Version July 2025
INTRODUCTION —
The term "carcinoid" has been generally applied to well-differentiated neuroendocrine tumors (NETs) originating in the digestive tract, lungs, or rare primary sites, such as the kidneys or ovaries. In modern use, the term carcinoid is still used to refer to well-differentiated NETs arising in the lung (typical or atypical carcinoids), but within the gastrointestinal tract, the term carcinoid has fallen out of favor, and the World Health Organization (WHO) preference is for the term "NET." Regardless of site, the term "neuroendocrine carcinoma" is assigned to high-grade or poorly differentiated NETs. (See "Pathology and classification of gastroenteropancreatic neuroendocrine neoplasms", section on 'Pathology and tumor classification'.)
NETs can present in several different ways:
●As a result of carcinoid syndrome – Chronic flushing and/or diarrhea are the typical manifestations of carcinoid syndrome, which is the result of secretion of serotonin and other vasoactive substances into the systemic circulation. Carcinoid syndrome is primarily associated with metastatic tumors originating in the midgut (distal small intestine and proximal colon). By contrast, hindgut (distal colorectal) and foregut (gastroduodenal, lung) NETs uncommonly produce carcinoid syndrome. (See "Clinical features of carcinoid syndrome" and "Lung neuroendocrine (carcinoid) tumors: Epidemiology, risk factors, classification, histology, diagnosis, and staging", section on 'Presenting signs and symptoms'.)
●As a result of tumor growth – Small bowel NETs may cause chronic/recurrent abdominal pain, occasionally leading to bowel obstruction. Metastatic tumors in the liver can cause right upper quadrant pain, hepatomegaly, and early satiety. (See "Clinical characteristics of well-differentiated neuroendocrine tumors arising in the gastrointestinal and genitourinary tracts", section on 'Jejunoileal small bowel tumors' and "Clinical presentation, imaging and biomarker monitoring, and prognosis of metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors", section on 'Clinical presentation'.)
●As an incidental finding – Many NETs are discovered during endoscopic or radiographic procedures planned for other purposes; this is especially true of NETs of the stomach and rectum.
This review will focus on the diagnosis of carcinoid syndrome and the localization/staging of well-differentiated NETs. Other topics related to the pathology, clinical diagnosis, and treatment of neuroendocrine neoplasms are discussed separately.
●(See "Pathology and classification of gastroenteropancreatic neuroendocrine neoplasms".)
●(See "Clinical features of carcinoid syndrome".)
●(See "Treatment of the carcinoid syndrome".)
●(See "Poorly differentiated gastroenteropancreatic neuroendocrine carcinoma".)
BIOCHEMICAL TESTING FOR CARCINOID SYNDROME —
Carcinoid syndrome is the result of secretion of serotonin and other vasoactive substances into the systemic circulation in the setting of a neuroendocrine tumor (NET), most often a small bowel primary tumor with liver metastases. Hormone measurements in the blood and/or urine can serve an important role in identifying and following patients with carcinoid syndrome. In general, nonhormonal peptide biomarkers (eg, chromogranin A [CgA]) markers are less useful. (See "Overview of tumor biomarkers in gastroenteropancreatic neuroendocrine tumors".)
The presence of carcinoid syndrome is usually considered when a patient has suggestive symptoms, such as otherwise unexplained chronic severe diarrhea and/or flushing. Clinical features of carcinoid syndrome other than flushing and diarrhea are presented elsewhere. (See "Clinical features of carcinoid syndrome".)
Differential diagnosis — Other conditions should be considered in the differential diagnosis, however:
●The differential diagnosis for flushing, for example, includes physiologic events, drugs, and a number of diseases other than carcinoid syndrome (table 1). (See "Approach to flushing in adults".)
●The differential diagnosis for diarrhea is broad. (See "Approach to the adult with chronic diarrhea in resource-abundant settings".)
