Full Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ionc20 Acta Oncologica ISSN: 0284-186X (Print) 1651-226X (Online) Journal homepage: https://www.tandfonline.com/loi/ionc20 Carcinoid A Comprehensive Review Isac I. Schnirer, James C. Yao & Jaffer A. Ajani To cite this article: Isac I. Schnirer, James C. Yao & Jaffer A. Ajani (2003) Carcinoid A Comprehensive Review, Acta Oncologica, 42:7, 672-692, DOI: 10.1080/02841860310010547 To link to this article: https://doi.org/10.1080/02841860310010547 Published online: 08 Jul 2009. Submit your article to this journal Article views: 1758 View related articles Citing articles: 9 View citing articles
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Carcinoid A Comprehensive ReviewFull Terms & Conditions of access and use can be found at https://www.tandfonline.com/action/journalInformation?journalCode=ionc20
Acta Oncologica
Carcinoid A Comprehensive Review
Isac I. Schnirer, James C. Yao & Jaffer A. Ajani
To cite this article: Isac I. Schnirer, James C. Yao & Jaffer A. Ajani (2003) Carcinoid A Comprehensive Review, Acta Oncologica, 42:7, 672-692, DOI: 10.1080/02841860310010547
To link to this article: https://doi.org/10.1080/02841860310010547
Published online: 08 Jul 2009.
Submit your article to this journal
Article views: 1758
View related articles
Isac I. Schnirer, James C. Yao and Jaffer A. Ajani
From the Department of Gastrointestinal Oncology and Digestive Diseases, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
Correspondence to: Jaffer A. Ajani, Department of GI Oncology, Box 78, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, Texas 77005-4341, USA. Tel: /1 713 792 2828. Fax: /1 713 745 1163. E-mail: [email protected]
Acta Oncologica Vol. 42, No. 7, pp. 672/692, 2003
Carcinoid tumors originate from the neuroendocrine cells throughout the body and are capable of producing various peptides. Their clinical course is often indolent but can also be aggressive and resistant to therapy. We examined all aspects of carcinoid tumors including the molecular biology oncogenesis, role of angiogenesis, recent advances in imaging, and therapy. The Medline and Cancerlit databases were searched using carcinoid as the keyword. English language manuscripts were reviewed and relevant references from a total of 7 741 were found. All titles were screened and all the relevant manuscripts were analyzed; we found 307 references pertinent to the history, epidemiology, clinical behavior, pathology, pathophysiology, molecular biology, radiologic imaging, supportive care of carcinoid syndrome, and results of therapeutic clinical trials. Management of patients with carcinoid tumors requires an understanding of the disease process and a multimodality approach. Introduction of long-acting somatostatin analogues has resulted in significant advances in the palliative care of patients with carcinoid syndrome. However, advanced carcinoid tumor remains incurable. Existing therapies for advanced disease have low biologic activity, high toxicity, or both. Clearly, more research is necessary in the areas of molecular biology, targeted therapy, and development of new drugs. Future advances in this field need to focus on clinical and biological predictors of outcome. Early works in the area of tumor biology such as the role of p53, bcl-2, bax, MEN1, FGF, TGF, PDGF and VEGF expression are of interest and need to be explored further.
Received 5 September 2002 Accepted 10 April 2003
BACKGROUND
The pathologic entity that is known as carcinoid was first
characterized by Lubarsh in 1888 (1). However, Ranson is
given credit for the first description of a carcinoid of the
ileum in 1890 (2). The term ‘karzinoide’ was used first by
Oberndorfer in 1907 to describe tumors that behaved in a
more indolent fashion than typical adenocarcinomas (3). In
1928, Masson stated that carcinoids should be considered
as endocrine tumors (4), since the malignant chromaffin, or
Kulchitsky, cells in this disease exhibit amine uptake and
decarboxylation characteristics. Subsequently, gastric carci-
noids were associated with multiple endocrine neoplasia
(MEN) syndromes (5). In 1953, Lembech demonstrated the
presence of serotonin in carcinoid tumors (6), and in 1955,
Page et al. described increased urinary 5-hydroxyindoleace-
tic acid (5-HIAA) in patients with carcinoid syndrome (7).
Although a relatively uncommon cancer, carcinoid can
present with dramatic manifestations that range from
asymptomatic massive hepatomegaly to flushing, diarrhea,
and asthma. Some patients present with bowel obstruction,
while others have tumors for unrelated reasons that are
found incidentally at time of surgery. Carcinoids often grow
slowly but can also be resistant to therapy. The management
of patients with carcinoid requires an understanding of the
disease process and the potentials of multiple modalities of
oncologic therapy.
syndrome in two parts. First, we review the history,
epidemiology, clinical behavior, pathology, pathophysiol-
ogy, molecular biology, and radiologic imaging of carcinoid
tumors. Next, we review advances in the supportive care of
carcinoid syndrome and results of clinical trials and
speculate on future directions of research.
EPIDEMIOLOGY
and race. The overall incidence in the United States is
estimated to be 2 cases per 100 000 people (8). The incidence
in England, Scotland, Spain, Italy, and Japan is similar (0.7
per 100 000 people (9/13). In autopsies, however, the rate
REVIEW ARTICLE
DOI: 10.1080/02841860310010547
tends to be much higher. In a 20-year study conducted at
the Mayo Clinic, Moertel et al. found carcinoid tumor of
the small intestine in 97 of 14 852 cases of unselected
necropsy (0.65%) (14). Furthermore, they found that
carcinoid tumors accounted for 28% of all small intestinal
tumors. In a separate report, Berge and Linell described the
findings of a similar necropsy study performed in Malmo,
Sweden. During a 12-year period, 199 (1.2%) cases of
carcinoids were identified among 16 294 unselected necrop-
sies (15).
