Version July 2025
INTRODUCTION —
Neuroendocrine neoplasms (NENs) are a heterogeneous group of malignancies characterized by variable biologic behavior. Clinical behavior and prognosis correlate closely with histologic differentiation and grade. NENs can also arise from many different sites since neuroendocrine cells are distributed throughout the body.
This topic discusses the clinical presentation, prognosis, radiographic imaging, and tumor marker evaluation of patients with well-differentiated neuroendocrine tumors (NETs) arising in the gastrointestinal tract (GINETs) or the pancreatic islet cell tumors (pancreatic NETs). Related topics on the pathology and classification, diagnosis, and treatment of NENs are presented separately.
●(See "Pathology and classification of gastroenteropancreatic neuroendocrine neoplasms".)
●(See "Diagnosis of carcinoid syndrome and tumor localization".)
●(See "Insulinoma".)
●(See "Glucagonoma and the glucagonoma syndrome".)
●(See "Somatostatinoma: Clinical manifestations, diagnosis, and management".)
●(See "Clinical presentation, diagnosis, and management of VIPoma".)
●(See "Neuroendocrine neoplasms of unknown primary site".)
●(See "Well-differentiated high-grade (G3) gastroenteropancreatic neuroendocrine tumors".)
●(See "Poorly differentiated gastroenteropancreatic neuroendocrine carcinoma".)
CLASSIFICATION AND NOMENCLATURE —
The World Health Organization classification of neuroendocrine neoplasms (NENs) arising in the digestive system separates these tumors into two broad categories (table 1) [1,2] (see "Pathology and classification of gastroenteropancreatic neuroendocrine neoplasms", section on 'Pathology and tumor classification'):
●Well-differentiated neuroendocrine tumors (NETs), which show a solid, trabecular, gyriform, or glandular pattern, with fairly uniform nuclei, salt-and-pepper chromatin, and finely granular cytoplasm. They are divided into low-grade (G1), intermediate-grade (G2), and high-grade (G3) subtypes based on proliferative rate. (See "Well-differentiated high-grade (G3) gastroenteropancreatic neuroendocrine tumors".)
●Poorly differentiated neuroendocrine carcinomas (NECs), which are G3 carcinomas. Similar to their lung counterparts, gastroenteropancreatic NEC are divided into large cell and small cell subtypes based on tumor morphology (picture 1) [3]. (See "Poorly differentiated gastroenteropancreatic neuroendocrine carcinoma".)
Poorly differentiated NECs are often associated with a rapid clinical course. Treatment paradigms for poorly differentiated gastroenteropancreatic NEC parallel those established for small cell lung cancer and typically utilize platinum-based chemotherapy.
By contrast, most well-differentiated gastroenteropancreatic NETs generally have a much better prognosis. Even in the presence of liver metastases, some patients may survive for many years. However, these tumors are not a homogeneous group, but instead display a spectrum of aggressiveness. Within the subgroup of well-differentiated NETs, grade as assessed by proliferative measures including mitotic count and/or Ki-67 labeling index, is of prognostic significance, independent of tumor stage [4,5].
There is a small subset of patients with NETs that appear histologically well differentiated, with fewer than 20 mitoses per 10 high-power fields (G2 by mitotic count), but are associated with high Ki-67 proliferation indices (>20 percent) that fall into the G3 range. The clinical behavior of these grade-discordant tumors is somewhat worse than grade-concordant well-differentiated G2 NETs but is better than that of bona fide poorly differentiated NECs. (See "Pathology and classification of gastroenteropancreatic neuroendocrine neoplasms", section on 'Well-differentiated high-grade (G3) NET'.)
Digestive tract NETs can also be defined by their functional, or hormone-secreting, status. Functioning NETs are characterized by the presence of clinical symptoms due to excess hormone secretion by the tumor. Functioning pancreatic NETs are classified according to the predominant hormone they secrete and the resulting clinical syndrome (eg, insulinoma, gastrinoma, glucagonoma, VIPoma, somatostatinoma). Functioning gastrointestinal NETs can secrete hormones including serotonin and other vasoactive peptides that result in symptoms of carcinoid syndrome including flushing and diarrhea. Although functionality may impact prognosis (eg, insulinomas are generally indolent tumors), the biologic behavior of most functioning NETs is defined by the grade and stage of the tumor, just as it is in nonfunctioning tumors. The vast majority of functioning tumors are well differentiated. (See "Insulinoma" and "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis" and "Glucagonoma and the glucagonoma syndrome" and "Clinical presentation, diagnosis, and management of VIPoma" and "Somatostatinoma: Clinical manifestations, diagnosis, and management" and "Clinical features of carcinoid syndrome" and "Diagnosis of carcinoid syndrome and tumor localization".)
