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NCI/PDQ^® Health professionals: Gastrointestinal Carcinoid Tumors Treatment (PDQ®)

National Cancer Institute
Ultima Vez Modificado: 1 de junio del 2012

TABLE OF CONTENTS

• General Information About Gastrointestinal Carcinoid Tumors
  • Epidemiology
  • Anatomy
  • Histology
    • Molecular genetics
    • Carcinoid syndrome
  • Site-Specific Clinical Features
    • Gastric carcinoids
    • Duodenal carcinoids
    • Jejunal and ileal carcinoids
    • Appendiceal carcinoids
    • Colorectal carcinoids
  • Diagnostics: Biochemical Markers, Imaging, and Approach
    • Biochemical markers
    • Imaging
      • Somatostatin receptor scintigraphy
      • Bone scintigraphy
      • CT/MRI
      • PET
      • EUS
      • CE
        • Enteroscopy
      • Angiography
    • General diagnostic approaches
  • Prognostic Factors
  • Related Summaries

• Cellular and Pathologic Classification of Gastrointestinal Carcinoid Tumors

• Stage Information for Gastrointestinal Carcinoid Tumors
  • Definitions of TNM
  • Neuroendocrine Tumors: Stomach
  • Neuroendocrine Tumors: Duodenum/Ampulla/Jejunum/Ileum
  • Neuroendocrine Tumors: Colon or Rectum
  • Appendiceal Carcinoids

• Treatment Option Overview
  • Surgery
  • Somatostatin Analogues
  • Interferons
  • Treatment of Hepatic Metastases
  • Radionuclides
  • Management of Carcinoid-Related Fibrosis
  • Symptomatic Therapy
  • Molecular-Targeted Therapies
  • General Therapeutic Approaches

• Gastric Carcinoids
  • Current Clinical Trials

• Duodenal Carcinoids
  • Current Clinical Trials

• Jejunal and Ileal Carcinoids
  • Current Clinical Trials

• Appendiceal Carcinoids
  • Current Clinical Trials

• Colonic Carcinoids
  • Current Clinical Trials

• Rectal Carcinoids
  • Current Clinical Trials

• Metastatic Gastrointestinal Carcinoid Tumors
  • Current Clinical Trials

• Recurrent Gastrointestinal Carcinoid Tumors
  • Current Clinical Trials

• Changes to This Summary (06/01/2012)

• About This PDQ® Summary
  • Purpose of This Summary
  • Reviewers and Updates
  • Levels of Evidence
  • Permission to Use This Summary
  • Disclaimer
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• Get More Information From NCI

General Information About Gastrointestinal Carcinoid Tumors

Epidemiology

The age-adjusted incidence of carcinoid tumors worldwide is approximately 2 per 100,000 persons. 1 2 The average age at diagnosis is 61.4 years. 3 Carcinoid tumors represent about 0.5% of all newly diagnosed malignancies. 2 3

Anatomy

Carcinoid tumors are rare, slow-growing tumors that originate in cells of the diffuse neuroendocrine system. They occur most frequently in tissues derived from the embryonic gut. Foregut tumors, which account for up to 25% of cases, arise in the lung, thymus, stomach, or proximal duodenum. Midgut tumors, which account for up to 50% of cases, arise in the small intestine, appendix, or proximal colon, with the appendix being the most common site of origin. Hindgut tumors, which account for approximately 15% of cases, arise in the distal colon or rectum. 4 Other sites of origin include the gallbladder, kidney, liver, pancreas, ovary, and testis. 3 4 5

Gastrointestinal (GI) carcinoid tumors, especially tumors of the small intestine, are often associated with other cancers. Synchronous or metachronous cancers occur in approximately 29% of patients with small intestinal carcinoids. 3 However, it is possible that the association may be due in part to the serendipitous discovery of slow-growing carcinoid tumors, which are found while investigating symptoms from, or staging, other tumors.

Histology

The term carcinoid should be used for well-differentiated neuroendocrine tumors (NETs) or carcinomas of the GI tract only; the term should not be used to describe pancreatic NETs or islet cell tumors. 6 (Refer to the PDQ® summary on Pancreatic Neuroendocrine Tumors (Islet Cell Tumors) for more information.) Data regarding carcinoids and other NETs, such as poorly differentiated neuroendocrine carcinomas, may be combined in some epidemiologic and clinical studies, rendering separate consideration difficult. Occurring nonrandomly throughout the GI tract are more than 14 cell types, which produce different hormones. 7 (Refer to the Cellular and Pathologic Classification of Gastrointestinal Carcinoid Tumors section of this summary for more information.) Although the cellular origin of NETs of the GI tract is uncertain, consistent expression of cytokeratins in NETs and the expression of the caudal-related homeodomain protein 2 (CdX2 protein), an intestinal transcription factor in endocrine tumors of the small intestine, suggests an origin from an epithelial precursor cell. 8

Most NETs of the small and large intestines occur sporadically, while others may occur within the background of an inherited neoplasia syndrome such as multiple endocrine neoplasia type 1 (MEN1) or neurofibromatosis type 1 (NF1) (e.g., gastrin-producing G-cell tumors and somatostatin-producing D-cell tumors of the duodenum, respectively). 9 Tumor multifocality is the rule within the background of neuroendocrine cell hyperplasia, but multifocality is found in approximately one-third of patients with small enterochromaffin cell tumors in the absence of proliferative or genetic factors; clonality studies suggest that most of these neoplasms are separate primary lesions. 10 11 Gastric carcinoids may be associated with chronic atrophic gastritis. 7

Individual carcinoid tumors have specific histologic and immunohistochemical features based on their anatomic location and endocrine cell type. However, all carcinoids share common pathologic features that characterize them as well-differentiated NETs. 5 In the gastric or intestinal wall, carcinoids may occur as firm white, yellow, or gray nodules and may be intramural masses or may protrude into the lumen as polypoid nodules; the overlying gastric or intestinal mucosa may be intact or have focal ulceration.