Carcinoid tumors are often diagnosed in a person’s fifth
or sixth decade of life (8, 11). Except in appendiceal and
bronchopulmonary sites, African Americans have a higher
incidence than other ethnic groups (8). According to the
Surveillance, Epidemiology, and End Results (SEER) data
from the US National Cancer Institute (NCI), it is slightly
more common in females (55% of all cases) than males (8,
10).
Modlin et al. evaluated 8 305 cases of carcinoid tumors
identified by the SEER program from 1973 to 1991,
together with two earlier NCI programs, the End Results
Group (1950/1969) and the Third National Cancer Survey
(1969/1971) (8). In this database, 74% of carcinoid tumors
originated in the gastrointestinal tract. The second most
frequent site was in the tracheobronchopulmonary tree
(25%). Within the gastrointestinal tract, small intestine was
the most common primary site, followed by appendix and
rectum (Table 1).
Carcinoid tumors have a relatively slow rate of growth. (16).
Patients may survive for many years even in the face of
advanced disease. Forty to 60% of patients are asympto-
matic at presentation (14, 16). Delay in diagnosis of up to 20
years has been described (14, 17).
Gastrointestinal carcinoids
time of endoscopy but may also present with abdominal
pain and, rarely, gastrointestinal bleeding as well as anemia
(18). Gastric carcinoid accounts for as many as 0.3% of
stomach neoplasms (18). Gastric carcinoids originate from
enterochromaffin-like (ECL) cells (19). ECL cells secrete
histamine, which regulates gastric acid secretion. Gastrin is
an important inducer of the growth of ECL cells. An
abnormal increase in gastrin production may be mitogenic
for ECL cells (19).
and histological methods into three distinct groups (20/23).
The first group is associated with chronic atrophic gastritis
type A. The second group is associated with Zollinger-
Ellison syndrome. The third group comprises sporadic
gastric carcinoid (24, 25).
also have chronic atrophic gastritis type A, and often,
pernicious anemia (19, 26/28). These patients have an
absence of parietal cells, achlorhydria, and hypergastrine-
mia (19). The tumors are usually less than 1 cm in diameter
and metastasize in 10% of cases (29).
About 5% to 10% of gastric carcinoids are associated
with Zollinger-Ellison syndrome and the familial MEN1
gene (20). These tumors appear equally in both sexes at a
mean age of 50 years (range, 28/67 years). The tumor size is
less than 1.5 cm, and about 25% metastasize (18, 26).
The third type, sporadic carcinoids, constitutes 15% to
25% of gastric carcinoids (29). These are more common in
Table 1
face and neck, sometimes whole body
Kallikrein, histamine, 5-hydroxytryptamine, prosta-
dins, vasoactive intestinal peptide
Abdominal
pain
35 Long history Small bowel obstruction due to tumor or tumor
products, mesenteric ischemia, hepatomegaly
Bronchospasm 15 / Histamine, 5-hydroxytryptamine
Heart disease
Left side 10
Acta Oncologica 42 (2003) Carcinoid: a comprehensive review 673
men than in women and are larger than 1 cm at diagnosis
(29, 30). They can be associated with atypical carcinoid
syndrome. These tumors have a higher metastatic potential
and a less favorable prognosis than the other types (29, 30).
Midgut carcinoid represents the most common type of
carcinoid. It frequently presents with intestinal obstruction,
abdominal pain, diarrhea, and gastrointestinal bleeding (16)
Carcinoid of the small bowel may account for as many as
90% of patients with carcinoid syndrome (31). Small-bowel
carcinoids can also cause fibrosis, bowel obstruction,
strangulation, and ischemia (14, 17, 18, 32).
As many as 28% of patients with gastric or small-bowel
carcinoid have multiple carcinoid primaries (33). Synchro-
nous diagnosis of non-neuroendocrine cancer has also been
observed (8, 34). The frequency of this diagnosis ranges
from 17% to 53% of patients with carcinoid (34, 35).
Carcinoid can also arise from other portions of the
gastrointestinal tract, including appendix, colon, and rec-
tum (36).
Non-gastrointestinal carcinoid
Carcinoid tumors of the lung were first described in 1972
and account for approximately 2% of all lung tumors (37,
38). Patients with pulmonary carcinoid tumors often have a
good prognosis, with 5-year survival rates between 60% and
100% and 10-year survival rates between 40% and 100%
(39, 40). Symptoms are highly variable and are often present
years before diagnosis. Cushing’s syndrome occurs in 2% of
patients; moreover, 1% of patients presenting with Cush-
ing’s syndrome have a pulmonary carcinoid tumor (39, 41,
42). Acromegaly, from ectopic secretion of growth hor-
mone-releasing hormone, has also been reported in cases of
bronchopulmonary carcinoid. However, classic carcinoid
syndrome occurs in fewer than 5% of the cases (23, 43).
Ovarian carcinoids have also been described; these may
produce symptoms such as severe constipation due to over
secretion of peptide YY (44).