CLINICAL PRESENTATION —
The clinical course of patients with metastatic well-differentiated gastroenteropancreatic neuroendocrine tumor (NET) is highly variable. Some untreated patients with indolent tumors remain symptom free for years, while others have symptomatic disease, either from tumor bulk or peptide hormone hypersecretion. Patients with functioning pancreatic NETs typically have symptoms caused by the specific type of hormone being produced by the tumor. (See "Glucagonoma and the glucagonoma syndrome", section on 'Clinical features' and "Insulinoma", section on 'Clinical presentation' and "Somatostatinoma: Clinical manifestations, diagnosis, and management", section on 'Clinical manifestations' and "Clinical presentation, diagnosis, and management of VIPoma", section on 'Clinical features'.)
For patients with metastatic gastrointestinal NETs, the secretion of serotonin and other vasoactive substances causes carcinoid syndrome, which is manifested by episodic flushing, wheezing, diarrhea, and eventual right-sided valvular heart disease [6]. Carcinoid syndrome is most commonly seen with midgut NETs (small intestine, appendix, proximal large bowel), almost exclusively in the setting of metastatic (usually liver) disease. It is rare with foregut (gastric, bronchial) and hindgut (distal colon, rectum, genitourinary) NETs. In addition, foregut NETs can be associated with an atypical variant of carcinoid syndrome. Patients with extraintestinal (eg, ovarian and bronchial) NETs can develop carcinoid syndrome in the absence of liver metastases (table 2). (See "Clinical features of carcinoid syndrome" and "Clinical characteristics of well-differentiated neuroendocrine tumors arising in the gastrointestinal and genitourinary tracts" and "Diagnosis of carcinoid syndrome and tumor localization".)
IMAGING STUDIES —
The predominant site of metastatic spread well-differentiated neuroendocrine tumors (NETs) is the liver. Liver function tests are an unreliable indicator of tumor involvement; the serum total bilirubin and/or alkaline phosphatase are frequently normal despite extensive liver involvement. Imaging is therefore an important aspect of monitoring patients with advanced gastroenteropancreatic NETs for evidence of disease progression or treatment response.
Well-differentiated neuroendocrine tumors
Cross-sectional imaging (CT and MRI) — Patients with advanced gastroenteropancreatic NETs are monitored using cross-sectional anatomic imaging with multiphase computed tomography (CT) of the abdomen [7,8]. These images include postcontrast arterial and portal venous phase images. Noncontrast or delayed phases may also be used, but this varies based on practice patterns and specific clinical circumstances. Multiphase CT imaging is necessary to adequately evaluate hepatic metastases [9]. These are generally hypervascular and show early arterial phase enhancement but their appearance can vary (image 1). For example, 6 to 20 percent of liver lesions may only be seen with more delayed postcontrast phases beyond initial arterial phase imaging [10]. Additionally, a multiphase abdominal CT helps to assess the treatment response of hepatic metastases and can be useful for treatment planning for liver-directed therapy (eg, percutaneous ablation or intra-arterial therapy) [11]. A contrast-enhanced CT of the pelvis may also be required for disease monitoring when there is a tumor involving the peritoneum, ovaries, or lower abdominal/upper pelvic lymphadenopathy. However, evaluation of pelvic tumor generally does not require multiphase imaging.
Gadolinium-enhanced magnetic resonance imaging (MRI) of the abdomen has a higher sensitivity than CT to detect hepatic metastatic disease. However, CT is still the preferred imaging modality given the increased cost of MRI and its relative inconvenience (eg, patient time in an MRI scanner is much longer than that in a CT scanner; access to MRIs may be more limited than CT), particularly with advanced gastroenteropancreatic NETs where maximum sensitivity may not be the primary concern. MRI for follow-up imaging is an appropriate alternative to CT in specific clinical circumstances, such as a severe allergy to CT contrast or in cases where CT imaging does not display the disease well. When MRI is used, the use of a liver-specific contrast agent (gadoxetate; Eovist or Primovist) and hepatobiliary phase imaging improves lesion detection and accuracy of measurements (image 2) [9,12].