Neuroendocrine cells have uniform nuclei and abundant granular or faintly staining (clear) cytoplasm, and are present as solid or small trabecular clusters, or are dispersed among other cells, which may make them difficult to recognize in sections stained with hematoxylin and eosin; immunostaining enables their exact identification. 12 At the ultrastructural level, neuroendocrine cells contain cytoplasmic membrane-bound dense-cored secretory granules (diameter >80 nm) and may also contain small clear vesicles (diameter 4080 nm) that correspond to the synaptic vesicles of neurons.

Molecular genetics

Occasionally, GI carcinoids occur in association with inherited syndromes, such as MEN1 and NF1. 13 14 15

MEN1 is caused by alterations of the MEN1 gene located at chromosomal region 11q13. (Refer to the PDQ® summary on Genetics of Medullary Thyroid Cancer for more information.) Most carcinoids associated with MEN1 appear to be of foregut origin. 13 NF1 is an autosomal dominant genetic disorder caused by alteration of the NF1 gene at chromosome 17q11. 16 Carcinoids in patients with NF1 appear to arise primarily in the periampullary region. 5 17 18

In sporadic GI carcinoids, numerous chromosomal imbalances have been found by comparative genome hybridization analysis. Gains involving chromosomes 5, 14, 17 (especially 17q), and 19 and losses involving chromosomes 11 (especially 11q) and 18 appear to be the most common. 19 20

The most frequently reported mutated gene in GI carcinoids is -catenin (CTNNB1). In one study, -catenin exon 3 mutations were found in 27 (37.5%) of 72 cases. 21

However, no consistent genetic markers for GI carcinoid prognosis have yet been identified. 9 (Refer to the Cellular and Pathologic Classification of Gastrointestinal Carcinoid Tumors section of this summary for more information.)

Carcinoid syndrome

Carcinoid syndrome, which occurs in fewer than 20% of patients with carcinoid tumors, is caused by the release of metabolically undegraded vasoactive amines into the systemic circulation. It is associated with flushing, abdominal pain and diarrhea, bronchoconstriction, and carcinoid heart disease. 22 23 Because vasoactive amines are efficiently metabolized by the liver, carcinoid syndrome rarely occurs in the absence of hepatic metastases. Exceptions include circumstances in which venous blood draining from a tumor enters directly into the systemic circulation (e.g., primary pulmonary or ovarian carcinoids, pelvic or retroperitoneal involvement by metastatic or locally invasive small bowel carcinoids, or extensive bone metastases).

Carcinoid heart disease develops in more than one-third of patients with carcinoid syndrome. Pathologically, the cardiac valves become thickened because of fibrosis, and the tricuspid and pulmonic valves are affected to a greater extent than the mitral and aortic valves. Symptoms include: 22

• Tricuspid and pulmonic regurgitation.
• Pulmonary stenosis.
• Mitral and aortic insufficiency.
• Cardiac dysrhythmias.

Severe carcinoid heart disease is associated with reduced survival. (Refer to the Prognostic Factors section of this summary for more information.)

Site-Specific Clinical Features

The clinical features of GI carcinoids vary according to anatomical location and cell type. 5 12 24 Most carcinoids in the GI tract are located within 3 feet (~90 cm) of the ileocecal valve, with 50% found in the appendix. 25 They are often detected fortuitously during surgery for another GI disorder or during emergency surgery for appendicitis, GI bleeding, or perforation. 26

Gastric carcinoids

Most gastric carcinoids are enterochromaffin-like (ECL)-cell carcinoids; rarely, other types may occur in the stomach. (Refer to Table 1 in the Cellular and Pathologic Classification of Gastrointestinal Carcinoid Tumors section of this summary for more information.)

Type I ECL-cell gastric carcinoids, the most common type, typically do not have clinical symptoms. They are often discovered during endoscopy for reflux, anemia, or other reasons; and are typically multifocal. Occurring most commonly in women (female-to-male ratio, 2.5:1) at a mean age of 63 years, achlorhydria may be present, and hypergastrinemia or evidence of antral G-cell hyperplasia is usually found. 5 24 27 These tumors are gastrin-driven and arise in a background of chronic atrophic gastritis of the corpus, usually because of autoimmune pernicious anemia but sometimes caused by Helicobacter pylori infection. 9

Type II ECL-cell carcinoids, the least common type of gastric carcinoids, occur at a mean age of 50 years with no gender predilection. The hypergastrinemia associated with MEN1-Zollinger-Ellison syndrome (ZES) is thought to promote the ECL-cell hyperplasia that leads to type II tumors. 27 28

Type I and type II ECL-cell gastric carcinoids have been reported to metastasize in fewer than 10% of cases. 27 29 Type III gastric ECL-cell carcinoids, the second most common type of gastric carcinoid, occur mostly in men (male-to-female ratio, 2.8:1) at a mean age of 55 years. 27 There are no neuroendocrine manifestations, and patients typically present with signs and symptoms related to an aggressive tumor. 5 30

Duodenal carcinoids

Comprising only 2% to 3% of GI NETs and discovered incidentally or because of symptoms from hormonal or peptide production, duodenal carcinoids may also arise in the periampullary region, obstruct the ampulla of Vater, and produce jaundice. 3 5 31 The age at presentation varies widely (range, 1990 years; mean age, 53 years). 15 32

The most common duodenal carcinoids are gastrin-producing G-cell tumors (~two thirds) followed by somatostatin-producing D-cell tumors (~one fifth), which rarely produce systemic manifestations of somatostatin excess. 5 31 33

Gastrin production from G-cell carcinoids (also called gastrinomas if serum gastrin levels are elevated) results in ZES in approximately one-third of the cases of duodenal G-cell tumors. 24 Although duodenal G-cell carcinoids may occur sporadically, 90% of patients with MEN1 develop them. 5 The clinical manifestations of serum gastrin elevation include:

• Nausea.
• Vomiting.
• Abdominal pain.
• Hemorrhage from multiple and recurrent peptic ulcers.
• Gastroesophageal reflux caused by excess acid production.
• Diarrhea from hypergastrinemia.