PATHOPHYSIOLOGY OF CARCINOID SYNDROME
Carcinoid tumors are derived from dispersed neuroectoder-
mal cells (45). ECL cells, also known as Kulchitsky’s cells,
are the most common endocrine cells and are frequently
found in the gastrointestinal tract. They are most numerous
in the duodenum, the terminal ileum, and the appendix
(46). ECL cells also occur in the bronchial epithelium and
within the urogenital tract (47). Thus, carcinoid tumors are
neoplasms of peptide- and amine-producing cells, and their
variable hormone profiles are based on the site of origin (46,
48).
substances, including neuron-specific enolase, 5-hydroxy-
tryptophan (5-HTP), synaptophysin, chromogranin-A and
C, growth hormone, neurotensin, pancreatic polypeptide,
calcitonin, tachykinins, growth hormone-releasing hor-
mone, bombesin, adrenocorticotropic hormone (ACTH),
kallikrein, glucagon, histamine, catecholamines, prostaglan-
dins, substance P, gastrin, insulin, pancreastatin, and
various growth factors such as transforming growth factor
(TGF-), platelet-derived growth factor (PDGF), and b-
fibroblast growth factor (16, 18, 49/51).
Under normal conditions, as much as 99% of dietary
tryptophan is metabolized by the oxidative pathway into
nicotinic acid, and 1% or less is made into 5-HTP (52, 53).
In carcinoid tumors, however, 5-HTP and 5-HIAA pre-
dominate as the metabolites of tryptophan (52, 54). A
disequilibrium of tryptophan metabolism has been hypothe-
sized whereby as much as 60% of the body’s tryptophan
may be shunted to 5-hydroxylation instead of being
oxidized into nicotinic acid (52, 54). This results in synthesis
of large quantities of serotonin and other molecules,
including 5-HTP and 5-HIAA. The bulk of the serotonin
in the circulatory system is metabolized into 5-HIAA (52,
55). This shunting of tryptophan to the tumor, rather than
to the brain, and the reduction in nicotinic acid pools can
cause pellagra (17, 49, 52, 54) characterized by dermatitis,
diarrhea, and dementia (Table 2) (52).
Foregut carcinoids have a low serotonin content, and
thus clinical syndromes are rare (18). These tumors
occasionally secrete 5-HTP or ACTH and are associated
with atypical carcinoid syndrome. Production of ACTH can
cause Cushing’s syndrome (32). Acromegaly due to growth
hormone-releasing hormone has also been reported (18).
Midgut carcinoids have a high serotonin content and
frequently cause a classical carcinoid syndrome (18).
Hindgut carcinoid tumors rarely contain serotonin, rarely
cause carcinoid syndrome, and rarely secrete 5-HTP or
Table 2
Site and embryonic origin Site distribution (%)
Foregut
Rectum 10/12
Unknown B/1/2
References: (8), (9), (14), (17), (36), (51), (117), (227), (228), (229), (230).
674 I. I. Schnirer et al. Acta Oncologica 42 (2003)
ACTH (18). The absence of the syndrome may also be
related to the presence of biologically inactive peptides (46).
The incidence of carcinoid syndrome, which is character-
ized by flushing, diarrhea, abdominal cramping, and, less
often, wheezing, heart-valve dysfunction, and pellagra,
varies depending on the study population. Studies that
include patients with localized and incidental tumors report
the incidence of carcinoid syndrome to be about 10% to
18% (52, 56). Among patients with more extensive disease,
the incidence is about 40% to 50%.
The syndrome results from synergistic interactions be-
tween 5-HTP metabolites, kinins, and prostaglandins.
Carcinoid syndrome is often observed in patients with
metastatic disease or when the primary tumor site allows
the secreted amines to escape enteral hepatic circulation (18,
57, 58).
Flushing is thought to be related to tachykinins. It is
controlled by somatostatin analogues but not by serotonin
antagonists (46, 59/61). However, direct proof that tachy-
kinins cause flushing has not yet been discovered. Four
types of flushing patterns may occur, including diffuse
erythematous, violaceous, prolonged, and bright red
patches. These patterns can last from 2 to 10 min, affecting
the face, neck, and upper chest, or up to 2 to 3 days,
affecting the whole body with lacrimation, edema of the
salivary glands, and hypotension. Wheezing and asthma
attacks are sometimes observed during flushing. Both
serotonin and bradykinin have been implicated as causes
of bronchospasm (62/64). Serotonin seems to play a major
role in diarrhea.
caused by continuously high concentrations of circulating
amines. This can lead to failure of the right heart (52). It is
often associated with high urinary 5-HIAA levels and high
plasma levels of neurokinin A and substance P (65/67).
It is hypothesized that carcinoid crisis is caused by
massive release of bioactive products, especially catechola-
mines, from the tumor. It is characterized by profound
hypotension (occasionally hypertension) and severe flushing
with or without bronchospasm (68).
MOLECULAR BIOLOGY
The genetics of carcinoid tumorigenesis have yet to be fully
elucidated. However, interesting familial and hereditary
mutations of p53 , K-ras-2 , C-raf-1 , Bcl2 , MEN1 , n-myc ,
and c-jun , abnormal bcl-2:bax ratio, and DNA ploidy have
been implicated in connection with prognostic factors of
carcinoid tumors (69/75).
The p53 protein is encoded by a recessive gene on
chromosome 17. The p53 wild-type gene has a short half-
life and cannot be detected by immunohistochemical
methods. However, most mutant types have longer half-
lives and are easily detectable (76). Reports of p53 mutation
in carcinoid tumors have been limited to atypical carcinoid
of the lung (Table 3) (16, 77).
