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Gastrointestinal Carcinoid Tumors Treatment (PDQ®)

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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.[3-5]

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 staging or investigating symptoms from 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]

Histopathology

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 40–80 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.[13-15]

MEN1 is caused by alterations of the MEN1 gene located at chromosomal region 11q13. (Refer to the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasias 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 β-catenin (CTNNB1). In one study, β-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 undergraded 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, 19–90 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.[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 P–containing, 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, argentaffin-like 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%.[39-41] 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.[44-46] 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 NETs—including substance P, neurotensin, bradykinin, human chorionic gonadotropin, neuropeptide L, and pancreatic polypeptide—but 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 99mTc-methylene diphosphonate (99mTcMDP); 123 I-metaiodobenzylguanidine (MIBG) scintigraphy; computed tomography (CT); 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 magnetic resonance imaging (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 positron emission tomography (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.[57-59] 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 with 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

Endoscopic ultrasonography (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 (2 mm–3 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.

Follow-up and Survivorship

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.[3,68-71] 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.[73-77] 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.[74,76-78] 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 μmol/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 μmol/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:

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  • Updated: July 31, 2014