The most common symptom is abdominal pain; the combination of abdominal pain and diarrhea is present in approximately 50% of patients. In contrast to sporadic gastrinomas, which are usually solitary lesions, gastrinomas in patients with MEN1-ZES are usually multiple and smaller than 5 mm in size. 5

Somatostatin-producing D-cell tumors occur exclusively in and around the ampulla of Vater, and as many as 50% of patients with D-cell carcinoids have NF1. 34 Most of the patients with NF1 are black women, and their tumors are exclusively located in the periampullary region. 15 32 As a result of their location, these tumors may cause local obstructive symptoms and signs such as jaundice, pancreatitis, or hemorrhage. Although D-cell carcinoids produce somatostatin, systemic manifestations of excess somatostatin such as steatorrhea, diarrhea, diabetes mellitus, hypochlorhydria and achlorhydria, anemia, and cholelithiasis are rare. 31

Jejunal and ileal carcinoids

Most jejunal and ileal carcinoids are argentaffin-positive, substance Pcontaining, and serotonin-producing EC-cell tumors that generate carcinoid syndrome when hepatic or retroperitoneal nodal metastases are present. L-cell, glucagon-like polypeptide-producing, and pancreatic polypeptide- and polypeptide YY-producing tumors occur less frequently. 24 Ileal carcinoids develop preferentially in the terminal ileum. 12 Jejunal and ileal carcinoids occur equally in men and women at a mean age of 65.4 years. 3 Similar to all carcinoids, jejunal and ileal carcinoids vary in their biologic behavior and ability to metastasize. Typically, EC-cell carcinoids of the small intestine metastasize to lymph nodes and the liver. 5 Patients with these lesions may be asymptomatic. The primary tumor may cause small intestinal obstruction, ischemia, or bleeding, and some patients may complain of a long history of intermittent crampy abdominal pain, weight loss, fatigue, abdominal distention, diarrhea, or nausea and vomiting. 5 23 35

At the time of diagnosis, ileal NETs (i.e., carcinoids plus poorly differentiated neuroendocrine carcinomas) are commonly larger than 2 cm and have metastasized to regional lymph nodes; in as many as 40% of cases, the tumors are multifocal. 12 Immunocytochemically, the cells contain serotonin, substance P, kallikrein, and catecholamine. Approximately 20% of patients with ileal NETs have regional lymph node and liver metastases. Most GI carcinoids secrete their bioactive peptides and amines into the portal circulation, and the effects of these biochemical mediators are diminished or negated by hepatic detoxification; accordingly, carcinoid syndrome (e.g., flush, diarrhea, and endocardial fibrosis) occurs only in patients with liver metastases because hepatic detoxification of serotonin is bypassed.

Appendiceal carcinoids

Most appendiceal carcinoids are serotonin-producing EC-cell tumors similar to carcinoids that occur in the jejunum and ileum; less commonly, appendiceal carcinoids are L-cell tumors similar to those in the colon. 16 The biologic behavior of both cell types is strikingly different in the appendix compared with tumors of the ileum and nonappendiceal colon. Most appendiceal carcinoids have a benign clinical course and do not metastasize, perhaps because growth in the appendix produces obstruction, appendicitis, and subsequent surgical removal. 5 36 Although appendiceal carcinoids occur in patients of all ages, patients with these tumors tend to be much younger than patients diagnosed with other appendiceal neoplasms or carcinoids at other sites. Appendiceal carcinoids are reportedly more common in female patients. 3 5 However, age and gender patterns may be spurious, reflecting the younger age range of patients who typically undergo appendectomy for inflammatory appendicitis, and the larger number of incidental appendectomies performed in women during pelvic operations.

Colorectal carcinoids

Most colorectal carcinoids occur in the rectum; fewer arise in the cecum. 5 In the cecum, argentaffinic EC-cell carcinoids are most common, become increasingly less common in the more distal colon, and are uncommon in the rectum. 31 Rectal carcinoids account for approximately one-fourth of GI carcinoids and fewer than 1% of all rectal cancers. 3 31 Most rectal carcinoids have L-cell differentiation. The mean age of patients at diagnosis for colonic carcinoids is 66 years and for rectal carcinoids, 56.2 years. Although there is no specific gender predilection for colorectal carcinoids, rectal carcinoids are more common in the black population. 3 37 Abdominal pain and weight loss are typical symptoms of colonic carcinoids, but more than 50% of patients with rectal carcinoids are asymptomatic, and the tumors are discovered at routine rectal examination or screening endoscopy. 24 Symptoms of rectal carcinoids include bleeding, pain, and constipation. Metastatic disease from colonic carcinoids may produce carcinoid syndrome, whereas metastatic disease from rectal carcinoids is not associated with carcinoid syndrome. 5 38

