Version May 2024
INTRODUCTION — Neuroendocrine neoplasms (NENs) comprise a heterogenous family of benign and malignant tumors. Neoplasms arising from neuroendocrine cells in the gastrointestinal system are termed gastroenteropancreatic NENs They are subdivided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs) (table 1).
Well-differentiated NETs often retain their ability to secrete peptides, amines, and other molecules, and functional NETs are defined as those that have a propensity to produce hormones and other vasoactive substances, which can give rise to various clinical syndromes [1-8]. Nonhormonal secretory products, such as chromogranin A, pancreastatin, and pancreatic polypeptide are often produced by both functional and nonfunctional NETs, and can serve as circulating serum tumor markers [9]. In addition to these hormonal and nonhormonal peptide markers, novel circulating RNA-based tests have been developed that are prognostic and potentially predictive for benefit from certain treatments.
This topic provides a brief summary of available tumor markers in gastroenteropancreatic NETs and offers guidance on the practical use of circulating tumor and hormonal markers in patients with gastroenteropancreatic well-differentiated NETs. The use of neuroendocrine tumor markers for specific clinical scenarios such as diagnosis of carcinoid syndrome, diagnostic evaluation for NENs, including those with an unknown primary site, post-treatment surveillance, and biochemical monitoring for individuals receiving therapy for advanced gastroenteropancreatic NENs, and the role of tumor markers for patients with high-grade NECs is described in detail elsewhere.
●(See "Thymic neuroendocrine (carcinoid) tumors", section on 'Laboratory testing'.)
●(See "Diagnosis and staging of small bowel neoplasms", section on 'Neuroendocrine tumors'.)
●(See "Well-differentiated neuroendocrine tumors of the appendix", section on 'Assay of tumor markers'.)
●(See "High-grade gastroenteropancreatic neuroendocrine neoplasms", section on 'Tumor markers'.)
DEFINITIONS — A tumor biomarker is a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathologic processes, or pharmacologic responses to a therapeutic intervention [10]. Biomarkers can be diagnostic, prognostic, or predictive.
This topic focuses mainly on the diagnostic use of several circulating biomarkers that may identify the presence of a NET, and inform the disease stage and extent, as well as the response to therapy.
Key metrics for the diagnostic use of biomarkers are sensitivity (the percentage of patients with the condition who are accurately detected by the test) and specificity (the percentage of control participants with normal test outcomes). The sensitivity and specificity of various biomarker cutoff levels can be depicted in a receiver-operating characteristic curve, where the area under the curve (AUC) represents the diagnostic power of the biomarker (figure 1). An AUC of 1.0 describes a perfect discriminatory marker, whereas an AUC > 0.9 is generally considered an excellent metric. However, the performance characteristics of biomarkers are also dependent on the prevalence of true positive cases in the population being evaluated and perform best in subpopulations with high likelihood of the suspected disease or when the disease is at a more advanced stage. (See "Glossary of common biostatistical and epidemiological terms", section on 'Measures of diagnostic test performance'.)
NONHORMONAL PEPTIDE TUMOR MARKERS
Chromogranin A (CgA) — CgA is a glycoprotein secreted by neurons and neuroendocrine cells [11]. It is a part of a family of granins, which are all precursors of biologically active substances [11,12]. CgA, specifically, is a precursor of pancreastatin, catestatin, and vasostatin I and II [11]. While all members of the granin family can be secreted by NETs, CgA is the marker most widely used in clinical practice.
Some studies report a high sensitivity [12], and specificity for CgA in patients with advanced NETs, both functional and nonfunctional [13]. A correlation has been reported between changes in CgA levels and progression or response to treatment, in many but not all studies [14-21], but especially in patients undergoing peptide receptor radiotherapy using 177-Lu Dotatate [22].
