Neuroendocrine Tumors Diagnostics

Last updated: 24 July 2025

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Laboratory Tests and Ancillaries

Content on this page:

Laboratory Tests and Ancillaries

Laboratory Tests and Ancillaries

Biochemical Markers  

Biochemical markers are hormones or amines secreted by the neuroendocrine cells from which the NETs are derived. The detection of these substances can provide a more accurate diagnosis and earlier detection of the presence of NETs which leads to improved control of symptoms related to hormone oversecretion. However, isolated elevation of these markers is generally not sufficient for diagnosis without tissue confirmation. These are also used for surveillance and prognosis of NETs. 



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Chromogranin A (CgA)  

Chromogranin A is a 49-kd acidic polypeptide widely present in the neuroendocrine cells’ secretory granules. It is elevated in most patients with either functional or non-functional NETs. This has high sensitivity for the detection of NETs but is not recommended for screening since levels can be elevated in several non-malignant diseases. Chromogranin A is a useful marker to detect the progression and metastasis of NETs because it correlates with tumor volume. However, care should be taken into consideration when measuring and interpreting results. Higher CgA levels correlate with higher recurrence risk after resection, more advanced disease, shorter survival and poor prognosis. CgA levels are elevated in patients with renal or hepatic impairment and in those taking PPIs which may lead to false positive results.  

5-Hydroxyindoleacetic acid (5-HIAA) Levels  

5-Hydroxyindoleacetic acid (5-HIAA) is a metabolite of serotonin found in a 24-hour urine collection or plasma that is a useful marker for evaluating and assessing response to treatment in patients with carcinoid tumors. This is a surrogate measure of serotonin metabolism and has high specificity. A decreasing level indicates response to treatment while increasing levels mean unsuccessful treatment. Certain foods (eg avocado, kiwi, banana, tomato, walnut) and medications (eg Acetaminophen, Ephedrine, Diazepam, Nicotine, Phenobarbital) can affect the result and should be avoided 48 hours prior to collection of samples.  

Neuron-Specific Enolase  

Neuron-specific enolase is a dimer of the glycolytic enzyme enolase. This is present in the cytoplasmic compartment of the cells of neuronal and neuroectodermal origin. This is a useful marker for follow-up of patients with NETs but less specific and sensitive than CgA.  

Other Tests  

Functional hormonal biomarkers should be measured in patients with sporadic or inherited NETs. Calcitonin, parathyroid hormone-related peptide and growth hormone-releasing hormone may be obtained for the detection of pancreatic NETs. Serum insulin, pro-insulin, C-peptide and fasting blood glucose is requested for insulinomas. Other tests such as serum VIP and electrolytes for VIPomas, serum glucagon for glucagonomas, serum somatostatin for somatostatinoma, and serum gastrin and gastric pH measurement for gastrinoma should be done. Workup for hypercortisolemia, if clinically indicated, in patients with thymus NETs should be requested. Pancreatic polypeptide, when elevated, can serve as a tumor marker for patients with pancreatic NETs.

Imaging

Imaging studies assist in:

  • Localizing the tumor
  • Assessing the extent of the disease and identifying the sites of metastases
  • Planning of treatment by determining whether surgical resection for possible cure or cytoreductive surgery is needed, and assessing whether treatment for advanced metastatic disease is appropriate
  • Monitoring the response to therapy and evaluating the need for additional treatment

The standard of care includes somatostatin receptor (SSTR)-based positron emission tomography (PET) imaging and standard imaging studies (eg magnetic resonance imaging [MRI] and computed tomography [CT]). These are useful in assessing receptor status, distant disease and whether patient may benefit from SSTR-directed therapy.  

Computed Tomography (CT) Scan  

Multiphasic computed tomography (CT) scan of the liver is readily available and should be a standard component of imaging modality of NETs because the liver is the most common site of metastasis. This can also be done to evaluate tumors before radiofrequency ablation and hepatic arterial embolization. This should be routinely used preoperatively for evaluation of potentially resectable primary or metastatic tumors. Multiphasic CT is also recommended for abdominal and pelvic imaging. Thin sections and the use of a negative oral contrast agent may be helpful in identifying small primary tumors in the small bowel. This is superior for localizing primary tumors, mesenteric invasion, tumor metastasis and thoracic lesions. Chest and mediastinal CT are used as needed for suspected lung and thymic tumors.