Diagnostics: Biochemical Markers, Imaging, and Approach

Biochemical markers

Biochemical investigations in the diagnosis of GI carcinoids include the use of 24-hour urinary 5-hydroxyindoleacetic acid (5-HIAA) collection, which has a specificity of approximately 88%, although the sensitivity is reported to be as low as 35%. 39 40 41 A time-consuming test, 5-HIAA requires dietary avoidance of serotonin-rich foods, such as bananas, tomatoes, and eggplant. 42 Measurement of plasma chromogranin A (CgA), first described in a study of adrenal gland secretions in 1967 as one of the soluble protein fractions (also including CgB and CgC) of chromaffin granules, is also useful. 43 Although plasma levels of CgA are very sensitive markers of carcinoids, they are nonspecific because they are also elevated in other types of NETs, such as pancreatic and small cell lung carcinomas. 44 45 46 Plasma CgA appears to be a better biochemical marker of carcinoids than does urinary 5-HIAA. 47 Numerous investigations have revealed an association between plasma CgA levels and disease severity. 26 However, false-positive plasma levels of CgA may occur in patients on proton pump inhibitors, reported to occur even with short-term, low-dose treatment. 48 49 Many other biochemical markers are associated with NETsincluding substance P, neurotensin, bradykinin, human chorionic gonadotropin, neuropeptide L, and pancreatic polypeptidebut none match the specificity or predictive value of 5-HIAA or CgA. 44

Imaging

Imaging modalities for GI carcinoids include the use of somatostatin scintigraphy with 111Indium-octreotide; bone scintigraphy with 99mTcMDP; 123I-MIBG scintigraphy; computed tomography (CT); magnetic resonance imaging (MRI); positron emission tomography (PET); endoscope ultrasound (EUS); capsule endoscopy (CE); enteroscopy; and angiography. 26

Somatostatin receptor scintigraphy

There are five different somatostatin receptor (SSTR) subtypes; more than 70% of NETs of both the GI tract and pancreas express multiple subtypes, with a predominance of receptor subtype 2 [sst(2)] and receptor subtype 5 [sst(5)]. 50 51 The synthetic radiolabeled SSTR analog 111In-DTP-d-Phe10-{octreotide} affords an important method, somatostatin receptor scintigraphy (SRS), to localize carcinoid tumors, especially sst(2)-positive and sst(5)-positive tumors; imaging is accomplished in one session, and small primary tumors and metastases are diagnosed more readily than with conventional imaging or imaging techniques requiring multiple sessions. 26 52 53 Overall sensitivity of the octreotide scan is reported to be as high as 90%; however, failed detection may result from various technical issues, small tumor size, or inadequate expression of SSTRs. 26 54

Bone scintigraphy

Bone scintigraphy with 99mTcMDP is the primary imaging modality for identifying bone involvement in NETs and detection rates are reported to be 90% or higher. 26 123I-MIBG is concentrated by carcinoid tumors in as many as 70% of cases using the same mechanism as norepinephrine and is used successfully to visualize carcinoids; however, 123I-MIBG appears to be about half as sensitive as 111In-octreotide scintigraphy in detecting tumors. 26 55

CT/MRI

CT and MRI are important modalities used in the initial localization of carcinoid primaries and/or metastases. The median detection rate and sensitivity of CT and/or MRI have been estimated at 80%; detection rates by CT alone vary between 76% and 100%, while MRI detection rates vary between 67% and 100%. 26 CT and MRI may be used for initial localization of the tumor only because both imaging techniques may miss lesions otherwise detected by 111In-octreotide scintigraphy; one study has shown that lesions in 50% of patients were missed, especially in lymph nodes and extrahepatic locations. 26 56

PET

A promising approach for PET as an imaging modality to visualize GI carcinoids appears to be the use of the radioactive-labeled serotonin precursor 11C-5-hydroxytryptophan (11C-5-HTP). With 11C-5-HTP, tumor detection rates have been reported to be as high as 100%, and some investigators have concluded that 11C-5-HTP PET should be used as a universal detection method for detecting NETs. 57 58 59 In one study of NETS, including 18 patients with GI carcinoids, 11C-5-HTP PET detected tumor lesions in 95% of patients. In 58% of cases, 11C-5-HTP PET detected more lesions than SRS and CT, compared to the 7% that 11C-5-HTP PET did not detect. 59 Other imaging approaches have been investigated using technetium-labeled isotopes, combining CT/MRI with 18F-DOPA PET, combining 131 MIBG with 111In-octreotide, and coupling the isotopes 68Ga and 64Cu to octreotide. 26

EUS

EUS may be a sensitive method for the detection of gastric and duodenal carcinoids and may be superior to conventional ultrasound, particularly in the detection of small tumors (2mm3 mm) that are localized in the bowel lumen. 60 61 In one study, the EUS was reported to have an accuracy of 90% for the localization and staging of colorectal carcinoids. 62

CE

The development of CE in the diagnosis of GI carcinoids is nascent, although this technique may prove useful in the detection of small bowel carcinoids. 63

Enteroscopy

Double-balloon enteroscopy is a time-consuming procedure that is being studied in the diagnosis of small bowel tumors, including carcinoids. 64 65 It is usually performed under general anesthesia, although it can be done under conscious sedation.

Angiography

MRI angiography has replaced angiography to a large extent. However, selective and supraselective angiography may be useful to:

• Demonstrate the degree of tumor vascularity.
• Identify the sources of vascular supply.
• Delineate the relationship of the tumor to adjacent major vascular structures.
• Provide information regarding vascular invasion.

