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Biochemical tests for NETs

Neuroendocrine tumors (NETs) produce specific tumor biomarkers that may help in detection and differential diagnosis.7 Preliminary biomarker results should be confirmed with imaging and endoscopic techniques, along with histopathologic analysis, when appropriate.1

Certain medications, such as antacids and proton pump inhibitors, can alter tumor biomarker levels.1,8

Circulating and cellular biomarkers

Chromogranin A (CgA)

CgA is a circulating NET marker that is elevated in up to 90% of patients with NETs.9,10 CgA levels are independent of hormone secretion, so elevated levels may indicate the presence of both functional and nonfunctional NETs.11,12

5-Hydroxyindoleacetic acid (5-HIAA)

5-HIAA, the primary metabolite of serotonin, has diagnostic and prognostic value in NETs associated with carcinoid syndrome that oversecrete serotonin and other substances.1,2,12 5-HIAA is measured by high-precision liquid chromatography in a 24-hour urine sample.13

Neuron-specific enolase (NSE)

NSE is a glycolytic enzyme that is secreted into plasma and can be elevated in patients with functional as well as nonfunctional neoplasms.14-16

Synaptophysin (SNAP)

SNAP is widely distributed in neurons and neuroendocrine cells and their neoplasms. It is a reliable broad-spectrum neuroendocrine marker and a fairly sensitive indicator for both low- and high-grade malignancies.14

Specific tests for functional NETs

Some biochemical substances secreted by NETs are specific to the type of neoplasm.1 Excessive levels of these substances may suggest the presence of a NET.1


A standard 72-hour fasting test should be used to measure glucose (<45 mg/dL) and insulin (>30 pmol/L) levels and to exclude all differential diagnoses of insulinoma, except for very rare conditions.7,17,18 Measurement of proinsulin and C-peptide levels may be helpful.19


Diagnosis often begins with determination of fasting serum gastrin levels (≥1000 pg/mL) and gastric pH (<2.5).17 Over repeated testing, <0.5% of patients with Zollinger-Ellison syndrome (ZES) will have normal values.7,18


Diagnosis can be made when plasma glucagon levels are increased to 500 to 1000 pg/mL (normal range
<50 pg/mL).19


Diagnosis is based on elevated levels (>200 pg/mL) of plasma vasoactive intestinal peptide (VIP) in patients with large-volume secretory diarrhea (>700 mL/d).19,20


Diagnosis can be confirmed by elevated plasma somatostatin levels in the setting of a histologically confirmed NET.19