Test performance is better with advanced than with localized disease, and varies according to site and disease burden. Reported sensitivity and specificity rates for localized tumors are 32 to 92, and 10 to 96 percent, respectively [14,23-30]. A meta-analysis of 13 heterogeneous studies on CgA as a diagnostic marker that compared patients with NETs versus healthy controls reported an overall sensitivity of 73 percent, a specificity of 95 percent, and a receiver-operating characteristic area under the curve of 0.90 [30]. Sensitivity is lower in patients with colorectal and lung NETs compared with those who have gastroenteropancreatic NETs as tumors originating in those sites more commonly manifest intense secretory activity (eg, small bowel NETs) [31,32].
However, there are several important caveats to take into account when CgA is used as a tumor marker for NETs, that limit its utility:
●Several medications, notably proton pump inhibitors (PPI), and some foods increase CgA levels, leading to false positive results (table 2); CgA should ideally be measured in a fasting state, and no sooner than two weeks after discontinuation of the PPI [33].
●CgA levels are often elevated in nonneoplastic conditions such as chronic atrophic gastritis, renal failure, and inflammatory diseases (table 2).
●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 [34].
●Sensitivity is limited in cases with localized disease or low metastatic tumor burden [31,35].
●Caution is needed when using serum CgA as a marker indicative of changing tumor burden in patients treated with somatostatin analogs. These agents significantly reduce plasma CgA levels, and this change may reflect diminished hormonal synthesis and release from tumor cells rather than a reduction in tumor mass [36].
As a result of all of these issues, the utility of CgA, particularly as an aid to diagnosis of NETs, in post-treatment surveillance following resection of localized disease, or in following the response to treatment for advanced disease, is limited. An important point is that if serial measurements of CgA are used in patients with advanced NETs, they should be performed using the same assay.
Neuron-specific enolase — Neuron-specific enolase (NSE) is a soluble protein present in the cytoplasm of neurons and neuroendocrine cells [37]. NSE is neither sensitive nor specific for NETs; in two series totaling over 200 patients with gastroenteropancreatic NETs, sensitivity and specificity rates were 39 to 43, and 65 to 73 percent, respectively for differentiating NETs from nonendocrine tumors [38,39]. When elevated in NETs, however, high levels of NSE can be a marker indicating aggressive disease that portends a poor prognosis [38].
Pancreatic polypeptide — Pancreatic polypeptide (PP) is an oligopeptide primarily secreted by a subset of pancreatic islet cells in the head of the pancreas that do not produce insulin, glucagon, or somatostatin [40,41]. (See "Pancreatic polypeptide, peptide YY, and neuropeptide Y", section on 'Tissue distribution'.)
PP is most commonly elevated in patients with pancreatic NETs and when elevated, it can serve as a tumor marker. It can be elevated in other types of gastrointestinal NETs as well [13]. However, in general, PP has limited clinical utility in patients with gastroenteropancreatic NETs due to its low and variable sensitivity [23,42].
Pancreastatin — Pancreastatin is a peptide derived from proteolytic processing of CgA [43]. Pancreastatin serum levels are reportedly uninfluenced by PPIs, indicating that they may be a preferred tumor marker over CgA in patients being treated with PPIs. Some studies have reported improved correlation of pancreastatin with disease progression or response compared with CgA [44-46]; however, sensitivity (46 to 81 percent) is still limited [24,25,47,48]. Furthermore, while pancreastatin might offer some advantages over CgA, particularly in patients using PPIs, the data supporting its use derive from a small number of institutions.
Role of nonhormonal tumor markers in clinical practice — Despite a multitude of published studies evaluating multiple circulating tumor markers in NETs, guidelines have increasingly deemphasized their role in clinical care. As examples:
●Routine measurement of CgA in patients with newly diagnosed NETs of the gastrointestinal tract, lung thymus, and nonfunctional pancreatic NETs is now considered a category III recommendation (controversial) by the National Comprehensive Cancer Network [49]. Following potentially curative treatment, the utility of serial monitoring of biochemical markers as an indicator of recurrent disease, and its use for monitoring disease response or progression in patients with metastatic disease are also described as category III recommendations, to be performed only "as clinically indicated."