Angiography may be useful as an adjunct to surgery, particularly in the case of large invasive lesions in proximity to the portal vein and superior mesenteric artery. Overall, this imaging technique provides a more precise topographic delineation of the tumor or tumor-related vessels and facilitates resection. 26

General diagnostic approaches

As might be expected, diagnostic approaches to GI carcinoids vary according to anatomical location. In 2004, a consensus statement regarding the diagnosis and treatment of GI NETs was published on behalf of the European Neuroendocrine Tumor Society, 66 which details site-specific approaches to the diagnosis of GI carcinoids.

Prognostic Factors

Factors that determine the clinical course and outcome of patients with GI carcinoid tumors are complex and multifaceted and include the following: 67

• The site of origin.
• The size of the primary tumor.
• The anatomical extent of disease.

Elevated expression of the proliferation antigen Ki-67 and the tumor suppressor protein p53 have been associated with poorer prognosis; however, some investigators suggest that the Ki-67 index may be helpful in establishing prognosis of gastric lesions only and maintain that no consistent genetic markers of prognosis have yet been discovered. 9 Adverse clinical prognostic indicators include:

• Carcinoid syndrome.
• Carcinoid heart disease.
• High concentrations of the tumor markers urinary 5-HIAA and plasma chromogranin A.

In general, patients with carcinoid tumors of the appendix and rectum experience longer survival than patients with tumors arising from the stomach, small intestine, and colon. Carcinoid tumors occurring in the small intestine, even those of small size, have a greater propensity to metastasize than those in the appendix, colon, and rectum. 67 Appendiceal and rectal carcinoids are usually small at the time of initial detection, and have rarely metastasized. The presence of metastases has been associated with a reduction in 5-year survival ranging from 39% to 60% in several case series and reviews. 3 68 69 70 71 However, some patients with metastatic carcinoid tumors have an indolent clinical course with survival of several years, whereas others experience an aggressively malignant course with short survival. Although metastases are associated with a shorter survival in large patient samples, the presence of metastases alone does not sufficiently predict the clinical course of the individual patient.

Approximately 35% of carcinoids of the small intestine are associated with carcinoid syndrome. The relatively common carcinoids of the appendix and rectum rarely produce this syndrome, and carcinoids from other sites have intermediate risks. 71 72 Investigations using echocardiographic criteria for carcinoid heart disease found prevalences ranging from 35% to 77% among patients with carcinoid syndrome. 73 74 75 76 77 The tricuspid valve is affected more frequently and severely than the pulmonic valve, and the presence and severity of carcinoid heart disease, particularly tricuspid valve dysfunction, is associated with shortened survival. 74 76 77 78 One study involving 64 patients with midgut carcinoid syndrome found 5-year survival rates of 30% for those with severe carcinoid heart disease versus 75% for those with no cardiac disease. 76

In another study, statistically significantly reduced survival was observed for patients with midgut carcinoids who had urinary 5-HIAA concentrations greater than 300 ¼mol/24 hours compared with patients who had lower concentrations of urinary 5-HIAA. 79 Correspondingly, a study of patients with midgut carcinoid syndrome showed that urinary 5-HIAA levels greater than 500 ¼mol/24 hours were associated with shorter survival. 76 The degree of elevation of urinary 5-HIAA is also associated with the severity of carcinoid symptoms, with the highest levels being observed in patients with carcinoid heart failure. 76 80 In one study, vascular endothelial growth factor (VEGF) expression by low-grade tumors and surrounding stromal cells was associated with progression-free survival (PFS); median durations of PFS in patients with strong and weak VEGF expression were 29 months and 81 months, respectively. 81

Related Summaries

Other PDQ® summaries containing information related to GI carcinoid tumors include the following:

• Non-Small Cell Lung Cancer.
• Rectal Cancer.
• Small Intestine Cancer.
• Unusual Cancers of Childhood (carcinoid tumors in children).

References:

