What laboratory tests can be ordered to diagnose endocrine tumors in a patient presenting with symptoms such as weight loss, fatigue, or hormonal imbalances?

Laboratory Testing for Endocrine Tumors

Begin with chromogranin A and 24-hour urinary 5-HIAA as baseline screening tests for all suspected neuroendocrine tumors, then add specific hormone assays based on the clinical syndrome present. 1

Initial Baseline Testing for All Suspected Cases

• Chromogranin A (serum) is the single most important pan-neuroendocrine marker, elevated in 60% or more of patients with both functioning and nonfunctioning pancreatic endocrine tumors and 75% of carcinoid tumors 1, 2
• 24-hour urinary 5-HIAA should be measured alongside chromogranin A as the initial screening panel, particularly valuable for midgut carcinoids where sensitivity reaches 70% 1, 3
• Important caveat: Chromogranin A levels are spuriously elevated by proton pump inhibitors, renal or liver failure, hypertension, and chronic gastritis—discontinue PPIs for at least 1 week before testing 1, 3

Syndrome-Specific Hormone Testing

For Gastrinoma (Zollinger-Ellison Syndrome)

• Basal and stimulated gastrin levels are essential, but must be measured after stopping proton pump inhibitors for at least 1 week 1
• Most patients with elevated gastrin do NOT have gastrinoma but rather achlorhydria or are on acid-suppressing medications 1
• Secretin stimulation test can be performed when diagnosis remains uncertain 1, 2

For Insulinoma

• Insulin/glucose ratio after 48-72 hour observed fast is the definitive test 1, 2
• Insulin level >3 mcIU/mL (usually >6 mcIU/mL) when blood glucose <40-45 mg/dL, with insulin-to-glucose ratio ≥0.3 indicates insulinoma 1
• C-peptide levels should be elevated (distinguishes from exogenous insulin) 1
• Urinary sulfonylurea testing rules out factitious hypoglycemia 1

For Glucagonoma

• Serum glucagon levels in patients presenting with recent-onset diabetes, cachexia, and/or necrolytic erythematous skin rash 1
• Blood glucose measurement 1

For VIPoma

• Vasoactive intestinal polypeptide (VIP) levels in patients with characteristic watery diarrhea 1
• Serum electrolytes to assess for hypokalemia and metabolic acidosis 1

For Pheochromocytoma (Adrenal Endocrine Tumor)

• Plasma free metanephrines (fractionated) is the preferred screening test—must be performed in ALL patients with adrenal masses >10 HU on non-contrast CT 1, 4, 5
• 24-hour urinary fractionated metanephrines is an alternative 4, 5
• Include normetanephrine and methoxytyramine when available 1
• Critical warning: Never perform adrenal biopsy without first excluding pheochromocytoma, as this triggers life-threatening hypertensive crisis 4, 5

For Adrenal Cortical Tumors

• 1 mg overnight dexamethasone suppression test (give 1 mg at 11 PM, measure 8 AM cortisol) screens for cortisol excess 1, 4, 5
• Plasma ACTH levels as part of cortisol assessment 1, 4
• Aldosterone-to-renin ratio in all patients with hypertension and/or hypokalemia (ratio >20 ng/dL per ng/mL/hr indicates primary aldosteronism) 1, 4
• Serum potassium to assess for hypokalemia 1, 4
• DHEA-S, 17-OH-progesterone, androstenedione, testosterone, 17-beta-estradiol in patients with virilization signs or suspected adrenocortical carcinoma 1, 4, 5

Additional Markers to Consider

• Pancreatic polypeptide (PPoma) may be tested as clinically appropriate for nonfunctioning islet cell tumors 1
• Neuron-specific enolase (NSE) has high specificity but low sensitivity (32.9%) 3, 2
• Thyroid function tests, parathyroid hormone, calcium, calcitonin, prolactin, alpha-fetoprotein, CEA, beta-HCG should be obtained when evaluating for MEN1 syndrome or second endocrine tumors 1, 3

Critical Pre-Collection Requirements for 5-HIAA

Dietary restrictions for 48 hours before and during 24-hour urine collection are mandatory to avoid false positives 3:

• Avoid: avocados, bananas, coffee, alcohol, pineapples, plums, walnuts, tomatoes
• Discontinue medications that interfere: acetaminophen, ephedrine, phenobarbital 3

Genetic Testing Considerations

• Clinical examination and family history should be performed in ALL cases to exclude MEN1 syndrome 1
• Germline MEN1 mutation testing should be considered in patients with sporadic or familial bronchial or gastric carcinoid, or when multiple endocrine tumors are present 1
• Screen first-degree relatives of known MEN1 mutation carriers from late childhood 1

Location-Specific Testing Algorithm

Midgut Carcinoids (Small Intestine)

• Measure both chromogranin A AND 24-hour urinary 5-HIAA (5-HIAA elevated in 70% of cases) 3

Foregut Carcinoids (Stomach, Bronchopulmonary)

• Prioritize chromogranin A over 5-HIAA, as 5-HIAA is only occasionally elevated 3

Hindgut Carcinoids (Rectum)

• Use chromogranin A exclusively; 5-HIAA is NOT elevated in these tumors 3

Pancreatic Neuroendocrine Tumors

• Chromogranin A is the primary marker regardless of functional status 3
• Add specific hormone assays based on clinical syndrome (insulin, gastrin, glucagon, VIP) 1, 2

Common Pitfalls to Avoid

• Never rely solely on 5-HIAA for diagnosis—it has limited sensitivity (35.1%) for general NET detection and misses non-serotonin producing tumors 3
• Do not skip hormonal testing even in apparently non-functioning tumors, as subtle hormone production impacts surgical management and perioperative care 4, 5
• Radiological appearance cannot predict hormone secretion status—biochemical testing is mandatory 4, 5
• Proton pump inhibitors must be stopped at least 1 week before measuring gastrin or chromogranin A to avoid false elevations 1, 3