MEN1
somal, dominantly inherited disorder. The MEN1 gene
localizes to chromosome 11 (11q13). MEN1 can manifest as
parathyroid and pancreatic islet cell tumors and, less
frequently, as adenoma of the anterior pituitary (71). The
classic syndrome includes neoplasia of parathyroid glands,
anterior pituitary, endocrine pancreas, and endocrine duo-
denum and, rarely, neuroendocrine tumors of the lung,
thymus, and stomach (72). Carcinoids can occur with
familial MEN1 but with lower frequency (71, 78).
Fewer than 10% of patients with MEN1 have carcinoid
tumors (52). The MEN1 gene, however, may be involved in
the tumorigenesis of sporadic carcinoid tumors. Jakobovitz
et al. studied tissue from 46 patients with spontaneous
carcinoid tumors for loss of heterozygosity (LOH) on
chromosome 11; 78% were found to have LOH (79/82).
MEN1 and LOH on chromosome 11 have been found in
association with pulmonary carcinoids. In a recent study it
was found that sporadic lung carcinoid tumors had two
inactivated copies of the MEN1 gene in 44% of cases (72,
83). MEN1 is the first well-characterized genetic alteration
of these tumors (72). The MEN1 gene in pulmonary tumors
indicates a possible familial component to these cancers
(84). Also, LOH at chromosome 3p14.2-p21.3 is signifi-
cantly more extensive in atypical carcinoid tumors (85, 86).
bcl-2 and bax
protein and can be considered as the main effector of
apoptosis. Bax functions in active cell death through
dimerization of bax:bax. This can be opposed by bax:bcl-
2 heterodimerization, which inactivates the apoptosis pro-
cess. Bcl-2 is regulated by p53. Therefore, the balance of
bax :bcl2 and its effect on activated cell death is regulated
through p53 (69, 73).
Expression of bcl-2 and bax also has been studied in
carcinoid tumors of the lung. Brambilla et al. studied the
bcl-2:bax expression ratios of neuroendocrine tumors of the
lung (73). Carcinoid tumors had higher bax expression and
lower bcl-2 expression than large-cell neuroendocrine
carcinomas and small-cell lung carcinomas. The same
investigators also reported that in patients with pulmonary
carcinoid, bcl-2 over-expression, bax down-regulation, and
a bcl-2:bax ratio /1 predicted shorter survival times. Both
Copolla et al. (77) and Zirbes et al. (69) found bcl-2
overexpression to be more frequent among atypical carci-
noid tumors than among typical pulmonary carcinoid.
In gastric carcinoids, bcl-2 has been implicated as an
active oncogene in the early phases of the carcinogenic
Acta Oncologica 42 (2003) Carcinoid: a comprehensive review 675
sequence (87). In one study, bcl-2 expression was more
pronounced in metastatic lesions than in the primary tumor.
Other oncogenes
N-myc and c-jun have also been implicated as oncogenes;
they may be involved in the early onset of bowel carcinoid
in transgenic mice (75, 88). In the mastomy model,
amplification of c- and n-myc oncogenes has been suggested
(75, 89/91).
by desmoplastic reactions. Basic fibroblast growth factor, a
potent stimulant of endothelial cell growth is expressed in
both carcinoid tumor tissue and a carcinoid cell line (92),
(93). Vascular endothelial growth factor (VEGF) expression
has been demonstrated in both gastrointestinal and pul-
monary carcinoids (94, 95).
tumors (92, 93, 96/99). While TGF-a expression has been
found by both Nilsson et al. (97) and Krishnamurthy et al.
(98), EGFR expression is more complex. Nilsson et al.
found evidence of EGFR expression by immunocytochem-
istry and northern analysis (100). Krishnamurthy et al.,
however, found evidence of the extracellular domain of
EGFR but not expression of the intracellular domain of
EGFR (98). Finally, Facco et al. found EGFR expression in
the stromal cells of some metastatic ileal carcinoids (99).
PDGF and its receptors (PDGFR) are also expressed in
carcinoids. Expression of PDGF has been found in 70% of
carcinoid tumors (92). Additionally, PDGFR-a has been
found on both carcinoid tumor cells and stroma of
carcinoid tumors, which indicates a possible autocrine
loop supporting tumor growth. PDGFR-b has been found
in the stroma of carcinoid tumors. PDGFR-a expression is
more intense in metastatic tissue than in primary tumor.
PDGFR-b expression also appears to be more intense in the
stroma and small capillaries around tumor clusters, suggest-
ing that carcinoid cells may simultaneously produce PDGF
and up-regulate PDGFR-b in a paracrine fashion (101).
These studies have shown that carcinoid tumors secrete a
number of biologically active growth factors that interact
with the tumor and the surrounding stroma in a complex
autocrine/paracrine fashion. Further systematic investiga-
tions in this promising field may lead to discovery of novel
therapeutic targets.
Table 3
Silver
staining
676 I. I. Schnirer et al. Acta Oncologica 42 (2003)
PATHOLOGY
Classification
has not yet been adopted. In 1963, Williams & Sandler
classified carcinoid tumors on the basis of embryonic
divisions of the gut: foregut carcinoids, midgut carcinoids,
and hindgut carcinoids (102). The foregut includes the
thymus, respiratory tract, ovaries and stomach, pancreas,
and duodenum (103/110). The midgut includes the jeju-
num, ileum, appendix, cecum, Meckel’s diverticulum, and
ascending colon. The hindgut includes the colon and
rectum (Table 2).