Somatostatin receptor-based imaging studies — Over 90 percent of gastroenteropancreatic NETs, including nonfunctioning NETs (except for insulinomas), have high concentrations of somatostatin-receptors (SSTRs). Thus, these tumors can be imaged using radiolabeled SSTR analogs [9]. When obtaining SSTR-based positron emission tomography (PET) imaging, multiple SSTR analogs can be used as radiotracers, but studies have not shown a significant difference in efficacy between these analogs [9,13]. The most frequently used SSTR analogs in clinical practice are gallium Ga-68 dotatate and copper Cu-64 dotatate. Although Ga-68 dotatate is most commonly used, some centers prefer Cu-64 dotatate because of its longer half-life [9]. Other SSTR analogs include gallium Ga-68 dotanoc and gallium Ga-68 dotatoc (where available).
SSTR-based PET imaging with SSTR analogs has largely replaced the use of single-photon emission computed tomography (SPECT)/CT imaging with the radiolabeled somatostatin analog (SSA) octreotide (111-In pentetreotide), also known as Octreoscan.
Baseline imaging using one of the SSTR-based imaging techniques is generally recommended in patients with advanced NETs, both as an adjunct to routine cross-sectional imaging and because evidence of SSTR expression (based on a positive scan) can be predictive of a clinical response to therapy with SSAs, such as octreotide and lanreotide [14], as well as peptide receptor radioligand therapy. (See "Systemic therapy for metastatic well-differentiated low-grade (G1) and intermediate-grade (G2) gastrointestinal neuroendocrine tumors", section on 'Initial therapy' and "Systemic therapy of metastatic well-differentiated pancreatic neuroendocrine tumors".)
Studies have shown that the use of SSTR-PET changes management more frequently than cross-sectional imaging (CT or MRI) or SPECT/CT [13]. When SSTR-PET is used, the improved sensitivity must be taken into account when comparing results between modalities. For example, often if SSTR-PET is performed after cross-sectional imaging, PET detects more extensive disease, and this may be secondary to the improved sensitivity of PET rather than disease progression (image 3) [13].
The role of SSTR-PET in monitoring response to therapy and for surveillance is not well established. These imaging techniques rely in part on the assessment of SSTR density, rather than direct measurements of tumor volume. Using SSTR-based techniques may, in theory, not always correlate with disease progression or response to therapy. The North American Neuroendocrine Tumor Society guidelines for the use of SSTR-PET imaging recommend that if cross-sectional imaging detects the known sites of tumor, then it is preferred for disease monitoring, with PET employed in certain situations (eg, rising tumor markers but no cross-sectional imaging evidence of progression) [13].
For patients treated with SSAs, it has generally been recommended that therapy with short-acting analogs be discontinued for 24 hours before SSTR-based imaging, with treatment resumed the day after, when clinically feasible [11]. For patients receiving long-acting SSA preparations, the recommendation has been to allow a wash-out period of three to four weeks before imaging or to image just prior to dosing with long-acting SSAs. However, some evidence suggests the timing of the wash-out period is not as important if the patient has been on a stable dose for months and a serum steady state is reached [11]. For example, some studies have found that treatment with long-acting SSAs (lanreotide, octreotide) did not alter Ga-68 dotatate uptake into tumors or affect imaging results [15-17].
A pitfall of whole-body SSTR-PET imaging is that many other entities can show uptake in addition to NETs, including other benign and malignant tumors and various inflammatory and physiologic processes. This spans the spectrum from central nervous system meningiomas to physiologic increased uptake in the pancreatic uncinate process to uptake in healing fractures [18]. When areas of PET uptake are noted outside regions typical for gastroenteropancreatic NET metastatic disease, a focused clinical work-up is indicated for better characterization. For example, a brain MRI could be used to analyze unexpected intracranial SSTR-PET uptake.