In addition to the well-differentiated NETs of the gastrointestinal tract that cause carcinoid syndrome, other well-differentiated NETs arising in the pancreas may cause severe diarrhea, including gastrinomas and VIPomas. (See "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis" and "Management and prognosis of gastrinoma (Zollinger-Ellison syndrome)" and "Clinical presentation, diagnosis, and management of VIPoma".)
Assay of hormonal biomarkers can help in the differential diagnosis.
Hormonal markers
Urinary excretion of 5-HIAA — A preferred initial diagnostic test for carcinoid syndrome is to measure 24-hour urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA), which is the end product of serotonin metabolism (figure 1). This test has a sensitivity of over 90 percent and a specificity of 90 percent for carcinoid syndrome [1]. Sensitivity is low in patients with NETs without carcinoid syndrome [2].
False-positive results may be induced by the ingestion of certain drugs and tryptophan/serotonin-rich foods (table 2). These foods should be avoided for three days prior to urine collection [3].
Measurement of urinary excretion of 5-HIAA is generally most useful in patients with primary midgut (jejunoileal and cecal) NETs, which produce the highest levels of serotonin. Foregut (gastroduodenal, bronchus) and hindgut (transverse, descending, and sigmoid colon, rectum, genitourinary) NETs only rarely secrete serotonin; they lack the enzyme dopa decarboxylase and cannot convert 5-hydroxytryptophan (5-HT) into serotonin and, therefore, into 5-HIAA (figure 1) [4]. These tumors may produce 5-HT (and histamine) instead of serotonin. However, there is no commercially available assay for urinary 5-HT.
The normal rate of 5-HIAA excretion ranges from 2 to 8 mg/day (10 to 42 micromol/day). Values of up to 30 mg/day (157 micromol/day) may be found in patients with malabsorption syndromes, such as celiac and Whipple's disease, as well as after the ingestion of large amounts of tryptophan- or serotonin-rich foods (table 2). Although many patients with carcinoid syndrome have similar modest elevations, some have values for urinary 5-HIAA excretion above 100 mg/day (523 micromol/day) [1].
Plasma 5-HIAA concentration — Plasma 5-hydroxyindoleacetic acid (5-HIAA) is not widely obtained as studies with this assay are limited and this test has yet to be validated in large clinical series. Plasma 5-HIAA measurement is an option for patients who have difficulty providing 24-hour urine specimens for 5-HIAA.
Plasma 5-HIAA levels can be obtained from several laboratories, and reportedly correlate closely with urine 5-HIAA [5-7]. In one study of 115 NET patients, levels of fasting plasma 5-HIAA correlated very closely with levels of urine 5-HIAA [6].
No role for blood serotonin concentration — We do not measure blood serotonin levels as a standard diagnostic test for carcinoid syndrome. Various serotonin assays have been described in the literature, including whole-blood serotonin, platelet-rich plasma serotonin, and platelet-poor plasma serotonin assays. However, the sensitivities and specificities of these assays are not well established. In one report, the mean fasting-blood serotonin concentration in normal subjects ranged from 71 to 310 ng/mL (0.4 to 1.8 micromol/L). Ten patients with carcinoid syndrome had markedly elevated values, from 790 to 4500 ng/mL (4.5 to 25.5 micromol/L); of these, two had normal urinary 5-HIAA excretion [8]. Notably, false-positive serotonin tests may occur due to release of platelet serotonin in stored blood samples, as well as from the ingestion of tryptophan/serotonin-rich foods [9].
Other hormonal syndromes associated with diarrhea in neuroendocrine tumors — In patients with NETs, diarrhea can be caused by hormonal syndromes other than the carcinoid syndrome. Examples include Zollinger-Ellison syndrome (associated with gastrinoma) and VIPomas, which secrete vasoactive intestinal peptide. Further details are discussed separately. (See "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis", section on 'Serum gastrin concentration' and "Clinical presentation, diagnosis, and management of VIPoma", section on 'Diagnosis' and "Overview of tumor biomarkers in gastroenteropancreatic neuroendocrine tumors", section on 'Hormones associated with pancreatic NETs'.)