In 1994, Kloppel et al. and Cappela et al. proposed a
method of classification based on location, size, invasive-
ness, angioinvasion, differentiation, metastatic pattern, and
clinical presentation (111, 112). Others have adopted a
classification system based on histologic characteristics
(23).
sheets of small round cells with uniform nuclei and
cytoplasm. Five growth patterns are noticed: insular,
trabecular, glandular, undifferentiated (usually designated
A through D or I through IV), and mixed (113). Tumors
with increased nuclear atypia, high mitotic activity, or…
Acta Oncologica
Carcinoid A Comprehensive Review
Isac I. Schnirer, James C. Yao & Jaffer A. Ajani
To cite this article: Isac I. Schnirer, James C. Yao & Jaffer A. Ajani (2003) Carcinoid A Comprehensive Review, Acta Oncologica, 42:7, 672-692, DOI: 10.1080/02841860310010547
To link to this article: https://doi.org/10.1080/02841860310010547
Published online: 08 Jul 2009.
Submit your article to this journal
Article views: 1758
View related articles
Isac I. Schnirer, James C. Yao and Jaffer A. Ajani
From the Department of Gastrointestinal Oncology and Digestive Diseases, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
Correspondence to: Jaffer A. Ajani, Department of GI Oncology, Box 78, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Houston, Texas 77005-4341, USA. Tel: /1 713 792 2828. Fax: /1 713 745 1163. E-mail: [email protected]
Acta Oncologica Vol. 42, No. 7, pp. 672/692, 2003
Carcinoid tumors originate from the neuroendocrine cells throughout the body and are capable of producing various peptides. Their clinical course is often indolent but can also be aggressive and resistant to therapy. We examined all aspects of carcinoid tumors including the molecular biology oncogenesis, role of angiogenesis, recent advances in imaging, and therapy. The Medline and Cancerlit databases were searched using carcinoid as the keyword. English language manuscripts were reviewed and relevant references from a total of 7 741 were found. All titles were screened and all the relevant manuscripts were analyzed; we found 307 references pertinent to the history, epidemiology, clinical behavior, pathology, pathophysiology, molecular biology, radiologic imaging, supportive care of carcinoid syndrome, and results of therapeutic clinical trials. Management of patients with carcinoid tumors requires an understanding of the disease process and a multimodality approach. Introduction of long-acting somatostatin analogues has resulted in significant advances in the palliative care of patients with carcinoid syndrome. However, advanced carcinoid tumor remains incurable. Existing therapies for advanced disease have low biologic activity, high toxicity, or both. Clearly, more research is necessary in the areas of molecular biology, targeted therapy, and development of new drugs. Future advances in this field need to focus on clinical and biological predictors of outcome. Early works in the area of tumor biology such as the role of p53, bcl-2, bax, MEN1, FGF, TGF, PDGF and VEGF expression are of interest and need to be explored further.
Received 5 September 2002 Accepted 10 April 2003
BACKGROUND
The pathologic entity that is known as carcinoid was first
characterized by Lubarsh in 1888 (1). However, Ranson is
given credit for the first description of a carcinoid of the
ileum in 1890 (2). The term ‘karzinoide’ was used first by
Oberndorfer in 1907 to describe tumors that behaved in a
more indolent fashion than typical adenocarcinomas (3). In
1928, Masson stated that carcinoids should be considered
as endocrine tumors (4), since the malignant chromaffin, or
Kulchitsky, cells in this disease exhibit amine uptake and
decarboxylation characteristics. Subsequently, gastric carci-
noids were associated with multiple endocrine neoplasia
(MEN) syndromes (5). In 1953, Lembech demonstrated the
presence of serotonin in carcinoid tumors (6), and in 1955,
Page et al. described increased urinary 5-hydroxyindoleace-
tic acid (5-HIAA) in patients with carcinoid syndrome (7).
Although a relatively uncommon cancer, carcinoid can
present with dramatic manifestations that range from
asymptomatic massive hepatomegaly to flushing, diarrhea,
and asthma. Some patients present with bowel obstruction,
while others have tumors for unrelated reasons that are
found incidentally at time of surgery. Carcinoids often grow
slowly but can also be resistant to therapy. The management
of patients with carcinoid requires an understanding of the
disease process and the potentials of multiple modalities of
oncologic therapy.
syndrome in two parts. First, we review the history,
epidemiology, clinical behavior, pathology, pathophysiol-
ogy, molecular biology, and radiologic imaging of carcinoid
tumors. Next, we review advances in the supportive care of
carcinoid syndrome and results of clinical trials and
speculate on future directions of research.
EPIDEMIOLOGY
and race. The overall incidence in the United States is
estimated to be 2 cases per 100 000 people (8). The incidence
in England, Scotland, Spain, Italy, and Japan is similar (0.7
per 100 000 people (9/13). In autopsies, however, the rate
REVIEW ARTICLE
DOI: 10.1080/02841860310010547
tends to be much higher. In a 20-year study conducted at
the Mayo Clinic, Moertel et al. found carcinoid tumor of
the small intestine in 97 of 14 852 cases of unselected
necropsy (0.65%) (14). Furthermore, they found that
carcinoid tumors accounted for 28% of all small intestinal
tumors. In a separate report, Berge and Linell described the
findings of a similar necropsy study performed in Malmo,
Sweden. During a 12-year period, 199 (1.2%) cases of
carcinoids were identified among 16 294 unselected necrop-
sies (15).
