Connect Sign In
Cite this page
FeedbackMedical Experts
Bayrak-Toydemir
Doyle
Frank
Mao
Nelson H
Straseski
Neuroendocrine tumors (NETs) are tumors that originate from the endocrine system, including tumors that arise in the adrenal, parathyroid, pituitary, thymus, and thyroid glands, as well as the autonomic nervous system, gastrointestinal (GI) tract, and respiratory system. NETs usually arise sporadically, although they may occur in association with hereditary syndromes (e.g., multiple endocrine neoplasia types 1, 2, and 4 [MEN1, MEN2, and MEN4], neurofibromatosis, tuberous sclerosis complex, and von Hippel-Lindau [VHL] disease). NETs that hypersecrete hormones or other active molecules that produce symptoms in a patient are referred to as functional tumors. The specific symptoms of these NETs vary by tumor variety and secretion(s). Laboratory testing for NETs complements imaging and other evaluations and entails specialized biochemical testing for diagnosis, monitoring, and treatment decision-making. Specific laboratory testing recommendations depend on the location and/or type of tumor.
This topic provides an overview of laboratory testing for NETs by location and type. For guidance on thyroid tumors, refer to the ARUP Consult Thyroid Nodules and Thyroid Cancer Molecular Assessment topics.
For a comprehensive review of laboratory testing considerations (including genetic testing) for MEN1 and MEN2, refer to the ARUP Consult Multiple Endocrine Neoplasias - MEN topic.
Quick Answers for Clinicians
No, catecholamine testing is not recommended in the assessment of pheochromocytomas and paragangliomas (PPGLs). The initial biochemical evaluation of PPGLs should use plasma-free or 24-hour urinary fractionated metanephrines because these tests provide higher diagnostic accuracy than direct catecholamine measurement. Assessment of catecholamine concentrations should only be considered if cervical or head and neck paragangliomas or dopamine-producing tumors are suspected. Refer to the Initial Evaluation of PPGLs table for more information.
Pheochromocytomas are associated with multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau (VHL) disease, and neurofibromatosis, and paragangliomas can occur due to somatic mutations in the HIF2A gene in polycythemia-paraganglioma-somatostatinoma syndrome. Germline mutations in various genes have additionally been associated with pheochromocytomas and paragangliomas (PPGLs), including SDHB, SDHA, SDHAF2, SDHD, SDHC, TMEM127, MAX, FH, and MDH2. Patients with PPGLs who are younger than 45 years, those with family members with relevant tumors who are not available for testing, and those with bilateral, multifocal, or recurrent PPGLs should receive genetic counseling for coordination of appropriate genetic testing. Additional scenarios in which genetic testing should be considered include clinical suspicion for MEN1 or MEN2, adrenal cortical carcinoma (increased risk for Li-Fraumeni and Lynch syndromes), gastrinoma, and pancreatic or duodenal neuroendocrine tumors (NETs).
Carcinoid syndrome refers to a collection of symptoms, including diarrhea, wheezing, and episodic flushing, that result from the secretion of histamine, serotonin, or tachykinins from functional neuroendocrine tumors (NETs) into the systemic circulation. Carcinoid syndrome is typically associated with NETs in the appendix, small bowel, or proximal colon (midgut) but may also occur with lung or pancreatic NETs. Valvular complications of the cardiac system, such as pulmonary stenosis or tricuspid regurgitation, may occur in about half of these patients. When carcinoid syndrome is suspected, recommended laboratory testing includes 24-hour urine or plasma 5-hydroxyindoleacetic acid (5-HIAA) measurement.