1. Crocetti E, Paci E: Malignant carcinoids in the USA, SEER 1992-1999. An epidemiological study with 6830 cases. Eur J Cancer Prev 12 (3): 191-4, 2003. [PUBMED Abstract]
2. Taal BG, Visser O: Epidemiology of neuroendocrine tumours. Neuroendocrinology 80 (Suppl 1): 3-7, 2004. [PUBMED Abstract]
3. Modlin IM, Lye KD, Kidd M: A 5-decade analysis of 13,715 carcinoid tumors. Cancer 97 (4): 934-59, 2003. [PUBMED Abstract]
4. Scarsbrook AF, Ganeshan A, Statham J, et al.: Anatomic and functional imaging of metastatic carcinoid tumors. Radiographics 27 (2): 455-77, 2007 Mar-Apr. [PUBMED Abstract]
5. Levy AD, Sobin LH: From the archives of the AFIP: Gastrointestinal carcinoids: imaging features with clinicopathologic comparison. Radiographics 27 (1): 237-57, 2007 Jan-Feb. [PUBMED Abstract]
6. Arnold R: Endocrine tumours of the gastrointestinal tract. Introduction: definition, historical aspects, classification, staging, prognosis and therapeutic options. Best Pract Res Clin Gastroenterol 19 (4): 491-505, 2005. [PUBMED Abstract]
7. Klíppel G, Anlauf M: Epidemiology, tumour biology and histopathological classification of neuroendocrine tumours of the gastrointestinal tract. Best Pract Res Clin Gastroenterol 19 (4): 507-17, 2005. [PUBMED Abstract]
8. Barbareschi M, Roldo C, Zamboni G, et al.: CDX-2 homeobox gene product expression in neuroendocrine tumors: its role as a marker of intestinal neuroendocrine tumors. Am J Surg Pathol 28 (9): 1169-76, 2004. [PUBMED Abstract]
9. Williams GT: Endocrine tumours of the gastrointestinal tract-selected topics. Histopathology 50 (1): 30-41, 2007. [PUBMED Abstract]
10. Yantiss RK, Odze RD, Farraye FA, et al.: Solitary versus multiple carcinoid tumors of the ileum: a clinical and pathologic review of 68 cases. Am J Surg Pathol 27 (6): 811-7, 2003. [PUBMED Abstract]
11. Katona TM, Jones TD, Wang M, et al.: Molecular evidence for independent origin of multifocal neuroendocrine tumors of the enteropancreatic axis. Cancer Res 66 (9): 4936-42, 2006. [PUBMED Abstract]
12. Klíppel G: Tumour biology and histopathology of neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab 21 (1): 15-31, 2007. [PUBMED Abstract]
13. Duh QY, Hybarger CP, Geist R, et al.: Carcinoids associated with multiple endocrine neoplasia syndromes. Am J Surg 154 (1): 142-8, 1987. [PUBMED Abstract]
14. Levy AD, Patel N, Dow N, et al.: From the archives of the AFIP: abdominal neoplasms in patients with neurofibromatosis type 1: radiologic-pathologic correlation. Radiographics 25 (2): 455-80, 2005 Mar-Apr. [PUBMED Abstract]
15. Levy AD, Taylor LD, Abbott RM, et al.: Duodenal carcinoids: imaging features with clinical-pathologic comparison. Radiology 237 (3): 967-72, 2005. [PUBMED Abstract]
16. Zikusoka MN, Kidd M, Eick G, et al.: The molecular genetics of gastroenteropancreatic neuroendocrine tumors. Cancer 104 (11): 2292-309, 2005. [PUBMED Abstract]
17. Karatzas G, Kouraklis G, Karayiannakis A, et al.: Ampullary carcinoid and jejunal stromal tumour associated with von Recklinghausen's disease presenting as gastrointestinal bleeding and jaundice. Eur J Surg Oncol 26 (4): 428-9, 2000. [PUBMED Abstract]
18. Mayoral W, Salcedo J, Al-Kawas F: Ampullary carcinoid tumor presenting as acute pancreatitis in a patient with von Recklinghausen's disease: case report and review of the literature. Endoscopy 35 (10): 854-7, 2003. [PUBMED Abstract]
19. Tínnies H, Toliat MR, Ramel C, et al.: Analysis of sporadic neuroendocrine tumours of the enteropancreatic system by comparative genomic hybridisation. Gut 48 (4): 536-41, 2001. [PUBMED Abstract]
20. Terris B, Meddeb M, Marchio A, et al.: Comparative genomic hybridization analysis of sporadic neuroendocrine tumors of the digestive system. Genes Chromosomes Cancer 22 (1): 50-6, 1998. [PUBMED Abstract]
21. Fujimori M, Ikeda S, Shimizu Y, et al.: Accumulation of beta-catenin protein and mutations in exon 3 of beta-catenin gene in gastrointestinal carcinoid tumor. Cancer Res 61 (18): 6656-9, 2001. [PUBMED Abstract]
22. Dierdorf SF: Carcinoid tumor and carcinoid syndrome. Curr Opin Anaesthesiol 16 (3): 343-7, 2003. [PUBMED Abstract]
23. Sweeney JF, Rosemurgy AS: Carcinoid Tumors of the Gut. Cancer Control 4 (1): 18-24, 1997. [PUBMED Abstract]
24. Capella C, Solcia E, Sobin L, et al.: Endocrine tumours of the small intestine. In: Hamilton SR, Aaltonen LA: Pathology and Genetics of Tumours of the Digestive System. Lyon, France: International Agency for Research on Cancer, 2000, pp 67-90. [PUBMED Abstract]
25. Northrop JA, Lee JH: Large bowel carcinoid tumors. Curr Opin Gastroenterol 23 (1): 74-8, 2007. [PUBMED Abstract]
26. Modlin IM, Latich I, Zikusoka M, et al.: Gastrointestinal carcinoids: the evolution of diagnostic strategies. J Clin Gastroenterol 40 (7): 572-82, 2006. [PUBMED Abstract]
27. Rindi G, Bordi C, Rappel S, et al.: Gastric carcinoids and neuroendocrine carcinomas: pathogenesis, pathology, and behavior. World J Surg 20 (2): 168-72, 1996. [PUBMED Abstract]