Carcinoid tumors are often diagnosed in a person’s fifth
or sixth decade of life (8, 11). Except in appendiceal and
bronchopulmonary sites, African Americans have a higher
incidence than other ethnic groups (8). According to the
Surveillance, Epidemiology, and End Results (SEER) data
from the US National Cancer Institute (NCI), it is slightly
more common in females (55% of all cases) than males (8,
10).
Modlin et al. evaluated 8 305 cases of carcinoid tumors
identified by the SEER program from 1973 to 1991,
together with two earlier NCI programs, the End Results
Group (1950/1969) and the Third National Cancer Survey
(1969/1971) (8). In this database, 74% of carcinoid tumors
originated in the gastrointestinal tract. The second most
frequent site was in the tracheobronchopulmonary tree
(25%). Within the gastrointestinal tract, small intestine was
the most common primary site, followed by appendix and
rectum (Table 1).
Carcinoid tumors have a relatively slow rate of growth. (16).
Patients may survive for many years even in the face of
advanced disease. Forty to 60% of patients are asympto-
matic at presentation (14, 16). Delay in diagnosis of up to 20
years has been described (14, 17).
Gastrointestinal carcinoids
time of endoscopy but may also present with abdominal
pain and, rarely, gastrointestinal bleeding as well as anemia
(18). Gastric carcinoid accounts for as many as 0.3% of
stomach neoplasms (18). Gastric carcinoids originate from
enterochromaffin-like (ECL) cells (19). ECL cells secrete
histamine, which regulates gastric acid secretion. Gastrin is
an important inducer of the growth of ECL cells. An
abnormal increase in gastrin production may be mitogenic
for ECL cells (19).
and histological methods into three distinct groups (20/23).
The first group is associated with chronic atrophic gastritis
type A. The second group is associated with Zollinger-
Ellison syndrome. The third group comprises sporadic
gastric carcinoid (24, 25).
also have chronic atrophic gastritis type A, and often,
pernicious anemia (19, 26/28). These patients have an
absence of parietal cells, achlorhydria, and hypergastrine-
mia (19). The tumors are usually less than 1 cm in diameter
and metastasize in 10% of cases (29).
About 5% to 10% of gastric carcinoids are associated
with Zollinger-Ellison syndrome and the familial MEN1
gene (20). These tumors appear equally in both sexes at a
mean age of 50 years (range, 28/67 years). The tumor size is
less than 1.5 cm, and about 25% metastasize (18, 26).
The third type, sporadic carcinoids, constitutes 15% to
25% of gastric carcinoids (29). These are more common in
Table 1
face and neck, sometimes whole body
Kallikrein, histamine, 5-hydroxytryptamine, prosta-
dins, vasoactive intestinal peptide
Abdominal
pain
35 Long history Small bowel obstruction due to tumor or tumor
products, mesenteric ischemia, hepatomegaly
Bronchospasm 15 / Histamine, 5-hydroxytryptamine
Heart disease
Left side 10
Acta Oncologica 42 (2003) Carcinoid: a comprehensive review 673
men than in women and are larger than 1 cm at diagnosis
(29, 30). They can be associated with atypical carcinoid
syndrome. These tumors have a higher metastatic potential
and a less favorable prognosis than the other types (29, 30).
Midgut carcinoid represents the most common type of
carcinoid. It frequently presents with intestinal obstruction,
abdominal pain, diarrhea, and gastrointestinal bleeding (16)
Carcinoid of the small bowel may account for as many as
90% of patients with carcinoid syndrome (31). Small-bowel
carcinoids can also cause fibrosis, bowel obstruction,
strangulation, and ischemia (14, 17, 18, 32).
As many as 28% of patients with gastric or small-bowel
carcinoid have multiple carcinoid primaries (33). Synchro-
nous diagnosis of non-neuroendocrine cancer has also been
observed (8, 34). The frequency of this diagnosis ranges
from 17% to 53% of patients with carcinoid (34, 35).
Carcinoid can also arise from other portions of the
gastrointestinal tract, including appendix, colon, and rec-
tum (36).
Non-gastrointestinal carcinoid
Carcinoid tumors of the lung were first described in 1972
and account for approximately 2% of all lung tumors (37,
38). Patients with pulmonary carcinoid tumors often have a
good prognosis, with 5-year survival rates between 60% and
100% and 10-year survival rates between 40% and 100%
(39, 40). Symptoms are highly variable and are often present
years before diagnosis. Cushing’s syndrome occurs in 2% of
patients; moreover, 1% of patients presenting with Cush-
ing’s syndrome have a pulmonary carcinoid tumor (39, 41,
42). Acromegaly, from ectopic secretion of growth hor-
mone-releasing hormone, has also been reported in cases of
bronchopulmonary carcinoid. However, classic carcinoid
syndrome occurs in fewer than 5% of the cases (23, 43).
Ovarian carcinoids have also been described; these may
produce symptoms such as severe constipation due to over
secretion of peptide YY (44).
PATHOPHYSIOLOGY OF CARCINOID SYNDROME
Carcinoid tumors are derived from dispersed neuroectoder-
mal cells (45). ECL cells, also known as Kulchitsky’s cells,
are the most common endocrine cells and are frequently
found in the gastrointestinal tract. They are most numerous
in the duodenum, the terminal ileum, and the appendix
(46). ECL cells also occur in the bronchial epithelium and
within the urogenital tract (47). Thus, carcinoid tumors are
neoplasms of peptide- and amine-producing cells, and their
variable hormone profiles are based on the site of origin (46,
48).
substances, including neuron-specific enolase, 5-hydroxy-
tryptophan (5-HTP), synaptophysin, chromogranin-A and
C, growth hormone, neurotensin, pancreatic polypeptide,
calcitonin, tachykinins, growth hormone-releasing hor-
mone, bombesin, adrenocorticotropic hormone (ACTH),
kallikrein, glucagon, histamine, catecholamines, prostaglan-
dins, substance P, gastrin, insulin, pancreastatin, and
various growth factors such as transforming growth factor
(TGF-), platelet-derived growth factor (PDGF), and b-
fibroblast growth factor (16, 18, 49/51).