Nonhormonal markers
Chromogranin concentration — Due to its relatively low specificity, we do not use CgA as a screening test for the diagnosis of a NET or carcinoid syndrome. CgA may be an appropriate tumor biomarker for patients with an established diagnosis of advanced NET in order to assess disease progression, response to therapy, or, in some cases, recurrence after surgical resection. (See "Overview of tumor biomarkers in gastroenteropancreatic neuroendocrine tumors", section on 'Chromogranin A (CgA)'.)
Despite a high volume of published studies evaluating multiple circulating nonhormonal tumor markers like CgA in NETs, consensus-based guidelines have increasingly de-emphasized their role in clinical care for the following reasons:
●Levels of CgA secretion vary on a day-by-day basis in healthy subjects and those with NETs.
●Food intake also increases CgA levels [10,11]. False-positive elevations of CgA can be present in a number of other conditions, including atrophic gastritis (table 3). They are especially common in patients who are taking a proton pump inhibitor [12-14]. As a result, CgA is a relatively nonspecific marker for NETs [2,3,15].
●A recognized international standard for CgA assay is not available, and multiple CgA tests exist that use different assays, have widely divergent normal thresholds, and varying degrees of accuracy [16].
Sensitivity is limited for localized disease. Test performance is better with advanced disease and varies according to disease burden, and the specific cutoff value [17,18]. In general, serial measurements of CgA and/or other nonhormonal tumor markers are most useful in patients with metastatic NETs and highly elevated levels of the marker, which are more likely to be true-positives than false-positives. In such patients, serial assay of CgA levels may be a reasonable indicator of disease activity and response to antitumor therapy. Whenever we do measure tumor marker levels, we usually obtain them in conjunction with radiographic imaging, typically every 6 to 12 months. (See "Overview of tumor biomarkers in gastroenteropancreatic neuroendocrine tumors", section on 'Chromogranin A (CgA)' and "Clinical presentation, imaging and biomarker monitoring, and prognosis of metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors", section on 'Chromogranin A'.)
TUMOR LOCALIZATION AND STAGING
Tumors originating in intestinal tract — Carcinoid syndrome is primarily associated with metastatic neuroendocrine tumors (NETs) that originate in the small intestine or proximal colon. Vasoactive peptides that are produced by localized intestinal NETs are inactivated in the portal circulation and, thus, do not result in carcinoid syndrome. The liver is the most common distant metastatic site. Imaging studies should, therefore, focus on the abdomen and pelvis. Computed tomography (CT), magnetic resonance imaging (MRI), and somatostatin receptor (SSTR) positron emission tomography (PET) imaging (eg, gallium Ga-68 dotatate or copper Cu-64 dotatate PET scans) are the primary imaging modalities used to identify NETs.
Computed tomography — Contrast-enhanced CT imaging of the abdomen (multiphase) and pelvis is often used to evaluate patients with NETs, with the exception of tumors with a very low probability of spread, such as most type 1 and 2 gastric NETs or small (<1 to 2 cm) superficial (T1) rectal NETs [19,20]. (See "Staging, treatment, and surveillance of localized well-differentiated gastrointestinal neuroendocrine tumors", section on 'Staging evaluation'.)
Multiphase CT imaging of the abdomen involves acquiring images during the early "arterial" phase (approximately 20 seconds after contrast injection) and more delayed "portal venous phase" (approximately 70 seconds after contrast injection), to maximize the conspicuity of liver metastases compared with the surrounding normal liver parenchyma [21,22] (image 1). Most liver metastases from NETs are highly vascular and are most conspicuous during the arterial phase, but approximately 6 to 20 percent are hypovascular (most conspicuous in portal venous phase) [21].