●The most recent North American Neuroendocrine Tumor Society guidelines on diagnosis and post-treatment surveillance for midgut and pancreatic NETs likewise do not recommend routine use of CgA for diagnosis, post-treatment surveillance, or monitoring the response to therapy [50,51].
●Similarly, the consensus among the investigators in the Commonwealth Neuroendocrine Tumour Collaboration is that the role of these tumor markers in surveillance after surgical resection of a NET is limited due to their relatively poor sensitivity and specificity [52,53].
●Specific recommendations for using nonhormonal tumor markers in clinical practice are not available from the European Neuroendocrine Tumour Society [54].
There are multiple reasons for these positions, including the clinical perception that levels often fluctuate without corresponding changes in scans or clinical status, the widespread use of PPIs in the population which falsely elevate CgA results, and lack of evidence that tumor markers provide significant marginal benefit beyond radiographic and clinical evaluations. CgA is particularly not useful in the evaluation of patients with type I gastric NETs that are associated with atrophic gastritis, a condition in which CgA is usually high and where variations in CgA levels may fluctuate in ways that do not reflect the patient's burden of disease. (See "Staging, treatment, and post-treatment surveillance of non-metastatic, well-differentiated gastrointestinal tract neuroendocrine (carcinoid) tumors", section on 'Stomach'.)
Given the issues with sensitivity and specificity, changes in tumor marker levels that do not correlate with clinical or radiographic findings can contribute to patient anxiety and to unwarranted treatment decisions.
In practice, the utility of CgA in the management of gastroenteropancreatic NETs is limited.
Our recommended approach — The following reflects our approach to use of nonhormonal tumor markers, which is consistent with consensus-based guidelines:
●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 because upward trends in CgA levels in these patients are more likely to be reflective of disease burden rather than being false-positives. Whenever we do measure tumor marker levels, we usually obtain them in conjunction with radiographic imaging, typically every 6 to 12 months.
●We generally do not advocate using CgA or any other nonhormonal tumor marker as a diagnostic test for NETs, or for post-treatment surveillance after surgical treatment of a non-metastatic NET. Histopathologic evaluation of tissue by a dedicated pathologist remains the gold standard for the diagnosis of an NET.
HORMONES THAT LEAD TO CLINICAL SYNDROMES — Unlike nonhormonal tumor markers, hormone measurements in the blood and/or urine can serve an important role in identifying and following patients with clinical syndromes that result from secretion of certain hormones, in the differential diagnosis of symptoms such as chronic unexplained diarrhea, and for evaluating risk for carcinoid heart disease.
Serotonin and 5-hydroxyindoleacetic acid (5-HIAA) — Serotonin (5-hydroxytryptamine) is an amine derivative secreted by the enterochromaffin cells of the small intestine, and is the main hormone implicated in the carcinoid syndrome [12,13,55,56]. Since the liver completely metabolizes serotonin produced from small bowel NETs after delivery by the portal system, elevated circulating serotonin levels occur only in patients with metastatic disease, or when the portal vein is bypassed (eg, ovarian primaries) [57]. (See "Clinical features of carcinoid syndrome", section on 'Pathophysiology'.)
The systemic sequelae of increased serotonin levels, carcinoid syndrome, is predominantly diagnosed in patients with metastatic small intestine NETs. The major symptoms of carcinoid syndrome are diarrhea and flushing: the secretory diarrhea observed in carcinoid syndrome is directly caused by serotonin secretion, whereas multiple vasoactive substances, including tachykinins and histamine, are thought to be involved in flushing. (See "Clinical features of carcinoid syndrome", section on 'Clinical features'.)
Carcinoid heart disease is characterized by fibrosis and thickening of tricuspid and pulmonary valves, and is a long-term consequence of elevated serotonin levels [58,59]. The risk of carcinoid heart disease development correlates closely with serotonin elevations [60]. (See "Carcinoid heart disease", section on 'Role of serotonin'.)
