liver metastases.62 The five-year
`survival rate is 94 percent for patients with local dis-
`ease, 85 percent for patients with regional metastases,
`and 34 percent for patients with distant metastases.15
`The optimal surgical approach to appendiceal car-
`cinoid tumors has been inferred retrospectively from
`surgical series.70 Patients with tumors less than 2 cm
`in diameter are usually treated by simple appendec-
`tomy if there is no gross evidence of local spread. Al-
`though some authors consider the presence of me-
`soappendiceal invasion to be a poor prognostic factor
`and an indication for hemicolectomy, there have
`been no reported recurrences in these patients after
`simple appendectomy.75,77 Most tumors more than
`2 cm in diameter are treated with right colectomy,
`since local recurrence following simple appendecto-
`my, though uncommon, has been observed.70 Wheth-
`er right colectomy decreases the probability of dis-
`tant recurrence is unclear. In older patients with
`other illnesses, simple appendectomy may sometimes
`be appropriate, even for large tumors.
`
`CARCINOID TUMORS OF THE COLON
`Carcinoids make up less than 1 percent of colonic
`tumors.15 Like carcinoid tumors of the small intes-
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`MEDICAL PROGRESS
`
`tine, they are thought to arise from serotonin-pro-
`ducing epithelial endocrine cells. Patients with co-
`lonic carcinoids most commonly present in the
`seventh decade of life with symptoms of pain, ano-
`rexia, or weight loss.78 Less than 5 percent of pa-
`tients present with the carcinoid syndrome.78,79 Ap-
`proximately two thirds of these tumors are found in
`the right side of the colon, most of them in the
`cecum.78,80 Most patients do not become sympto-
`matic until they have advanced disease. The average
`tumor diameter at presentation is 5 cm, and over
`two thirds of patients have either nodal or distant
`disease at the time of presentation.78,80 The five-year
`survival rates are 70 percent for patients with local
`disease, 44 percent for those with regional metasta-
`ses, and 20 percent for those with distant metasta-
`ses.15 In rare cases when patients present with early-
`stage disease, local excision has been reported to be
`effective.80 The majority of patients, however, are
`treated with radical colectomy.
`
`RECTAL CARCINOID TUMORS
`Rectal carcinoid tumors make up 1 to 2 percent
`of all rectal tumors and are most common in the
`sixth decade of life.15 In contrast to carcinoids of the
`small intestine and colon, rectal carcinoids usually
`contain glucagon and glicentin-related peptides,
`rather than serotonin.12 Approximately 50 percent of
`tumors are asymptomatic and are found on routine
`endoscopy.81 Patients who have symptoms usually
`present with rectal bleeding, pain, or constipation.81,82
`The carcinoid syndrome is rare.82
`Rectal carcinoids most commonly metastasize to
`local lymph nodes and the liver; metastases to lung
`and bone are unusual. The size of the primary lesion
`correlates closely with the probability of metastases,
`which occur in less than 5 percent of patients with
`tumors measuring less than 1 cm in diameter but in
`the majority of cases in which lesions are more than
`2 cm in diameter.82,83 The five-year survival rates are
`81 percent for patients with local disease, 47 percent
`for patients with regional metastases, and 18 percent
`for patients with distant metastases.15
`Tumors less than 1 cm in diameter account for
`two thirds of rectal carcinoid tumors and are suc-
`cessfully treated with local excision. The manage-
`ment of tumors measuring 1 to 2 cm is controver-
`sial. Although most tumors of this size can be treated
`by local excision, several authors have suggested that
`muscular invasion, symptoms at diagnosis, and ul-
`ceration are poor prognostic factors that warrant
`more extensive surgical procedures.81-83 Tumors more
`than 2 cm in diameter have traditionally been treat-
`ed by low anterior resection or abdominoperineal
`resection. The value of these procedures in the treat-
`ment of rectal carcinoids has recently been ques-
`tioned, however, because they do not appear to ex-
`tend survival beyond that observed with local excision
`
`in retrospective series.84-86 An individualized approach,
`taking into account the patient’s age and coexisting
`conditions, may therefore be appropriate in deciding
`on a surgical approach to large rectal carcinoids.
`
`METASTATIC CARCINOID TUMORS
`Patients in whom metastatic disease is suspected
`should be evaluated with abdominal CT to rule out
`liver metastases. Liver-function tests are an unreli-
`able indicator of tumor involvement of the liver, and
`the serum alkaline phosphatase level is frequently
`normal despite extensive involvement of the liver by
`carcinoid tumor. Carcinoid liver metastases are often
`hypervascular and may appear isodense relative to
`the liver after the administration of intravenous con-
`trast material. CT should therefore be performed
`both before and after the administration of intrave-
`nous contrast agents.87,88
`Measurement of the serotonin metabolite 5-HIAA
`in a 24-hour urine collection may be useful in con-
`firming the diagnosis and in the subsequent moni-
`toring of patients with metastatic carcinoid tumors.