A high Ki-67 index and increased mitotic rate have been associated with worse prognosis in neuroendocrine tumors (NETs), as have elevated levels of chromogranin A, although the routine measurement of chromogranin A for disease monitoring has decreased due to reproducibility concerns between laboratories and other challenges such as unreliability in cases of concurrent medication use or comorbid medical conditions. Several other markers have been explored for possible prognostic use in NETs, including cyclin-dependent kinase inhibitor 1B (CDKN1B) expression, circulating tumor cells, and mammalian target of rapamycin (mTOR) expression. Research is ongoing, and these markers are not considered suitable for routine clinical use. Tumor profiling can provide tumor classification information in some cases, as well as identify clinically actionable genetic variants, and is thus becoming more routine.
Positive results in two of three relevant immunohistochemistry (IHC) markers are required for diagnosis of a neuroendocrine neoplasm; namely, chromogranin A, insulinoma-associated protein 1 (INSM1), and/or synaptophysin. In addition, a high Ki-67 index has been proven to correlate with a less favorable prognosis and more aggressive disease course. Site-specific IHC stain markers (such as thyroid transcription factor-1 [TTF-1], caudal-type homeobox transcription factor 2 [CDX2], and special AT-rich sequence-binding protein [SATB2]) may be used to assist in evaluating well-differentiated neuroendocrine tumors (NETs), and additional stains are available that help resolve clinical suspicion for NETs and assist with definitive diagnosis. IHC may be required in the evaluation of poorly differentiated NETs.
Indications for Testing
Laboratory testing for NETs is appropriate in individuals with:
- Suggestive signs or symptoms
- Suggestive findings on imaging
- An associated hereditary syndrome or family history of an associated hereditary syndrome
- A personal history of NETs
For comprehensive guidelines on laboratory testing for NETs, please refer to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology: Neuroendocrine and Adrenal Tumors.
Categorization of Functional Neuroendocrine Tumors
Functional NETs may be categorized by the locations in which they arise and/or the hormones or neurotransmitters they secrete, both of which affect testing recommendations.
Laboratory Testing Recommendations by Tumor Location
Biochemical testing may be recommended as a component in the initial evaluation of NETs, especially if symptoms are present. Testing recommendations vary by tumor location.
| Tumor Location | Tumor Types | Biochemical Tests | Syndromes for Which Evaluation Is Recommended | Comments |
|---|---|---|---|---|
| Adrenal glands | Adrenocortical carcinoma Neuroblastoma (mainly in pediatric patients) | Metanephrines (plasma or 24-hr urine) Urinary HVA Urinary VMA | MEN2 (pheochromocytoma) VHL (PPGL) | For suspicion of adrenocortical carcinoma, screen for hypercortisolemia (Cushing syndrome) and primary aldosteronism HVA and VMA should only be assessed if neuroblastoma is suspected In patients with current or previous cancer with risk of adrenal metastasis, perform metanephrines and normetanephrines testing to rule out pheochromocytoma |
| GI tract (appendix, colon, duodenum, ileum, jejunum, or rectum) | Carcinoids Gastrinoma (duodenum) | 5-HIAA (24-hr urine or plasma) Chromogranin A | Carcinoid syndrome | — |
| GI tract (stomach) | Gastrinoma | 5-HIAA (24-hr urine or plasma) Chromogranin A Gastrin (serum) Gastric pH | Carcinoid syndrome | Biopsy recommended |
| Lung | Carcinoids Neuroendocrine carcinoma | As clinically indicated Cortisol Molecular profiling (for atypical carcinoid) | Carcinoid syndrome | Tumor profiling can be considered for those with metastatic or unresectable disease who are candidates for treatment and in whom results may direct treatment choice |
| Pancreas | Gastrinoma Glucagonoma Insulinoma Somatostatinoma VIPoma | Chromogranin A Pancreatic polypeptides (serum) | VHL NF1 Cushing syndrome (uncommon) | Additional testing depends on the tumor type |
| Respiratory system (bronchopulmonary system) | Primary carcinoid tumors of lung | 5-HIAA Chromogranin A | Carcinoid syndrome | Test for hypercortisolemia to rule out Cushing syndrome |