Small intestinal NETs often produce mesenteric masses with dense desmoplastic fibrosis, either due to direct extension of primary tumors into the mesentery or due to mesenteric lymph node metastases (image 2). The classic finding on CT abdomen and pelvis is a mass-like process with soft tissue "spokes" radiating into the mesenteric fat toward the small bowel, often causing retraction of the bowel with angulation and tethering. The central mass may or may not be calcified. The differential diagnosis for these mesenteric lesions also includes sclerosing mesenteritis.
While staging CT imaging for small intestinal NETs may detect the primary tumor, this is not as important as the detection of involved lymph nodes and sites of metastatic disease since surgical resection includes palpation of the entire small bowel. Still, it is useful in these cases to avoid routine "positive" oral contrast, high-density compounds that appear white at CT imaging, which could obscure intraluminal lesions or areas of abnormal bowel wall tumoral enhancement. The use of water or "negative" contrast agents (compounds that distend the lumen but appear dark/gray) could also be used to improve potential visualization of small bowel tumors (ie, CT enterography).
Magnetic resonance imaging — Gadolinium-enhanced MRI of the abdomen and pelvis can also be used in the imaging evaluation of carcinoid syndrome and staging of small bowel NETs and is useful in certain clinical scenarios. For example, MRI could be performed with young patients to avoid radiation exposure or in patients who are allergic to CT contrast. Similar to CT, MRI can also be optimized to evaluate the bowel using enterography technique (ie, bowel distension with a negative oral contrast agent, multiphase postcontrast imaging) resulting in excellent assessment for NET. For example, one prospective study of magnetic resonance enterography for small bowel NET demonstrated a detection rate of 95 percent on a per-patient basis [23].
Another advantage of MRI is its superior sensitivity for hepatic metastatic disease. MRI has a higher sensitivity than CT for NET liver metastases and has even been found to outperform SSTR PET imaging for hepatic metastatic disease, particularly with the use of a liver-specific contrast agent (gadoextate) [24,25]. This subject is discussed in detail separately. (See "Clinical presentation, imaging and biomarker monitoring, and prognosis of metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors", section on 'Cross-sectional imaging (CT and MRI)'.)
Somatostatin receptor-based imaging — Most well-differentiated NETs express high levels of SSTRs and can be imaged with radiolabeled somatostatin analogs. Functional imaging with PET tracers for SSTR imaging (such as Ga-68 dotatate and Cu-64 dotatate), in combination with CT, are commonly used for the initial staging of NETs and to improve the detection of an occult primary site if it is not detected on initial CT imaging of the abdomen (multiphase) and pelvis [26]. SSTR PET-CT is widely available and has replaced 111-In pentetreotide imaging (Octreoscan) for staging and evaluation of small bowel NETs [27].
Although anatomic cross-sectional imaging with CT and MRI provides an excellent assessment of small bowel NETs, the information provided by functional SSTR PET-CT imaging frequently changes patient management [28]. For example, SSTR PET-CT has a much higher sensitivity for detecting occult primary sites, bone metastases and metastatic lymph nodes which are not abnormally enlarged, all of which have the potential to alter management plans. Further details on SSTR-based imaging studies for well-differentiated gastroenteropancreatic NETs are discussed separately. (See "Clinical presentation, imaging and biomarker monitoring, and prognosis of metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors", section on 'Somatostatin receptor-based imaging studies'.)
Poorly differentiated neuroendocrine carcinomas generally express fewer SSTRs and are not routinely evaluated with SSTR-based imaging [29]. (See "Poorly differentiated gastroenteropancreatic neuroendocrine carcinoma", section on 'Imaging studies'.)
Endoscopy — Upper and lower endoscopy (with attention to the terminal ileum) should be performed for the evaluation of metastatic NET if the primary site cannot be established through imaging studies. Other options include CT enterography. Although video capsule endoscopy has been used to detect the primary site in metastatic NETs, we do not recommend this study given several reports of obstruction following ingestion of the video capsule [30].