Poorly differentiated neuroendocrine carcinomas — Imaging for poorly differentiated neuroendocrine carcinomas (NECs) arising in the gastrointestinal tract is discussed separately. (See "Poorly differentiated gastroenteropancreatic neuroendocrine carcinoma", section on 'Imaging studies'.)
BIOMARKER MONITORING
Hormonal biomarkers
Urinary 5-HIAA — Elevated urinary levels of 5-hydroxyindoleacetic acid (5-HIAA) are highly specific for serotonin-producing neuroendocrine tumors (NETs; ie, those arising in the midgut), but they are not particularly sensitive. In one study, only 73 percent of patients with metastatic NETs had elevated levels [19]. Furthermore, 5-HIAA levels are generally most useful in patients with primary midgut NETs. Foregut and hindgut NETs only rarely secrete serotonin; they lack the enzyme DOPA decarboxylase and cannot convert 5-hydroxytryptophan to serotonin and, therefore, to 5-HIAA (figure 1).
Clinical utility can also be limited by false positives. The normal rate of 5-HIAA excretion ranges from 2 to 8 mg (10 to 42 micromol) per day. Values of up to 30 mg (157 micromol) per day may be found in patients with malabsorption syndromes (eg, celiac disease), and following ingestion of large amounts of tryptophan/serotonin-rich foods; use of certain drugs also interferes with assay of urinary 5-HIAA (table 3). Although many patients with advanced well-differentiated midgut NETs have values above 100 mg (523 micromol) per day, some have more modest elevations. In one study, urinary 5-HIAA excretion in patients with carcinoid syndrome ranged from 99 to 2070 mg (518 to 10826 micromol) per day [20]. Lower but still elevated values were seen in patients with metastatic NETs without carcinoid syndrome (50 to 260 mg [262 to 1360 micromol] per day).
Urinary 5-HIAA is the most sensitive test for establishing the diagnosis of carcinoid syndrome. Plasma or serum 5-HIAA testing can also be used as an alternative to urinary 5-HIAA testing [21,22]. (See "Diagnosis of carcinoid syndrome and tumor localization", section on 'Biochemical testing for carcinoid syndrome'.)
Functioning pancreatic neuroendocrine tumors — While they are specific for the individual hormonal syndrome, the hormones produced by functioning pancreatic NETs (ie, insulin, glucagon, somatostatin, vasoactive intestinal peptide [VIP]) may not be easily measurable. Assessment of specific hormone levels should be performed based on patient symptoms and suspicion for a functional NET. (See "Insulinoma", section on 'Diagnosis and staging' and "Glucagonoma and the glucagonoma syndrome", section on 'Serum glucagon' and "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 "Somatostatinoma: Clinical manifestations, diagnosis, and management", section on 'Diagnosis'.)
Nonhormonal biomarkers
Chromogranin A — Chromogranin A (CgA) is a 49-kD protein that is contained in the neurosecretory vesicles of NET cells and is detectable in the plasma of patients with a range of neuroendocrine neoplasms (NENs), including nonfunctioning pancreatic NETs. (See "Overview of tumor biomarkers in gastroenteropancreatic neuroendocrine tumors", section on 'Chromogranin A (CgA)'.)
Plasma CgA levels have been shown to correlate with treatment response and may also have prognostic value. Elevated CgA levels have been associated with shorter overall survival times in several studies [4,23-26]. However, the utility of CgA as a marker of prognosis has been limited by wide variability in CgA ranges in the setting of metastatic disease, as well as variability in CgA assays in the United States and Europe. Caution is also needed when using serum CgA as a marker of disease activity in patients treated with somatostatin analogs (SSAs). These agents significantly reduce plasma CgA levels, a change that may be more reflective of changes in hormonal synthesis and release from tumor cells than an actual reduction in tumor mass [27]. Finally, CgA is not recommended as a diagnostic marker for NETs, as it can be elevated in a number of unrelated conditions (table 4). These conditions include use of proton pump inhibitors, kidney Insufficiency, and hepatic insufficiency. For patients who are receiving treatment with a proton pump inhibitor, the drug should be stopped or replaced with an H2 receptor blocker if possible in order to obtain reliable CgA values [28]. The utility of measuring CgA levels in patients undergoing radiographic surveillance for detection of recurrence following surgery is debatable, as is its role in the routine follow-up of patients with advanced disease [29]. (See "Overview of tumor biomarkers in gastroenteropancreatic neuroendocrine tumors", section on 'Chromogranin A (CgA)'.)
