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Diagnostics of neuroendocrine tumors

Some tumors first cause symptoms only after metastasizing. It is not uncommon that a neuroendocrine tumor is discovered coincidentally while performing a work-up for another condition.

The paitent´s medical history may cause suspicion of a neuroendocrine tumor especially if there are hormone-related symptoms. The symptoms are however often unspecific and vague. Symptoms having lasted for many years do not usually lead to a comprehensive work-up.

Blood tests such as hematological status and liver tests are often normal even when the disease is extensive. No laboratory or image diagnostic examinations provide a 100% certain diagnosis. The final diagnosis is therefore based on the histological examination of the tumor tissue.

Chromogranin A

Around 90% of all highly differentiated neuroendocrine tumors release the protein chromogranin A, which is detected in the serum. The level increases with the size of the tumor. The test can therefore be used for both the work-up and to monitor treatment progress. Increasing values after treatment intended to cure the disease may be a sign of recurrence. 

Chromogranin A in serum can, however, be raised for a series of other conditions such as medications for ulcers/dyspepsia (proton pump inhibitors, H2 antagonists), gastritis, renal failure, hepatic failure, and disturbances of other hormone-producing organs. Certain other cancer types can also cause elevated chromogranin A in serum. 

Interpretation of raised chromogranin A values can therefore be difficult. The test should not be taken randomly, but only if there is suspicion of a neuroendocrine tumor (6).

Urinalysis

5-hydroxyindoleacetic acid (5-HIAA), which is a byproduct of serotonin, can be detected in raised levels in urine in 24 hours from patients with serotonin-producing tumors. These patients often have diarrhea and flushing. Elevated 5-HIAA is also found from tumors originating from the small intestines and first part of the colon. Raised levels are also observed after intake of certain foods such as bananas, tomoatoes, avocadoes, chocolate, pineapple, certain medications, and other diseases (7). 5-HIAA can be analyzed in a morning spot urine sample, 24-hour collection does not seem to be necessary.

Image diagnostics

A CT scan with oral and intravenous contrast is the most sensitive radiological examination. Images of both the arterial and potovenous phase are very important. Neuroendocrine tumors are normally hypervascular and are sometimes visible:  

  • only in the arterial phase
  • only in the venous phase
  • on MRI but not CT
  • only on ultrasound

A patient with liver metastasis may have some metastases which are only visible on CT and some which are only visible on MRI or ultrasound.

Intestinal MRI or X-ray with contrast can detect neuroendocrine tumors. The tumors can be <1 cm, and for the detection, the radiological procedures and interpretations must be of good quality.

Image examples:

  • CT
  • CT lungs 
  • Ultrasound
  • X-ray  

Endoscopic examinations

  • Gastroscopy is a useful work-up for neuroendocrine tumors in the stomach and duodenum . Small tumors in the stomach can be removed endoscopically.
  • Endoscopic ultrasound can detect tumors in the pancreas/duodenum which are not visible by CT/MRI/ordinary ultrasound.
  • Coloscopy may detect tumors in the colon and rectum. Small tumors can be removed during the procedure.

Octreotide scan

This type of scan is based on a radioactive isotope (as 111Indium) which is injected intravenously. This isotope which is attached to a somatostatin analogue (octreotide) binds to somatostatin receptors in the body. An increase of this tracer is detected by scanning the patient with a gamma camera. Over 50% of all neuroendocrine tumors have somatostatin receptors and will only be visible on octreotide scintigraphy . The tumor should normally be 1 cm or greater to be detected. Octreotide scintigraphy is not very specific for neuroendocrine tumors. Uptake is observed in a series of cancer forms such as lung cancer, lymphomas, and breast cancer. Inflammatory processes may also give rise to positive scans.

PET 

PET with 18F-FDG as a tracer is not very sensitive for neuroendocrine tumors and does not have a place in routine work-up. Some tracers, for instance 68Gallium, has a very high sensitivity for neuroendocrine tumors. 

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