What is the next step in management for a 70-year-old man with recurrent presyncope, hot flushes, and elevated chromogranin A?

Next Step in Management

The next step is to obtain multiphasic CT or MRI imaging of the abdomen and pelvis to localize a suspected neuroendocrine tumor, followed by somatostatin receptor scintigraphy (Octreoscan) if initial imaging is unrevealing. 1, 2

Critical First Action: Rule Out False Positive Chromogranin A

Before proceeding with extensive workup, you must exclude spurious elevation of chromogranin A by:

• Discontinuing proton pump inhibitors for at least 1-2 weeks – this is the most common cause of false positive results 3, 1
• Assessing renal function – renal failure causes spurious elevation 3, 1
• Evaluating liver function – hepatic failure elevates chromogranin A independently of neuroendocrine tumors 3, 1
• Checking blood pressure – hypertension alone can increase levels 3, 1
• Reviewing for chronic gastritis – another common cause of false elevation 3, 1

Imaging Strategy

Primary Localization Study

Obtain multiphasic CT or MRI of the abdomen and pelvis as the initial imaging modality to localize the tumor. 1, 2 This will identify:

• Pancreatic neuroendocrine tumors (69% have elevated chromogranin A for nonfunctioning tumors) 4
• Small intestinal carcinoids (80% have elevated chromogranin A) 4
• Gastrinomas (100% have elevated chromogranin A) 4

Secondary Functional Imaging

Follow with somatostatin receptor scintigraphy (Octreoscan) if CT/MRI is negative or equivocal, as 80% of neuroendocrine tumors express somatostatin receptors and this can detect lesions missed by conventional imaging. 5, 2

Syndrome-Specific Biochemical Testing

Given the presyncope and hot flushes, prioritize testing for specific functional syndromes:

For Carcinoid Syndrome (Most Likely Given Hot Flushes)

• Measure 24-hour urinary 5-hydroxyindoleacetic acid (5-HIAA) – particularly useful for midgut carcinoids with carcinoid syndrome 5, 2
• Patient must avoid avocados, bananas, cantaloupe, eggplant, pineapples, plums, tomatoes, hickory nuts, plantains, kiwi, dates, grapefruit, honeydew, walnuts, coffee, alcohol, and smoking for 48 hours before and during collection 5, 1

For Pheochromocytoma (Consider Given Presyncope)

• Measure plasma fractionated metanephrines and urinary metanephrines – the hormonal determination of choice for biochemical diagnosis 6
• Chromogranin A is elevated in 89% of pheochromocytomas 4
• This is critical to identify before any surgical intervention to prevent hypertensive crisis 7

For Gastrinoma (If Dyspepsia Present)

• Measure fasting serum gastrin levels after discontinuing proton pump inhibitors for at least 1 week 1

For VIPoma (If Watery Diarrhea Present)

• Measure serum vasoactive intestinal polypeptide (VIP) 1

Prognostic Significance

The elevated chromogranin A has important prognostic implications:

• Levels ≥2 times the upper limit of normal are associated with shorter survival in metastatic neuroendocrine tumors (HR 2.8; 95% CI 1.9-4.0; P<0.001) 3, 1
• Elevated levels strongly correlate with tumor volume 3, 8, 4

Critical Pitfalls to Avoid

• Do not interpret elevated chromogranin A while the patient is on proton pump inhibitors – this is the single most common cause of false positives 3, 1
• Do not assume rising chromogranin A in an asymptomatic patient with stable imaging requires new therapy 3, 2
• Be aware that chromogranin A is elevated in only 60% of neuroendocrine tumors, so a normal level does not exclude the diagnosis 3, 1
• If pheochromocytoma is suspected, do not use beta-blockers without alpha-blockade first – this can precipitate hypertensive crisis 7
• Consider genetic testing – 40% of pheochromocytomas are hereditary 6

Additional Considerations

Chromogranin A is the best general neuroendocrine serum marker available, with the highest specificity compared to neuron-specific enolase and alpha-subunit of glycoprotein hormones. 4 However, small tumors may go undetected even with elevated chromogranin A. 4

If carcinoid syndrome is confirmed, be prepared to administer prophylactic octreotide acetate to prevent carcinoid crisis during any invasive procedures, which can cause bronchospasm, hypotension, arrhythmias, and cardiopulmonary failure. 2