PROGNOSIS —
Even when advanced, survival times for patients with well-differentiated gastroenteropancreatic neuroendocrine tumors (NETs) are generally better than those for patients with other malignancies [30], although prognosis can be highly variable. The main prognostic factors are differentiation and grade (table 1), tumor site (table 5), disease burden, and the presence of extrahepatic metastases.
Primary tumor site — One major factor impacting overall survival is primary tumor site [30]. In an analysis of cases in the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) database of NETs diagnosed between 2000 and 2012, the median survival for patients with distant metastases from grade 1 to 2 pancreatic NETs was 50 months. For patients with distant metastases from grade 1 to 2 small intestinal NETs, median survival was 103 months; by contrast, it was only 14 months for patients with colonic primary tumors [31].
Histologic grade — Another major prognostic factor is histologic grade, which is assigned based on the mitotic rate or Ki-67 labeling index [31,32]. As an example, in the SEER database analysis, patients with a grade 1 or 2 appendiceal NET or a grade 1 rectal NET had a median survival >30 years. By contrast, patients with grade 3 neuroendocrine carcinoma (NEC) had poor overall survival irrespective of primary tumor site, ranging from 30 to 33 months for small intestine and appendix, respectively, to eight months for cecum and colon [31]. (See "Pathology and classification of gastroenteropancreatic neuroendocrine neoplasms", section on 'Staging system'.)
Other prognostic factors — Other prognostic factors in patients with metastatic disease include disease burden, the presence of distant extrahepatic metastases, race, and older age [31,33].
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".)
SUMMARY
●Classification – Neuroendocrine neoplasms (NENs) arising at different sites within the body are classified according to their histologic features. All commonly used classification systems reflect a basic separation between more indolent, well-differentiated tumors and far more aggressive, high-grade, poorly differentiated neoplasms (neuroendocrine carcinomas [NECs]) that behave clinically more like small cell lung cancer (table 1). (See 'Classification and nomenclature' above.)
●Clinical presentation – The clinical course of patients with metastatic well-differentiated gastroenteropancreatic neuroendocrine tumors (NETs) is highly variable. Some patients with indolent tumors may remain symptom free for years, even without treatment. Others have symptomatic metastatic disease, either from tumor bulk or peptide hormone hypersecretion, and require therapy (table 2). (See 'Clinical presentation' above.)
●Imaging studies
•CT or MRI of the abdomen and pelvis – The predominant site of metastatic spread is the liver. Patients with metastatic disease should be evaluated with multiphase contrast-enhanced abdomen CT or MRI to provide optimal assessment of liver metastases. (See 'Cross-sectional imaging (CT and MRI)' above.)
•Somatostatin receptor (SSTR) imaging studies – SSTR expression, as measured by uptake of radiolabeled somatostatin analogs (SSAs), is predictive of a clinical response to therapy with SSAs and to peptide receptor radionuclide therapy. When obtaining SSTR-based positron emission tomography (PET) imaging, the most frequently used SSTR analogs are gallium Ga-68 dotatate and copper Cu-64 dotatate. (See 'Somatostatin receptor-based imaging studies' above.)
●Biochemical markers
•Urinary 5-HIAA – Changes in biochemical markers may be associated with disease progression and/or response to treatment. Elevated urinary levels of 5-hydroxyindoleacetic acid (5-HIAA) are highly specific for serotonin-producing NETs (ie, those arising in the midgut) although they are not sensitive. (See 'Urinary 5-HIAA' above.)
•Chromogranin A (CgA) – The utility of measuring CgA levels in patients undergoing radiographic surveillance for detection of recurrence following surgery and the role of CgA in the follow-up of patients with advanced disease are debatable. Serum CgA is not specific to NETs and can also be elevated in non-neuroendocrine-related conditions (table 4). (See 'Chromogranin A' above.)
●Prognosis – Even when advanced, survival times for patients with well-differentiated gastroenteropancreatic NETs are generally better than those for patients with other malignancies, although highly variable. The main prognostic factors are differentiation and grade (table 1), tumor site (table 5), disease burden, and the presence of extrahepatic metastases. (See 'Prognosis' above.)