A problem with measurement of blood serotonin is that it is relatively nonspecific and can be affected not only by diet but also by platelet release during venipuncture and specimen processing (see "Diagnosis of carcinoid syndrome and tumor localization", section on 'Blood serotonin concentration'). Therefore, 24-hour urine measurements of 5-HIAA, a serotonin metabolite (figure 2), are preferred over blood serotonin levels, although they are cumbersome, and disliked by patients.
Several foods and medications can affect 5-HIAA levels, and it is important for patients to be provided with instructions on foods and medications to avoid during and for several days before the urine collection (table 3) [61]. Other conditions such as malabsorption, celiac disease, and renal failure can affect 5-HIAA levels.
Measurement of urinary excretion of 5-HIAA is generally most useful in patients with primary midgut (jejunoileal, appendiceal, ascending colon) 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 2) [62,63]. Foregut tumors may produce 5-HT (and histamine) instead of serotonin. However, there is no commercially available assay for urinary 5-HT. (See "Clinical characteristics of well-differentiated neuroendocrine (carcinoid) tumors arising in the gastrointestinal and genitourinary tracts".)
Elevation in excretion of urinary 5-HIAA is highly sensitive and specific for midgut tumors that have metastasized to the liver, and produce the carcinoid syndrome. Levels may be normal even in the presence of carcinoid syndrome, particularly if diarrhea is absent, but this is rare [64].
However, urinary 5-HIAA is relatively insensitive for isolated non-metastatic midgut NETs; any elevation in urinary 5-HIAA in this setting is likely to be a false positive test [14,64-66].
Plasma 5-HIAA levels can also be obtained from several laboratories, and reportedly correlate closely with urine 5-HIAA [67-69]. Plasma 5-HIAA measurement is a reasonable option, particularly for patients who have difficultly providing 24-hour urine specimens, although published experience with this assay is confined to a small number of institutions. (See "Diagnosis of carcinoid syndrome and tumor localization", section on 'Blood serotonin concentration'.)
Clinical utility — Measurements of 5-HIAA can be useful in several scenarios:
●Patients with chronic, unexplained diarrhea and/or flushing. An elevated level of 5-HIAA (with appropriate dietary restrictions) is suggestive of carcinoid syndrome and should lead to further radiographic workup. (See "Diagnosis of carcinoid syndrome and tumor localization", section on 'Urinary excretion of 5-HIAA'.)
●Monitoring of patients with metastatic (typically midgut) NETs and those with carcinoid syndrome:
•Highly elevated levels of 5-HIAA are predictive of heightened risk for carcinoid heart disease and need for echocardiographic screening [58,59,70], although there is no absolute cutoff value to predict the development of carcinoid heart disease. Because of this, even in the absence of flushing/diarrhea (carcinoid syndrome), we periodically measure 5-HIAA in most patients with metastatic midgut NETs for the purpose of identifying patients at risk for carcinoid heart disease. The addition of amino-terminal pro-brain natriuretic peptide increases the accuracy of the risk prediction (with an receiver-operating characteristic area under the curve of 0.82-0.86 [71,72]). (See 'Definitions' above and "Carcinoid heart disease", section on 'When and how to initially test for carcinoid heart disease'.)
•Patients with advanced serotonin-producing tumors with highly elevated levels of 5-HIAA are at risk for developing carcinoid crisis during surgery/anesthesia. For patients undergoing surgery for metastatic NET who have a history of carcinoid syndrome, prophylactic preoperative use of octreotide is optional, especially in those who are already receiving a long-acting somatostatin analog, but almost certainly unnecessary in patients without carcinoid syndrome. However, octreotide should be readily available intraoperatively for "as needed" intravenous use for patients who develop hemodynamic instability during surgery. (See "Treatment of the carcinoid syndrome", section on 'Carcinoid crisis: prevention and management'.)