Under normal conditions, as much as 99% of dietary
tryptophan is metabolized by the oxidative pathway into
nicotinic acid, and 1% or less is made into 5-HTP (52, 53).
In carcinoid tumors, however, 5-HTP and 5-HIAA pre-
dominate as the metabolites of tryptophan (52, 54). A
disequilibrium of tryptophan metabolism has been hypothe-
sized whereby as much as 60% of the body’s tryptophan
may be shunted to 5-hydroxylation instead of being
oxidized into nicotinic acid (52, 54). This results in synthesis
of large quantities of serotonin and other molecules,
including 5-HTP and 5-HIAA. The bulk of the serotonin
in the circulatory system is metabolized into 5-HIAA (52,
55). This shunting of tryptophan to the tumor, rather than
to the brain, and the reduction in nicotinic acid pools can
cause pellagra (17, 49, 52, 54) characterized by dermatitis,
diarrhea, and dementia (Table 2) (52).
Foregut carcinoids have a low serotonin content, and
thus clinical syndromes are rare (18). These tumors
occasionally secrete 5-HTP or ACTH and are associated
with atypical carcinoid syndrome. Production of ACTH can
cause Cushing’s syndrome (32). Acromegaly due to growth
hormone-releasing hormone has also been reported (18).
Midgut carcinoids have a high serotonin content and
frequently cause a classical carcinoid syndrome (18).
Hindgut carcinoid tumors rarely contain serotonin, rarely
cause carcinoid syndrome, and rarely secrete 5-HTP or
Table 2
Site and embryonic origin Site distribution (%)
Foregut
Rectum 10/12
Unknown B/1/2
References: (8), (9), (14), (17), (36), (51), (117), (227), (228), (229), (230).
674 I. I. Schnirer et al. Acta Oncologica 42 (2003)
ACTH (18). The absence of the syndrome may also be
related to the presence of biologically inactive peptides (46).
The incidence of carcinoid syndrome, which is character-
ized by flushing, diarrhea, abdominal cramping, and, less
often, wheezing, heart-valve dysfunction, and pellagra,
varies depending on the study population. Studies that
include patients with localized and incidental tumors report
the incidence of carcinoid syndrome to be about 10% to
18% (52, 56). Among patients with more extensive disease,
the incidence is about 40% to 50%.
The syndrome results from synergistic interactions be-
tween 5-HTP metabolites, kinins, and prostaglandins.
Carcinoid syndrome is often observed in patients with
metastatic disease or when the primary tumor site allows
the secreted amines to escape enteral hepatic circulation (18,
57, 58).
Flushing is thought to be related to tachykinins. It is
controlled by somatostatin analogues but not by serotonin
antagonists (46, 59/61). However, direct proof that tachy-
kinins cause flushing has not yet been discovered. Four
types of flushing patterns may occur, including diffuse
erythematous, violaceous, prolonged, and bright red
patches. These patterns can last from 2 to 10 min, affecting
the face, neck, and upper chest, or up to 2 to 3 days,
affecting the whole body with lacrimation, edema of the
salivary glands, and hypotension. Wheezing and asthma
attacks are sometimes observed during flushing. Both
serotonin and bradykinin have been implicated as causes
of bronchospasm (62/64). Serotonin seems to play a major
role in diarrhea.
caused by continuously high concentrations of circulating
amines. This can lead to failure of the right heart (52). It is
often associated with high urinary 5-HIAA levels and high
plasma levels of neurokinin A and substance P (65/67).
It is hypothesized that carcinoid crisis is caused by
massive release of bioactive products, especially catechola-
mines, from the tumor. It is characterized by profound
hypotension (occasionally hypertension) and severe flushing
with or without bronchospasm (68).
MOLECULAR BIOLOGY
The genetics of carcinoid tumorigenesis have yet to be fully
elucidated. However, interesting familial and hereditary
mutations of p53 , K-ras-2 , C-raf-1 , Bcl2 , MEN1 , n-myc ,
and c-jun , abnormal bcl-2:bax ratio, and DNA ploidy have
been implicated in connection with prognostic factors of
carcinoid tumors (69/75).
The p53 protein is encoded by a recessive gene on
chromosome 17. The p53 wild-type gene has a short half-
life and cannot be detected by immunohistochemical
methods. However, most mutant types have longer half-
lives and are easily detectable (76). Reports of p53 mutation
in carcinoid tumors have been limited to atypical carcinoid
of the lung (Table 3) (16, 77).
MEN1
somal, dominantly inherited disorder. The MEN1 gene
localizes to chromosome 11 (11q13). MEN1 can manifest as
parathyroid and pancreatic islet cell tumors and, less
frequently, as adenoma of the anterior pituitary (71). The
classic syndrome includes neoplasia of parathyroid glands,
anterior pituitary, endocrine pancreas, and endocrine duo-
denum and, rarely, neuroendocrine tumors of the lung,
thymus, and stomach (72). Carcinoids can occur with
familial MEN1 but with lower frequency (71, 78).