| Thymus | Primary carcinoid tumors of thymus | 5-HIAA Chromogranin A | Carcinoid syndrome | Test for hypercortisolemia to rule out Cushing syndrome |
| Thyroid | Refer to the ARUP Consult Thyroid Nodules and Thyroid Cancer Molecular Assessment topics | |||
5-HIAA, 5-hydroxyindoleacetic acid; ACTH, adrenocorticotropic hormone; HVA, homovanillic acid; NF1, neurofibromatosis type 1; TSC, tuberous sclerosis complex; VMA, vanillylmandelic acid Sources: NCCN, 2025 ; Kulke, 2010 ; Pavel, 2020 ; Kunz, 2013 | ||||
Laboratory Testing Recommendations by Tumor Type
Adrenocortical Carcinoma
Workup
The recommended workup for suspected adrenocortical carcinoma includes additional biochemical tests and genetic testing for hereditary cancer. Individuals with diagnosed or suspected adrenocortical carcinoma should be evaluated for Cushing syndrome or primary aldosteronism. An evaluation of sex hormones (i.e., dehydroepiandrosterone sulfate [DHEAS] and testosterone), glucocorticoids, mineralocorticoids, and adrenocortical steroid hormone precursors is also recommended. , Tests for tumor mutational burden (TMB), microsatellite instability (MSI), and/or mismatch repair (MMR) may also be considered.
Monitoring
Laboratory testing for biochemical markers of functional adrenocortical carcinoma may be appropriate to monitor for recurrence. Depending on the treatment regimen, monitoring the concentration of the therapeutic agent in the blood may be recommended. After treatment, patients should be evaluated with imaging and serum biomarker testing every 3-12 months for up to 5 years, and as clinically indicated after.
Genetic Evaluation
If the tumor is MMR deficient, the patient should be evaluated for Lynch syndrome. Additional testing for inherited genetic syndromes, such as Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome, and familial adenomatous polyposis, may be considered.
Carcinoid Tumors
Workup
If carcinoid GI, thymic, or lung NETs are suspected, serum chromogranin A should be assessed. Additionally, a 24-hour urine or plasma collection for 5-HIAA, a product of serotonin breakdown, is recommended, especially if the patient is experiencing diarrhea and flushing, which may be signs of hormone secretion. Evaluation for Cushing syndrome , or acromegaly may also be considered, especially if symptoms are present.
Monitoring
Chromogranin A may be useful for monitoring metastatic disease in patients if levels were abnormal at baseline. ,
Monitoring for recurrence includes imaging and 5-HIAA testing. Patients should be evaluated between 3 and 12 months after surgery and then every 12-24 months for up to 10 years. Surveillance after 10 years may be considered if clinically indicated.
Genetic Evaluation
In patients with thymic, GI tract, or lung NETs, a genetic evaluation for MEN1 should be considered. , For a detailed testing strategy, refer to the ARUP Consult Multiple Endocrine Neoplasias - MEN topic.
Gastrinoma
Workup
The recommended workup for gastrinoma includes imaging and a fasting serum gastrin test. Because the use of proton pump inhibitor (PPI) medication can increase the serum gastrin level, the patient should discontinue medication use for at least 7 days before testing (if safe for the patient). Fasting is also recommended. Additional biochemical testing (e.g., chromogranin A) may also be useful.
Monitoring
Monitoring for recurrence includes imaging and a serum gastrin test. Patients should be evaluated 3-12 months after resection and then every 12-24 months for up to 10 years. Surveillance after 10 years may be considered if clinically indicated.
Genetic Evaluation
Patients with gastrinomas in the pancreas or duodenum should be assessed for MEN1. For a detailed testing strategy, refer to the ARUP Consult Multiple Endocrine Neoplasias - MEN topic.
Glucagonoma
Workup
The recommended workup for glucagonoma includes imaging and tests for blood glucose and glucagon. A combination of symptoms (e.g., glucose intolerance, weight loss, necrolytic erythema) and a plasma glucagon level of 500-1,000 pg/mL is indicative of glucagonoma. Additional biochemical testing may also be useful as clinically indicated.
