• Credits
  • Section Writer: Dr. Om J Lakhani
  • Section Editor: Dr. Om J Lakhani

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• Q. What is the broad classification of Neuroendocrine tumors (NET) ?
  • Well differentiated Neuroendocrine tumors (NET)
  • Poorly differentiated Neuroendocrine tumors (NET)
    • 
• Q. Which are three important non-hormonal Neuroendocrine tumor markers ?
  • Chromogranin A
  • Pancreatic polypeptide
  • Pancreastatin
• Q. What is a ROC curve?
  • ROC curve spots Sensitivity on the Y axis against 1-specificity (false positive rates) in the X axis
• Q. How is the accuracy of a test determined from the ROC curve?
  • The Area under the curve (AUC) of a ROC curve represents the accuracy of a test
  • The AUC of 1.0 is considered a perfect test
    • Greater than 0.9 is excellent
  • A AUC of 0.5 is considered a useless test -as it is 50% and likely to occur by chance
  • 
• Chromogranin A
• Q. What is the sensitivity and specificity of Chromogranin A as a tumor marker for Neuroendocrine tumors (NET) ?
  • Sensitivity - 73%
  • Specificity- 95%
  • ROC AUC- 0.9
• Q. Chromogranin A are more sensitive for which Neuroendocrine tumors (NET) ?
  • They are more sensitive to gastropancreatic NET compared to other areas like Lung
• Q. When are Chromogranin A samples taken ?
  • In a fasting state
• Q. Which drug commonly produces false positive value for Chromogranin A ?
  • PPI
• Q. When should Chromogranin A be measured after discontinuation of PPI ?
  • Wait for 2 weeks after discontinuing PPI
• Q. Do they increase with H2 receptor antagonists also?
  • Yes
• Q. Which other endocrine conditions cause elevation of Chromogranin A ?
  • Hyperparathyroidism
  • Hyperthyroidism
  • Pheochromocytoma
  • Pituitary adenoma
  • Medullary thyroid carcinoma
• Q. Enlist all the conditions in which Chromogranin A is elevated ?
  • Gastroenteropancreatic NETS
    • Gastrointestinal tract (carcinoid tumors)
    • Pancreatic NETs (islet cell tumors*)
  • Endocrine disease
    • Hyperparathyroidism
    • Hyperthyroidism
    • Pheochromocytoma
    • Pituitary tumors
    • Medullary thyroid carcinoma
  • Drugs
    • Proton pump inhibitors
    • Histamine-2 receptor antagonists
  • Inflammatory disease
    • Airway obstruction in smokers
    • Chronic bronchitis
    • Systemic rheumatoid arthritis
    • Systemic inflammatory response syndrome
  • Renal disorders
    • Renal insufficiency/failure
  • Non-gastrointestinal cancers
    • Breast cancer
    • Ovarian cancer
    • Prostate cancer
    • Small cell lung cancer
    • Neuroblastoma
  • Gastrointestinal disorders
    • Chronic atrophic gastritis
    • Chronic hepatitis
    • Colon cancer
    • Hepatocellular carcinoma
    • Inflammatory bowel disease
    • Irritable bowel syndrome
    • Liver cirrhosis
    • Pancreatic adenocarcinoma
    • Pancreatitis
  • Cardiovascular disease
    • Acute coronary syndrome
    • Arterial hypertension
    • Cardiac insufficiency/failure
    • Essential hypertension
    • Giant cell arteritis
• Q. What is another important caveat to note for patients on Somatostatin analogs for the treatment of Neuroendocrine tumors (NET) ?
  • Since these agents impact the hormone activity more - the patients may have false lower values of the tumor marker
  • This may not necessarily reflect the tumor mass burden
• Q. So in which cases the use of Chromogranin A is limited for a follow-up?
  • 1. Those on Somatostatin analogues
  • 2. Those with more localized disease
  • 3. Those with very advanced disease
• Q. Which is potentially a better marker than Chromogranin A ?
  • Pancreastatin
  • This is derived from proteolytic cleavage of Chromogranin A
  • 
• Q. Why is Pancreastatin better?
  • Its level are not impacted by the use of PPI
  • In small studies, the levels correlate better with tumor burden
• Q. Do current guidelines recommend the use of Chromogranin A as a tumor marker?
  • Most guidelines are now moving away from recommending the same tumor marker both for diagnosis and for follow-up of patients
  • It has broadly moved to become a Category III recommendation
• Q. In which patients is 5-HIAA useful as a tumor marker?
  • 24-hour urinary 5-HIAA is a useful tumor marker mainly for Midgut NET
  • Remember they are associated with Carcinoid syndrome
• Q. Which is the midgut NET?
  • Jejunoileal
  • Appendiceal
  • Ascending colon
• Q. What level of gastrin is suggestive of Zollinger-Ellison syndrome (gastrinoma) ?
  • Fasting serum gastrin should be measured in any patient suspected of having ZES.
  • ^^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^^
• Q. Can PPI be given to patients with Zollinger-Ellison syndrome (gastrinoma) ?
  • Patients with ZES should be started on a high dose of a PPI (eg, omeprazole 40 mg twice daily, pantoprazole 80 mg twice daily).
  • PPIs have been generally safe, even when used in high doses.
  • Some patients require an early upward titration of these doses; however, once control of acid output has been achieved, a gradual dose reduction is usually possible
• Q. Which are other conditions causing increased gastrin levels?
  • 1. Chronic atrophic gastritis
  • 2. PPI use
  • 3. H. pylori infection
• Q. For how long should the PPI be stopped before retesting gastrin levels?
  • for 10-14 days
  • In such cases, patient can be shifted to a high dose of H2 blockers
• Q. Which tumor marker is suggestive of advanced or malignant Insulinoma ?
  • Proinsulin levels
  • They are strongly suggestive of advanced insulinoma
• Q. What is the NETest ?
  • This is an RNA-based test
  • This analyzes the tumor transcripts to look at the activity of the tumor
  • This is better than Chromogranin A
  • It is still under evaluation- but once we understand this better- this will become the standard of care
  • This test has 95% sensitivity and 98% specificity
  • It is also useful for differentiating stable disease from progressive disease
  •