Fewer than 10% of patients with MEN1 have carcinoid
tumors (52). The MEN1 gene, however, may be involved in
the tumorigenesis of sporadic carcinoid tumors. Jakobovitz
et al. studied tissue from 46 patients with spontaneous
carcinoid tumors for loss of heterozygosity (LOH) on
chromosome 11; 78% were found to have LOH (79/82).
MEN1 and LOH on chromosome 11 have been found in
association with pulmonary carcinoids. In a recent study it
was found that sporadic lung carcinoid tumors had two
inactivated copies of the MEN1 gene in 44% of cases (72,
83). MEN1 is the first well-characterized genetic alteration
of these tumors (72). The MEN1 gene in pulmonary tumors
indicates a possible familial component to these cancers
(84). Also, LOH at chromosome 3p14.2-p21.3 is signifi-
cantly more extensive in atypical carcinoid tumors (85, 86).
bcl-2 and bax
protein and can be considered as the main effector of
apoptosis. Bax functions in active cell death through
dimerization of bax:bax. This can be opposed by bax:bcl-
2 heterodimerization, which inactivates the apoptosis pro-
cess. Bcl-2 is regulated by p53. Therefore, the balance of
bax :bcl2 and its effect on activated cell death is regulated
through p53 (69, 73).
Expression of bcl-2 and bax also has been studied in
carcinoid tumors of the lung. Brambilla et al. studied the
bcl-2:bax expression ratios of neuroendocrine tumors of the
lung (73). Carcinoid tumors had higher bax expression and
lower bcl-2 expression than large-cell neuroendocrine
carcinomas and small-cell lung carcinomas. The same
investigators also reported that in patients with pulmonary
carcinoid, bcl-2 over-expression, bax down-regulation, and
a bcl-2:bax ratio /1 predicted shorter survival times. Both
Copolla et al. (77) and Zirbes et al. (69) found bcl-2
overexpression to be more frequent among atypical carci-
noid tumors than among typical pulmonary carcinoid.
In gastric carcinoids, bcl-2 has been implicated as an
active oncogene in the early phases of the carcinogenic
Acta Oncologica 42 (2003) Carcinoid: a comprehensive review 675
sequence (87). In one study, bcl-2 expression was more
pronounced in metastatic lesions than in the primary tumor.
Other oncogenes
N-myc and c-jun have also been implicated as oncogenes;
they may be involved in the early onset of bowel carcinoid
in transgenic mice (75, 88). In the mastomy model,
amplification of c- and n-myc oncogenes has been suggested
(75, 89/91).
by desmoplastic reactions. Basic fibroblast growth factor, a
potent stimulant of endothelial cell growth is expressed in
both carcinoid tumor tissue and a carcinoid cell line (92),
(93). Vascular endothelial growth factor (VEGF) expression
has been demonstrated in both gastrointestinal and pul-
monary carcinoids (94, 95).
tumors (92, 93, 96/99). While TGF-a expression has been
found by both Nilsson et al. (97) and Krishnamurthy et al.
(98), EGFR expression is more complex. Nilsson et al.
found evidence of EGFR expression by immunocytochem-
istry and northern analysis (100). Krishnamurthy et al.,
however, found evidence of the extracellular domain of
EGFR but not expression of the intracellular domain of
EGFR (98). Finally, Facco et al. found EGFR expression in
the stromal cells of some metastatic ileal carcinoids (99).
PDGF and its receptors (PDGFR) are also expressed in
carcinoids. Expression of PDGF has been found in 70% of
carcinoid tumors (92). Additionally, PDGFR-a has been
found on both carcinoid tumor cells and stroma of
carcinoid tumors, which indicates a possible autocrine
loop supporting tumor growth. PDGFR-b has been found
in the stroma of carcinoid tumors. PDGFR-a expression is
more intense in metastatic tissue than in primary tumor.
PDGFR-b expression also appears to be more intense in the
stroma and small capillaries around tumor clusters, suggest-
ing that carcinoid cells may simultaneously produce PDGF
and up-regulate PDGFR-b in a paracrine fashion (101).
These studies have shown that carcinoid tumors secrete a
number of biologically active growth factors that interact
with the tumor and the surrounding stroma in a complex
autocrine/paracrine fashion. Further systematic investiga-
tions in this promising field may lead to discovery of novel
therapeutic targets.
Table 3
Silver
staining
676 I. I. Schnirer et al. Acta Oncologica 42 (2003)
PATHOLOGY
Classification
has not yet been adopted. In 1963, Williams & Sandler
classified carcinoid tumors on the basis of embryonic
divisions of the gut: foregut carcinoids, midgut carcinoids,
and hindgut carcinoids (102). The foregut includes the
thymus, respiratory tract, ovaries and stomach, pancreas,
and duodenum (103/110). The midgut includes the jeju-
num, ileum, appendix, cecum, Meckel’s diverticulum, and
ascending colon. The hindgut includes the colon and
rectum (Table 2).
In 1994, Kloppel et al. and Cappela et al. proposed a
method of classification based on location, size, invasive-
ness, angioinvasion, differentiation, metastatic pattern, and
clinical presentation (111, 112). Others have adopted a
classification system based on histologic characteristics
(23).
sheets of small round cells with uniform nuclei and
cytoplasm. Five growth patterns are noticed: insular,
trabecular, glandular, undifferentiated (usually designated
A through D or I through IV), and mixed (113). Tumors
with increased nuclear atypia, high mitotic activity, or…
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