28. Solcia E, Capella C, Fiocca R, et al.: Gastric argyrophil carcinoidosis in patients with Zollinger-Ellison syndrome due to type 1 multiple endocrine neoplasia. A newly recognized association. Am J Surg Pathol 14 (6): 503-13, 1990. [PUBMED Abstract]
29. Rindi G, Luinetti O, Cornaggia M, et al.: Three subtypes of gastric argyrophil carcinoid and the gastric neuroendocrine carcinoma: a clinicopathologic study. Gastroenterology 104 (4): 994-1006, 1993. [PUBMED Abstract]
30. Debelenko LV, Emmert-Buck MR, Zhuang Z, et al.: The multiple endocrine neoplasia type I gene locus is involved in the pathogenesis of type II gastric carcinoids. Gastroenterology 113 (3): 773-81, 1997. [PUBMED Abstract]
31. Riddell R, Petras R, Williams G, et al.: Tumors of the Intestines. Washington, DC: Armed Forces Institute of Pathology, 2003. [PUBMED Abstract]
32. Burke AP, Sobin LH, Shekitka KM, et al.: Somatostatin-producing duodenal carcinoids in patients with von Recklinghausen's neurofibromatosis. A predilection for black patients. Cancer 65 (7): 1591-5, 1990. [PUBMED Abstract]
33. Klíppel G, Perren A, Heitz PU: The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification. Ann N Y Acad Sci 1014: 13-27, 2004. [PUBMED Abstract]
34. Dayal Y, Tallberg KA, Nunnemacher G, et al.: Duodenal carcinoids in patients with and without neurofibromatosis. A comparative study. Am J Surg Pathol 10 (5): 348-57, 1986. [PUBMED Abstract]
35. Akerstrím G, Hellman P, Hessman O, et al.: Management of midgut carcinoids. J Surg Oncol 89 (3): 161-9, 2005. [PUBMED Abstract]
36. Gore RM, Berlin JW, Mehta UK, et al.: GI carcinoid tumours: appearance of the primary and detecting metastases. Best Pract Res Clin Endocrinol Metab 19 (2): 245-63, 2005. [PUBMED Abstract]
37. Modlin IM, Sandor A: An analysis of 8305 cases of carcinoid tumors. Cancer 79 (4): 813-29, 1997. [PUBMED Abstract]
38. Jetmore AB, Ray JE, Gathright JB Jr, et al.: Rectal carcinoids: the most frequent carcinoid tumor. Dis Colon Rectum 35 (8): 717-25, 1992. [PUBMED Abstract]
39. Tormey WP, FitzGerald RJ: The clinical and laboratory correlates of an increased urinary 5-hydroxyindoleacetic acid. Postgrad Med J 71 (839): 542-5, 1995. [PUBMED Abstract]
40. Bajetta E, Ferrari L, Martinetti A, et al.: Chromogranin A, neuron specific enolase, carcinoembryonic antigen, and hydroxyindole acetic acid evaluation in patients with neuroendocrine tumors. Cancer 86 (5): 858-65, 1999. [PUBMED Abstract]
41. Seregni E, Ferrari L, Bajetta E, et al.: Clinical significance of blood chromogranin A measurement in neuroendocrine tumours. Ann Oncol 12 (Suppl 2): S69-72, 2001. [PUBMED Abstract]
42. Feldman JM, Lee EM: Serotonin content of foods: effect on urinary excretion of 5-hydroxyindoleacetic acid. Am J Clin Nutr 42 (4): 639-43, 1985. [PUBMED Abstract]
43. Blaschko H, Comline RS, Schneider FH, et al.: Secretion of a chromaffin granule protein, chromogranin, from the adrenal gland after splanchnic stimulation. Nature 215 (5096): 58-9, 1967. [PUBMED Abstract]
44. Eriksson B, Oberg K: Peptide hormones as tumor markers in neuroendocrine gastrointestinal tumors. Acta Oncol 30 (4): 477-83, 1991. [PUBMED Abstract]
45. Stridsberg M, Oberg K, Li Q, et al.: Measurements of chromogranin A, chromogranin B (secretogranin I), chromogranin C (secretogranin II) and pancreastatin in plasma and urine from patients with carcinoid tumours and endocrine pancreatic tumours. J Endocrinol 144 (1): 49-59, 1995. [PUBMED Abstract]
46. Drivsholm L, Paloheimo LI, Osterlind K: Chromogranin A, a significant prognostic factor in small cell lung cancer. Br J Cancer 81 (4): 667-71, 1999. [PUBMED Abstract]
47. Eriksson B, Arnberg H, Lindgren PG, et al.: Neuroendocrine pancreatic tumours: clinical presentation, biochemical and histopathological findings in 84 patients. J Intern Med 228 (2): 103-13, 1990. [PUBMED Abstract]
48. Sanduleanu S, De Bruíne A, Stridsberg M, et al.: Serum chromogranin A as a screening test for gastric enterochromaffin-like cell hyperplasia during acid-suppressive therapy. Eur J Clin Invest 31 (9): 802-11, 2001. [PUBMED Abstract]
49. Giusti M, Sidoti M, Augeri C, et al.: Effect of short-term treatment with low dosages of the proton-pump inhibitor omeprazole on serum chromogranin A levels in man. Eur J Endocrinol 150 (3): 299-303, 2004. [PUBMED Abstract]
50. Reubi JC, Kvols L, Krenning E, et al.: Distribution of somatostatin receptors in normal and tumor tissue. Metabolism 39 (9 Suppl 2): 78-81, 1990. [PUBMED Abstract]
51. de Herder WW, Hofland LJ, van der Lely AJ, et al.: Somatostatin receptors in gastroentero-pancreatic neuroendocrine tumours. Endocr Relat Cancer 10 (4): 451-8, 2003. [PUBMED Abstract]
52. Modlin IM, Tang LH: Approaches to the diagnosis of gut neuroendocrine tumors: the last word (today). Gastroenterology 112 (2): 583-90, 1997. [PUBMED Abstract]
53. Mufarrij P, Varkarakis IM, Studeman KD, et al.: Primary renal carcinoid tumor with liver metastases detected with somatostatin receptor imaging. Urology 65 (5): 1002, 2005. [PUBMED Abstract]