Monitoring
Monitoring for recurrence includes imaging and tests for blood glucose and glucagon. Patients should be evaluated 3-12 months after resection and then every 6-12 months for 10 years. Surveillance after 10 years may be considered if clinically indicated.
Genetic Evaluation
Patients with glucagonomas in the pancreas should be assessed for MEN1. For a detailed testing strategy, refer to the ARUP Consult Multiple Endocrine Neoplasias - MEN topic.
Insulinoma
Workup
The recommended workup for insulinoma includes imaging and serum biochemistry tests (fasting glucose as well as serum insulin, proinsulin, and C-peptide; other biochemical tests as clinically indicated). Insulinomas may be small enough that they are not visible via imaging, so they should be suspected even if no pancreatic mass is detected. After other causes of hypoglycemia are ruled out, serum tests for C-peptide, insulin, and proinsulin should be performed when the patient is in a hypoglycemic state (i.e., when blood glucose is <55 mg/dL).
Monitoring
Monitoring for recurrence includes imaging and serum tests for C-peptide, insulin, and proinsulin. Patients should be evaluated 3-12 months after resection and then every 6-12 months for 10 years. Surveillance after 10 years may be considered.
Genetic Evaluation
Patients with insulinomas in the pancreas should be assessed for MEN1. For a detailed testing strategy, refer to the ARUP Consult Multiple Endocrine Neoplasias - MEN topic.
Neuroblastoma
For a complete summary of the laboratory diagnostic testing and disease monitoring considerations for neuroblastoma, refer to the ARUP Consult Neuroblastoma topic.
Pheochromocytoma and Paraganglioma
For a complete summary of the laboratory diagnostic testing and disease monitoring considerations for PPGLs, refer to the ARUP Consult Pheochromocytoma - Paraganglioma topic and Pheochromocytoma - Paraganglioma Biochemical Testing Algorithm.
Somatostatinoma
Workup
The workup for somatostatinoma includes imaging and biochemical testing. Somatostatinoma syndrome results from tumors that secrete somatostatin and may be diagnosed based on elevated plasma somatostatin levels and appropriate symptoms. Additional biochemical testing may also be useful.
Genetic Evaluation
Somatostatinomas may be associated with MEN1 and, if located in the duodenum, NF1. ,
Poorly Differentiated Neuroendocrine Carcinomas
Workup
Immunohistochemistry (IHC) testing is necessary to aid in neuroendocrine differentiation of poorly differentiated neuroendocrine carcinomas. Informative stains may include chromogranin A, Ki-67, and synaptophysin.
Biochemical testing may also be appropriate in the initial evaluation of poorly differentiated neuroendocrine carcinomas. Consideration of MMR, MSI, and TMB testing may be useful to inform treatment decision-making.
Monitoring
In resected disease, monitoring for recurrence is recommended every 3 months for the first year and every 6 months after that. , In advanced disease, monitoring is recommended every 6-12 weeks.
VIPoma
Workup
The recommended workup for VIPoma includes imaging and tests for electrolyte and serum VIP concentrations. Additional biochemical testing may also be useful as clinically indicated.
Monitoring
Monitoring for recurrence includes imaging and tests for electrolyte and serum VIP concentrations. Patients should be evaluated 3-12 months after resection and then every 6-12 months for 10 years. Surveillance after 10 years may be considered.