•Patients with NETs who have diarrhea and elevated 5-HIAA (ie, carcinoid syndrome) may benefit symptomatically from efforts to reduce tumor bulk and/or serotonin using somatostatin analogs, cytoreductive treatments such as liver embolization or peptide receptor radioligand therapy, or telotristat, an inhibitor of the enzyme tryptophan hydroxylase, a rate limiting step in the conversion of tryptophan to serotonin within tumor cells. (See "Treatment of the carcinoid syndrome".)
•Conversely, patients with advanced NETs who have relatively normal 5-HIAA may have alternative explanations for their diarrhea such as bile malabsorption from surgery or pancreatic exocrine insufficiency, and may not benefit from specific therapies targeting the NET.
For most patients, measurement of 5-HIAA can be performed roughly every 6 to 12 months; more frequent measurements are generally not helpful. Outside of midgut NETs (urine 5-HIAA should not be measured unless there are symptoms suggestive of carcinoid syndrome). Patients undergoing 5-HIAA assay should be educated about the foods and medications to avoid before undertaking the test (table 3).
Hormones associated with pancreatic NETs — Multiple peptide hormones are associated with pancreatic NET syndromes such as Zollinger Ellison Syndrome (ZES), insulinoma syndrome, glucagonoma syndrome, and VIPoma syndrome. In general, we recommend that hormone levels be evaluated based on clinical symptoms only. We do not test nonspecific panels of hormone levels for all patients with nonfunctioning tumors, which account for the majority of pancreatic NETs. (See "Classification, epidemiology, clinical presentation, localization, and staging of pancreatic neuroendocrine neoplasms".)
Consistent with guidelines from the National Comprehensive Cancer Network, we periodically assay serum hormone levels that are initially elevated every 6 to 12 months in conjunction with radiographic imaging following resection of a functioning pancreatic NET [49].
Gastrin — Gastrin is a peptide hormone secreted by the G-cells of the pyloric antrum, duodenum, and pancreas. It is involved in the stimulation of gastric acid release [73].
Gastrinomas — Gastrin-secreting tumors, known as gastrinomas, are one of the most common functional NETs of the pancreas and duodenum. The clinical consequence of a gastrinoma is ZES, characterized by heartburn, diarrhea, and chronic multiple peptic ulcers. (See "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis".)
A serum gastrin value greater than 10 times the upper limit of normal (1000 pg/mL) in the presence of a gastric pH below 2 is diagnostic of ZES. While basal acid output measurement used to be described as a diagnostic test, this test is rarely performed; however, a gastric pH level can be measured during esophagogastroduodenoscopy and should be low in untreated ZES. (See "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis", section on 'Serum gastrin concentration'.)
Fasting gastrin can be physiologically elevated in chronic atrophic gastritis, in patients taking proton pump inhibitors (PPI), and with Helicobacter pylori infection [74]. PPIs should ideally be discontinued 10 to 14 days prior to measuring fasting gastrin; however, this can be difficult for patients whose symptoms are highly suspicious for ZES. High doses of H2 blockers can be used in place of PPIs to prevent peptic complications [56].
If the gastrin level is between the upper limit of normal and 1000 pg/mL, a secretin test can be performed [75], and is considered positive if gastrin rises more than 120 pg/mL, with a diagnostic sensitivity of 94 percent and specificity of 100 percent [76]. However, in the era of multiphasic computed tomography scans, somatostatin receptor imaging positron emission tomography scans, and endoscopic ultrasound, a secretin test is rarely necessary to establish a diagnosis of gastrinoma. (See "Zollinger-Ellison syndrome (gastrinoma): Clinical manifestations and diagnosis", section on 'Secretin stimulation test'.)
In patients with advanced gastrinoma, gastrin can be monitored as a tumor marker, although it is important to note that PPIs will elevate gastrin modestly in nearly all cases and may therefore confound results. Gastrin levels are also measured every two to three years in asymptomatic patients with Multiple Endocrine Neoplasia type 1 (starting at age 16 or when clinical symptoms are present regardless of age) since gastrinomas are the most common NETs associated with this hereditary syndrome [77]. (See "Multiple endocrine neoplasia type 1: Clinical manifestations and diagnosis", section on 'Monitoring for MEN1-associated tumors'.)