`In one study involving primarily patients with met-
`astatic disease, elevated urinary 5-HIAA excretion
`predicted the presence of carcinoid tumor with a
`sensitivity of 73 percent and a specificity of 100 per-
`cent.7 The measurement of serum chromogranin has
`also been reported to be useful in detecting carci-
`noid tumors.89
`The clinical course of patients with metastatic car-
`cinoid tumors is highly variable, and some patients
`remain free of symptoms for years. In a retrospective
`analysis of 71 patients, most of whom had metastatic
`carcinoid tumors of the midgut, an elevated level of
`plasma chromogranin A was an independent predic-
`tor of an adverse prognosis.90 Although the primary
`tumor site, the level of urinary 5-HIAA, and specific
`histologic growth patterns have all been suggested as
`potential prognostic factors, they have not reliably
`predicted survival in large studies.91,92 Positive anti-
`body staining of tumor cells for carcinoembryonic
`antigen is a poor prognostic factor and arouses con-
`cern that the tumor in question may contain features
`of adenocarcinoma.93,94 Such mixed tumors have been
`classified as adenocarcinoids and are usually treated
`as adenocarcinomas rather than as carcinoid tumors.
`
`TREATMENT WITH SOMATOSTATIN
`ANALOGUES
`Somatostatin analogues have a central role in both
`the diagnosis and the treatment of metastatic carci-
`noid tumors. Somatostatin is a 14-amino-acid pep-
`tide that inhibits the secretion of a broad range of
`hormones, including growth hormone, insulin, glu-
`cagon, and gastrin.95 It acts by binding to somato-
`statin receptors, which are expressed on more than
`80 percent of carcinoid tumors.96 Somatostatin re-
`ceptors belong to the superfamily of G protein–
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`
`The New England Journal of Medicine
`
`coupled receptors; activation of these receptors re-
`sults in inhibition of adenylyl cyclase, decreased con-
`ductance of voltage-sensitive calcium channels, acti-
`vation of potassium channels, and stimulation of
`tyrosine phosphatase activity.97 To date, five sub-
`types of somatostatin receptors have been cloned
`and characterized. Octreotide, an eight-amino-acid,
`long-acting somatostatin analogue that has been
`widely used for both detection and treatment of car-
`cinoid tumors, binds primarily to receptor subtypes
`2, 3, and 5.98 Its clinical efficacy appears to be related
`primarily to its ability to bind to receptor subtype 2.99
`Scintigraphy with radiolabeled octreotide has been
`successfully used to localize previously undetected
`primary or metastatic lesions.100 In two large Euro-
`pean studies, somatostatin scintigraphy detected car-
`cinoid lesions with a sensitivity of 89 percent.101 Such
`information is particularly helpful in confirming the
`presence of limited disease before one undertakes a
`potentially curative resection. In patients with the
`carcinoid syndrome, the detection of metastatic le-
`sions with somatostatin scintigraphy predicts a re-
`sponse to therapy with somatostatin analogues.100,102
`Somatostatin analogues are highly effective in re-
`lieving the symptoms of the carcinoid syndrome. In
`an initial study, subcutaneous administration of oc-
`treotide at a dosage of 150 µg three times a day im-
`proved symptoms in 88 percent of patients and de-
`creased urinary 5-HIAA excretion in 72 percent of
`patients.103 Subsequent studies with octreotide and a
`related peptide, lanreotide, have confirmed their ef-
`ficacy in treating the carcinoid syndrome.104,105 Ra-
`diographically demonstrated tumor regression, how-
`ever, is rare.
`
`CARCINOID HEART DISEASE
`Carcinoid heart disease occurs in two thirds of pa-
`tients with the carcinoid syndrome.106 Carcinoid
`heart lesions are characterized by plaquelike, fibrous
`endocardial thickening that classically involves the
`right side of the heart and often causes retraction
`and fixation of the leaflets of the tricuspid and pul-
`monary valves (Fig. 3). Tricuspid regurgitation is a
`nearly universal finding; tricuspid stenosis, pulmo-
`nary regurgitation, and pulmonary stenosis may also
`occur. Left-sided heart disease occurs in less than 10
`percent of patients.107,108
`The preponderance of lesions in the right side of
`the heart suggests that carcinoid heart disease is re-
`lated to factors secreted into the hepatic vein by liver
`metastases. Among patients with the carcinoid syn-
`drome, patients with heart disease have higher levels
`of serotonin in serum and 5-HIAA in urine.106-108
`Whether serotonin is directly responsible for the car-
`diac lesions, however, is unclear. Treatment resulting
`in decreased urinary 5-HIAA excretion does not re-
`sult in regression of cardiac lesions.108 The anorectic
`drugs fenfluramine and dexfenfluramine appear to
`
`864 · Ma