Laboratory Testing for Associated Hereditary Syndromes
Several hereditary syndromes, including MEN1 and MEN2, NF1, TSC, and VHL may present with NETs. Additionally, PPGLs may be associated with hereditary syndromes. For more information about laboratory testing in these conditions, refer to the following resources:
- ARUP Consult Multiple Endocrine Neoplasias - MEN topic
- ARUP Consult Pheochromocytoma - Paraganglioma Biochemical Testing Algorithm
ARUP Laboratory Tests
Quantitative Immunofluorescence
Quantitative Electrochemiluminescent Immunoassay
Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
Quantitative Electrochemiluminescent Immunoassay (ECLIA)
Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
Quantitative Liquid Chromatography-Tandem Mass Spectrometry
Quantitative Chemiluminescent Immunoassay
Quantitative Enzymatic Assay
Quantitative Enzyme-Linked Immunosorbent Assay (ELISA)
Quantitative Chemiluminescent Immunoassay
Quantitative Chemiluminescent Immunoassay (CLIA)
Quantitative Chemiluminescent Immunoassay (CLIA) / Quantitative Chemiluminescent Immunoassay (CLIA)
Quantitative Chemiluminescent Immunoassay (CLIA)
Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
Quantitative Chemiluminescent Immunoassay
Quantitative Enzymatic Assay
Quantitative Liquid Chromatography-Tandem Mass Spectrometry
Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
Quantitative High Performance Liquid Chromatography-Tandem Mass Spectrometry
Quantitative Extraction/Immunoassay
Quantitative Ion-Selective Electrode/Enzymatic Assay
Quantitative Enzyme-Linked Immunosorbent Assay (ELISA)
Massively Parallel Sequencing
Qualitative Methylation-Specific Multiplex Ligation-Dependent Probe Amplification (MS-MLPA)
Massively Parallel Sequencing / Multiplex Ligation-Dependent Probe Amplification (MLPA)
Massively Parallel Sequencing
Massively Parallel Sequencing
Massively Parallel Sequencing
References
-
NCCN - neuroendocrine and adrenal tumors v3.2025
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: neuroendocrine and adrenal tumors. Version 3.2025. Updated Oct 2025; accessed Dec 2025.
-
24893135
Lenders JWM, Duh QY, Eisenhofer G, et al. Pheochromocytoma and paraganglioma: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2014;99(6):1915-1942.
-
NCI - Neuroblastoma treatment-PDQ May 2026
PDQ Pediatric Treatment Editorial Board. Neuroblastoma treatment (PDQ®): health professional version. In: PDQ Cancer Information Summaries [Internet]. National Cancer Institute (US); 2025. Accessed May 2026.
-
20664472
Kulke MH, Anthony LB, Bushnell DL, et al. NANETS treatment guidelines: well-differentiated neuroendocrine tumors of the stomach and pancreas. Pancreas. 2010;39(6):735-752.
-
32272208
Pavel M, Öberg K, Falconi M, et al. Gastroenteropancreatic neuroendocrine neoplasms: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(7):844-860.
-
23591432
Kunz PL, Reidy-Lagunes D, Anthony LB, et al. Consensus guidelines for the management and treatment of neuroendocrine tumors. Pancreas. 2013;42(4):557-577.
-
32861807
Fassnacht M, Assie G, Baudin E, et al. Adrenocortical carcinomas and malignant phaeochromocytomas: ESMO-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2020;31(11):1476-1490.
-
33482246
Baudin E, Caplin M, Garcia-Carbonero R, et al. Lung and thymic carcinoids: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32(4):439-451.
-
32663527
Singh S, Bergsland EK, Card CM, et al. Commonwealth Neuroendocrine Tumour Research Collaboration and the North American Neuroendocrine Tumor Society Guidelines for the diagnosis and management of patients with lung neuroendocrine tumors: an international collaborative endorsement and update of the 2015 European Neuroendocrine Tumor Society Expert Consensus Guidelines. J Thorac Oncol. 2020;15(10):1577-1598.
-
20664474
Anthony LB, Strosberg JR, Klimstra DS, et al. The NANETS consensus guidelines for the diagnosis and management of gastrointestinal neuroendocrine tumors NETs): well-differentiated NETs of the distal colon and rectum. Pancreas. 2010;39(6):767-774.