Gastric NETs — A baseline gastrin level should also be measured in patients with gastric NETs: an elevated gastrin (ideally off PPI) is indicative of either type I (underlying atrophic gastritis; common) or type II (underlying gastrinoma; rare), whereas a normal gastrin level suggests type III (sporadic) gastric NET. In contrast to type II tumors, arising in the setting of ZES, for type I gastric NETs, there is no need to repeat gastrin levels after baseline collection. (See "Staging, treatment, and post-treatment surveillance of non-metastatic, well-differentiated gastrointestinal tract neuroendocrine (carcinoid) tumors", section on 'Stomach'.)
Insulin — Insulin is a peptide secreted by the pancreatic islet β cells, which plays a key role in glucose metabolism and uptake [78]. Insulinomas are insulin-producing-tumors that are typically small, and almost always localized to the pancreas; they are the most common functioning NET in that organ. However, many other conditions such as diabetes mellitus type 2, impaired glucose tolerance, and administration of exogenous insulin can cause elevated insulin levels [73].
Insulinomas should be suspected in a patient who exhibits "Whipple's triad," which is defined as symptoms or signs of hypoglycemia, a low plasma level of glucose, and an improvement of these symptoms after the administration of glucose [79]. The gold standard test for diagnosis of an insulinoma is the 72-hour fasting test, which should measure insulin, proinsulin, and C-peptide. Insulin, C-peptide, and proinsulin are elevated in insulinoma, whereas patients who are injecting excessive amounts of exogenous insulin typically have elevated insulin concentrations but suppressed C-peptide and proinsulin concentrations (table 4). Rarely, low levels of insulin and C-peptide might be caused by an insulin growth factor 2-producing non-islet cell tumor. (See "Insulinoma" and "Noninsulinoma pancreatogenous hypoglycemia syndrome".)
Several studies have shown that the sensitivity of this supervised 72-hour fasting test for insulinoma detection is 100 percent [80-83]. Proinsulin levels can be particularly elevated in patients with malignant/advanced insulinoma [84,85].
Glucagon — Glucagon is a peptide hormone produced by pancreatic alpha cells, which has an antagonistic effect to insulin, stimulating gluconeogenesis and glycogenolysis. Glucagonomas are rare functioning NETs that secrete glucagon. These pancreatic tumors are typically large (>3 cm) and most (50 to 80 percent) are metastatic at diagnosis [86]. Glucagonoma syndrome is characterized by hyperglycemia, glossitis, cachexia, and the distinctive skin eruption necrolytic migratory erythema.
The diagnosis of a glucagonoma requires the demonstration of elevated fasting glucagon levels. However, some glucagonomas are associated with serum levels of the peptide in the "physiologically elevated" range, even in the presence of necrolytic migratory erythema. Thus, in patients with the classic syndrome, a normal serum glucagon does not exclude a glucagonoma. (See "Glucagonoma and the glucagonoma syndrome", section on 'Serum glucagon'.)
Vasoactive intestinal peptide — Vasoactive intestinal peptide (VIP) is a peptide hormone released by pancreatic cells It derives its name from its splanchnic vasodilatory activity that regulates blood flow in the gastrointestinal tract, but it also stimulates contraction of enteric smooth muscles cells and pancreatic epithelial cell (exocrine) secretion, and inhibits gastric acid secretion. VIPomas, which are VIP secreting tumors, are rare and most commonly found in the pancreatic tail [87]. The VIPoma syndrome is characterized by severe watery diarrhea (>700 mL per day), typically leading to electrolyte imbalances including hypokalemia, acidosis, and achlorhydria. VIPomas have metastasized at the time of diagnosis in more than 80 percent of cases [86]. The diagnosis is established when patients have characteristic symptoms, pathologic evidence of disease, and elevated VIP levels. (See "VIPoma: Clinical manifestations, diagnosis, and management", section on 'Diagnosis'.)