54. Krenning EP, Kooij PP, Bakker WH, et al.: Radiotherapy with a radiolabeled somatostatin analogue, [111In-DTPA-D-Phe1]-octreotide. A case history. Ann N Y Acad Sci 733: 496-506, 1994. [PUBMED Abstract]
55. Hoefnagel CA, den Hartog Jager FC, Taal BG, et al.: The role of I-131-MIBG in the diagnosis and therapy of carcinoids. Eur J Nucl Med 13 (4): 187-91, 1987. [PUBMED Abstract]
56. Shi W, Johnston CF, Buchanan KD, et al.: Localization of neuroendocrine tumours with [111In] DTPA-octreotide scintigraphy (Octreoscan): a comparative study with CT and MR imaging. QJM 91 (4): 295-301, 1998. [PUBMED Abstract]
57. Orlefors H, Sundin A, Ahlstrím H, et al.: Positron emission tomography with 5-hydroxytryprophan in neuroendocrine tumors. J Clin Oncol 16 (7): 2534-41, 1998. [PUBMED Abstract]
58. Sundin A, Eriksson B, Bergstrím M, et al.: PET in the diagnosis of neuroendocrine tumors. Ann N Y Acad Sci 1014: 246-57, 2004. [PUBMED Abstract]
59. Orlefors H, Sundin A, Garske U, et al.: Whole-body (11)C-5-hydroxytryptophan positron emission tomography as a universal imaging technique for neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and computed tomography. J Clin Endocrinol Metab 90 (6): 3392-400, 2005. [PUBMED Abstract]
60. Rísch T, Lightdale CJ, Botet JF, et al.: Localization of pancreatic endocrine tumors by endoscopic ultrasonography. N Engl J Med 326 (26): 1721-6, 1992. [PUBMED Abstract]
61. Zimmer T, Ziegler K, Liehr RM, et al.: Endosonography of neuroendocrine tumors of the stomach, duodenum, and pancreas. Ann N Y Acad Sci 733: 425-36, 1994. [PUBMED Abstract]
62. Yoshida M, Tsukamoto Y, Niwa Y, et al.: Endoscopic assessment of invasion of colorectal tumors with a new high-frequency ultrasound probe. Gastrointest Endosc 41 (6): 587-92, 1995. [PUBMED Abstract]
63. Coates SW Jr, DeMarco DC: Metastatic carcinoid tumor discovered by capsule endoscopy and not detected by esophagogastroduodenoscopy. Dig Dis Sci 49 (4): 639-41, 2004. [PUBMED Abstract]
64. Bellutti M, Fry LC, Schmitt J, et al.: Detection of neuroendocrine tumors of the small bowel by double balloon enteroscopy. Dig Dis Sci 54 (5): 1050-8, 2009. [PUBMED Abstract]
65. Almeida N, Figueiredo P, Lopes S, et al.: Double-balloon enteroscopy and small bowel tumors: a South-European single-center experience. Dig Dis Sci 54 (7): 1520-4, 2009. [PUBMED Abstract]
66. Plíckinger U, Rindi G, Arnold R, et al.: Guidelines for the diagnosis and treatment of neuroendocrine gastrointestinal tumours. A consensus statement on behalf of the European Neuroendocrine Tumour Society (ENETS). Neuroendocrinology 80 (6): 394-424, 2004. [PUBMED Abstract]
67. Rorstad O: Prognostic indicators for carcinoid neuroendocrine tumors of the gastrointestinal tract. J Surg Oncol 89 (3): 151-60, 2005. [PUBMED Abstract]
68. Soga J: Carcinoids of the rectum: an evaluation of 1271 reported cases. Surg Today 27 (2): 112-9, 1997. [PUBMED Abstract]
69. Koura AN, Giacco GG, Curley SA, et al.: Carcinoid tumors of the rectum: effect of size, histopathology, and surgical treatment on metastasis free survival. Cancer 79 (7): 1294-8, 1997. [PUBMED Abstract]
70. Shebani KO, Souba WW, Finkelstein DM, et al.: Prognosis and survival in patients with gastrointestinal tract carcinoid tumors. Ann Surg 229 (6): 815-21; discussion 822-3, 1999. [PUBMED Abstract]
71. Soga J: Carcinoids and their variant endocrinomas. An analysis of 11842 reported cases. J Exp Clin Cancer Res 22 (4): 517-30, 2003. [PUBMED Abstract]
72. Soga J, Yakuwa Y, Osaka M: Carcinoid syndrome: a statistical evaluation of 748 reported cases. J Exp Clin Cancer Res 18 (2): 133-41, 1999. [PUBMED Abstract]
73. Lundin L, Norheim I, Landelius J, et al.: Carcinoid heart disease: relationship of circulating vasoactive substances to ultrasound-detectable cardiac abnormalities. Circulation 77 (2): 264-9, 1988. [PUBMED Abstract]
74. Pellikka PA, Tajik AJ, Khandheria BK, et al.: Carcinoid heart disease. Clinical and echocardiographic spectrum in 74 patients. Circulation 87 (4): 1188-96, 1993. [PUBMED Abstract]
75. Denney WD, Kemp WE Jr, Anthony LB, et al.: Echocardiographic and biochemical evaluation of the development and progression of carcinoid heart disease. J Am Coll Cardiol 32 (4): 1017-22, 1998. [PUBMED Abstract]
76. Westberg G, Wíngberg B, Ahlman H, et al.: Prediction of prognosis by echocardiography in patients with midgut carcinoid syndrome. Br J Surg 88 (6): 865-72, 2001. [PUBMED Abstract]
77. Míller JE, Connolly HM, Rubin J, et al.: Factors associated with progression of carcinoid heart disease. N Engl J Med 348 (11): 1005-15, 2003. [PUBMED Abstract]
78. Zuetenhorst JM, Bonfrer JM, Korse CM, et al.: Carcinoid heart disease: the role of urinary 5-hydroxyindoleacetic acid excretion and plasma levels of atrial natriuretic peptide, transforming growth factor-beta and fibroblast growth factor. Cancer 97 (7): 1609-15, 2003. [PUBMED Abstract]
79. Janson ET, Holmberg L, Stridsberg M, et al.: Carcinoid tumors: analysis of prognostic factors and survival in 301 patients from a referral center. Ann Oncol 8 (7): 685-90, 1997. [
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