Magnetic Resonance Imaging (MRI)  

T1-weighted, T2-weighted and multiphasic (arterial, portal venous and delayed) dynamic magnetic resonance imaging is recommended for NETs. This has a high sensitivity in detecting pancreatic NETs. However, some do not prefer to use it routinely in gastroenterohepatic NETs. This can be used to characterize hepatic tumors before surgery if the diagnosis is unclear and if CT or ultrasound results are inconclusive. This is also recommended to determine the presence of metastasis. Studies have shown that MRI is more sensitive than CT for the detection of small liver metastasis.  

Magnetic resonance imaging is the preferred imaging modality in the following cases:

  • When CT is contraindicated and less sensitive for tumor detection
  • Patients having contrast allergies, hepatic steatosis or renal insufficiency
  • Patients for possible liver resection or tumor cytoreduction surgery
  • Initial localization of tumor in children and pregnant or lactating women to avoid radiation exposure




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Ultrasonography  

Ultrasonography is an adjunct to CT scans in assessing tumor volume before radiofrequency ablation and hepatic arterial embolization and differentiating lesions with uncertain CT imaging characteristics. Pre-operative endoscopic ultrasound should be considered for rectal NETs 1-2 cm in size. Contrast-enhanced ultrasound may be used to assess liver lesions that are equivocal on CT/MRI. 

Somatostatin Receptor (SSTR)-Positron Emission Tomography (PET) Scan/CT or PET/MRI  

Somatostatin receptor (SSTR)-positron emission tomography (PET) scan/CT or PET/MRI uses radiolabeled somatostatin analog gallium-68 (68Ga) dotatate, copper-64 (64Cu) dotatate and 68G dotatoc. Studies showed high sensitivity and specificity for the diagnosis of NETs. This is useful in tumor staging, pre-operative imaging and restaging of NETs. SSTR-PET imaging is more sensitive than SSTR scintigraphy in assessing SSTR status. This may also be used to assess liver metastasis.  

Meta-iodobenzylguanidine (MIBG) Scintigraphy  

Meta-iodobenzylguanidine (MIBG) scintigraphy is used for staging, monitoring and performing preoperative evaluation, especially when there is negative or uncertain In-pentetreotide scan results. This is utilized for identifying patients for radiolabeled MIBG therapy.  

Indium-111-Diethylenetriamine Pentaacetate Octreotide Scintigraphy  

Indium-111-diethylenetriamine pentaacetate octreotide scintigraphy shares the receptor binding profile of Octreotide making it a good radiopharmaceutical for imaging of SSTRs 2- and 5-positive tumors. This is an important imaging study for identifying and staging gastroenterohepatic NETs. This is the most sensitive imaging modality for detecting widespread metastatic disease in NETs. However, it is less sensitive for metastatic insulinomas. This can detect Octreotide-avid lesions in the body and help in disease staging, preoperative evaluation, surveillance and monitoring treatment response. Indium-111-diethylenetriamine pentaacetate octreotide scintigraphy is extremely useful in confirming diagnosis and evaluating tumor distribution and burden. This has high sensitivity and is done as whole-body imaging that detects disease at unsuspected sites. This provides information on the site but not about the size of the tumor. It is advised that Octreotide treatment be temporarily discontinued before scintigraphy so as not to alter the results.

Invasive Procedures  

Bronchoscopy  

Bronchoscopy is used for diagnosing and staging of lung and thymic carcinoids. This may be used as a confirmatory test for suspected central lesions and a required procedure prior to surgical resection.  

Endoscopic Ultrasonography  

Endoscopic ultrasonography is a minimally invasive technique that can be used for peripheral lesions and to rule out bulky mediastinal nodes in patients suspected of lung and thymic carcinoids, and in evaluating duodenal NETs.  

Mediastinoscopy  

Mediastinoscopy may be used for evaluating mediastinal nodes in patients suspected of lung and thymic carcinoids.  

Endoscopy and Colonoscopy  

Endoscopy and colonoscopy can be used in the evaluation of metastatic NETs with unknown primary sites.  

Esophagogastroduodenoscopy (EGD)  

Esophagogastroduodenoscopy can be used to evaluate gastric and duodenal NETs.  

Transthoracic Echocardiogram  

Transthoracic echocardiogram is used to assess and monitor carcinoid (NET-related) heart disease.