Other hormones — Gastroenteropancreatic NETs can secrete numerous other hormones including parathyroid hormone (PTH) and PTH-related protein, which cause hypercalcemia; adrenocorticotropic hormone (ACTH), which can lead to ACTH dependent Cushing's syndrome; and others. In some cases, NETS will secrete multiple hormones leading to multiple syndromes associated with their oversecretion. In all cases, clinical and laboratory findings should guide decisions on which hormone levels to measure.
NOVEL CIRCULATING BIOMARKERS
NETest — The NET-related transcript-based evaluations test (NETest) is a novel RNA-based assay that has been reported to be superior to chromogranin A (CgA) in multiple metrics. However, the optimal way to integrate this test into clinical practice is not yet established. A key question is whether adjustments in treatment should be made solely based on changes in the marker level or is radiographic confirmation required to confirm tumor progression or response.
Tumor transcripts can be detected in the circulation and measured by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). NETest is a multianalyte qRT-PCR RNA-based essay that encompasses the simultaneous measurement of 51 different biologically relevant transcripts involved in NET proliferation, signaling, and secretion, as well as genes reported to have a defined association with tumor initiation and metastases [88,89]. The assay gives a single readout; scores range from 0 to 100 percent in 16 increments indicating disease activity risk. Thresholds of 0 to 20 are usually considered within normal range (minimal activity). while elevated levels (typically ≥80 percent), are considered to indicate high activity, and levels between 40 and 80 percent are considered intermediate. A cutoff score ≤40 percent can be used to rule in stable disease while a score >40 rules out stable disease [90].
Clinical utility — The available data suggest that high activity levels for NETest outperforms other NET biomarkers including CgA for diagnosis of neuroendocrine neoplasms [91-99], prediction of clinical disease stability/progression/tumor burden [89,97-102], and determination of therapeutic efficacy of somatostatin analog therapy and following peptide receptor radiotherapy [100,101,103-106]. A meta-analysis of ten studies evaluating the utility of NETest as a diagnostic and monitoring tool came to the following conclusions [90]:
●The diagnostic accuracy of NETest was high (95 percent) with a specificity of 95 to 98 percent.
●The mean estimated diagnostic odds ratio was very high (5853), the positive likelihood ratio was 195, and the negative likelihood ratio was 0.06. (See "Glossary of common biostatistical and epidemiological terms", section on 'Likelihood ratio'.)
●The NETest was 84 to 85 percent accurate in differentiating stable disease from progressive disease on disease monitoring.
●As an interventional/response biomarker, the accuracy was 94 to 97 percent.
●A pooled analysis of all studies indicated an area under the curve of 0.954.
However, the optimal way to integrate this test into clinical practice is unclear:
●For patients undergoing treatment for advanced disease, a key question is whether adjustments in treatment should be made solely based on changes in the marker level or is radiographic confirmation required? Ideally, studies should confirm that scans can be delayed in patients with stable (or improving) NETest values in order to further validate the practical role of this test before it can be incorporated into routine clinical practice.
●The optimal cutoff to define disease progression (ie, >40 or >80 percent) is not established [90,101].
●While these circulating transcripts represent an emerging opportunity for diagnosis of NETs, whether they can be used to differentiate NETs from other tumors (especially adenocarcinomas [95]) requires further study [13]. There are also concerns about the availability and cost of this biomarker for the diagnosis of NETs in clinical practice.
●Confirmation of these observations in larger series and by other groups is needed.
Peptide receptor radiotherapy prediction quotient — This test uses a similar methodology to the NETest to evaluate gene expression involved in metabolism and growth factor expression. When combined with tumor grade, it has been reported to be highly predictive of benefit (response or disease stabilization) with 177Lu-Dotatate in NETs [59,103,107]. Validation studies are underway.