Lung neuroendocrine tumors — Uncommonly, lung NETs can present with carcinoid syndrome, even in the absence of hepatic metastases. As with intestinal primaries, SSTR-based imaging can be used to localize well-differentiated lung NETs (bronchial carcinoids) (image 3). These tumors tend to be centrally located endobronchial lesions; however, approximately 20 percent arise peripherally and present as a well-circumscribed solitary pulmonary nodule (image 4). (See "Lung neuroendocrine (carcinoid) tumors: Epidemiology, risk factors, classification, histology, diagnosis, and staging", section on 'Clinical syndromes related to peptide production'.)
SOCIETY GUIDELINE LINKS —
Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Neuroendocrine neoplasms".)
INFORMATION FOR PATIENTS —
UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Carcinoid syndrome (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Differential diagnosis
•The presence of carcinoid syndrome due to a neuroendocrine tumor (NET) involving the gastrointestinal tract may be suspected when a patient has otherwise unexplained diarrhea or flushing.
•However, other diagnoses must be considered. The differential diagnosis of flushing, for example, includes physiologic events, drugs, and a number of diseases other than carcinoid syndrome (table 1). Moreover, other NET types arising in the pancreas (eg, VIPomas) can cause severe chronic diarrhea. (See 'Differential diagnosis' above.)
●Approach to biochemical testing
•Urinary 5-HIAA – The most useful initial diagnostic test for carcinoid syndrome is to measure 24-hour urinary excretion of 5-hydroxyindoleacetic acid (5-HIAA), which is the end product of serotonin metabolism (figure 1). Depending on the cutoff value used, this test has a high sensitivity and high specificity for carcinoid syndrome but requires strict avoidance of foods containing serotonin and tryptophan as well as certain drugs for three days prior to the urine collection (table 2). (See 'Urinary excretion of 5-HIAA' above.)
Measurement of urinary 5-HIAA excretion is generally not useful in foregut (gastroduodenal, lung) NETs, which often lack aromatic amino acid decarboxylase. In this setting, we would pursue imaging studies to search for a NET.
•Serum chromogranin A – Due to its relatively low specificity, we do not use serum chromogranin A (CgA) as a screening test for the diagnosis of carcinoid syndrome. (See 'Chromogranin concentration' above.)
●Tumor localization – Once the biochemical diagnosis of carcinoid syndrome is confirmed, usually by an elevated 24-hour excretion of 5-HIAA, the tumor must be localized. (See 'Tumor localization and staging' above.)
•Imaging studies – CT, MRI, and somatostatin receptor (SSTR)-based imaging have a complementary role in tumor localization:
-CT or MRI abdomen and pelvis – For the diagnostic workup of carcinoid syndrome and staging of small bowel NETs, we obtain a contrast-enhanced CT of the abdomen (multiphase) and pelvis. (See 'Computed tomography' above.)
Gadolinium-enhanced MRI of the abdomen and pelvis is an acceptable alternative and is useful in certain clinical scenarios (eg, avoidance of radiation exposure, allergy to CT contrast, superior sensitivity for hepatic metastases). (See 'Magnetic resonance imaging' above.)
-Somatostatin receptor-based imaging – Most well-differentiated NETs express high levels of SSTRs and can be imaged with radiolabeled somatostatin analogs. Functional imaging with either gallium Ga-68 dotatate or copper Cu-64 dotatate positron emission tomography (PET)-CT is commonly used for initial staging and to improve detection of an occult primary site. (See 'Somatostatin receptor-based imaging' above.)
Poorly differentiated neuroendocrine carcinomas generally express fewer SSTRs and are not routinely evaluated with SSTR-based imaging. (See "Poorly differentiated gastroenteropancreatic neuroendocrine carcinoma", section on 'Imaging studies'.)
•Endoscopy – Upper and lower endoscopy (with attention to the terminal ileum) should be performed for the evaluation of metastatic NET if the primary site cannot be established through imaging studies. (See 'Endoscopy' above.)
ACKNOWLEDGMENT —
The UpToDate editorial staff acknowledges Stephen Goldfinger, MD, who contributed to an earlier version of this topic review.