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 topic (see "Patient education: Carcinoid syndrome (The Basics)")
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: Well-differentiated gastroenteropancreatic neuroendocrine tumors".)
SUMMARY AND RECOMMENDATIONS
●Gastroenteropancreatic neuroendocrine tumors (NETs) have the ability to secrete peptides, amines, and other molecules. Functional NETs are defined as those that produce hormones and other vasoactive substances, which can give rise to various clinical syndromes. In addition, nonhormonal secretory products, such as chromogranin A (CgA), pancreastatin, and pancreatic polypeptide (PP) are often produced by both functional and nonfunctional NETs, and can serve as circulating serum tumor markers. (See 'Introduction' above.)
●However, the limitations of many tumor markers in terms of sensitivity, specificity (table 2), and prognostic utility have led to a deemphasis of nonhormonal tumor makers such as CgA in many guidelines, including those of the National Comprehensive Cancer Network (NCCN) and North American Neuroendocrine Tumor Society. Given their limited sensitivity and specificity, changes in tumor marker levels that do not correlate with clinical or radiographic findings can contribute to false conclusions regarding changes in disease burden and to unwarranted treatment decisions. (See 'Nonhormonal peptide tumor markers' above.)
For all of these reasons, we generally do not advocate using nonhormonal tumor markers such as CgA, PP, or pancreastatin for routine monitoring of patients. They should never be used as diagnostic tests in patients lacking pathologic evidence of disease nor should treatment ever be administered based solely upon elevated levels without a pathologic confirmation of the presence of disease. (See 'Nonhormonal peptide tumor markers' above.)
Unlike nonhormonal tumor markers, hormone measurements in the blood and/or urine can serve an important role in identifying and following patients with NETs who have clinical syndromes that result from secretion of certain hormones, in the differential diagnosis of symptoms such as chronic diarrhea, and for evaluating risk for carcinoid crisis and heart disease. (See 'Hormones that lead to clinical syndromes' above.)
For diagnostic testing, measurements of specific hormones that contribute to a clinical syndrome (eg, insulin for insulinomas, glucagon for glucagonomas) should usually be symptom based. We do not test nonspecific panels of hormone markers for patients with nonfunctioning tumors, which account for the majority of pancreatic NETs. Consistent with guidelines from the NCCN, we periodically assay serum hormone levels that are initially elevated every 6 to 12 months in conjunction with radiographic imaging following resection of a functioning pancreatic NET. (See 'Hormones associated with pancreatic NETs' above.)
However, regardless of symptoms, we recommend periodically checking urinary 5-hydroxyindoleacetic acid (5-HIAA) levels in most patients with metastatic small intestinal NETs. For other patients, the value of periodic assessment of 5-HIAA levels is uncertain. For most patients, we measure 5-HIAA approximately every 6 to 12 months; more frequent measurements are generally not helpful. Patients should be educated about the medications and foods that can interfere with 5-HIAA measurement, and avoid these substances prior to urine collection (table 3). (See 'Serotonin and 5-hydroxyindoleacetic acid (5-HIAA)' above.)
Plasma 5-HIAA measurement is a reasonable option, particularly for patients who have difficultly providing 24-hour urine specimens, although published experience with this assay is confined to a small number of institutions.
●The NETest is a novel RNA-based assay that has been reported to be superior to CgA in multiple metrics. The available data suggest that high activity levels for NETest outperforms other NET biomarkers including CgA for prediction of clinical disease stability/progression/tumor burden, and determination of therapeutic efficacy of somatostatin analog therapy and following peptide receptor radiotherapy. However, the optimal way to integrate this test into clinical practice is not yet established. (See 'NETest' above.)
46 : Prognostic Impact of Serum Pancreastatin Following Chemoembolization for Neuroendocrine Tumors.
52 : Follow-up Recommendations for Completely Resected Gastroenteropancreatic Neuroendocrine Tumors.
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