Feokromositoma

01Pathophysiology

Pheochromocytoma is a tumor of the chromaffin cells of the adrenal medulla. Chromaffin cells are embryologically derived from the neural crest and are the body's main source of circulating catecholamines: epinephrine (adrenaline) and norepinephrine (noradrenaline). When these cells undergo neoplastic transformation, the resulting tumor produces, stores, and secretes catecholamines in an unregulated fashion.

The hallmark of this disease is episodic catecholamine release. During these surges, norepinephrine acts on alpha-1 adrenergic receptors in the peripheral vasculature, producing intense vasoconstriction and a dramatic rise in blood pressure. Epinephrine acts on beta-1 receptors in the heart, increasing heart rate and contractility, which is why the patient develops palpitations and tachycardia. The combination of alpha-mediated vasoconstriction and beta-mediated cardiac stimulation creates the paroxysmal hypertensive crisis that defines the disease.

The chronic alpha-1 mediated vasoconstriction also explains a counterintuitive finding: orthostatic hypotension. Because the vasculature has been chronically constricted, the renin-angiotensin-aldosterone axis is suppressed and intravascular volume contracts over time. When the patient stands, the already depleted volume fails to compensate, and blood pressure drops. This is a frequently tested concept.

Catecholamines also stimulate hepatic glycogenolysis and gluconeogenesis, which is why patients may present with hyperglycemia or impaired glucose tolerance. Weight loss can occur from the chronic hypermetabolic state. Diaphoresis occurs through sympathetic stimulation of eccrine sweat glands. The patient appears pale rather than flushed because the dominant effect is alpha-mediated vasoconstriction of cutaneous vessels, driving blood away from the skin surface.

The concept of "paraganglioma" is closely related. Extra-adrenal chromaffin cells in the sympathetic ganglia can also give rise to catecholamine-secreting tumors, called paragangliomas. When the vignette describes a tumor near the organ of Zuckerkandl (at the aortic bifurcation) or in the bladder wall, think paraganglioma.

02Classification and Clinical Manifestation

The "Rule of 10s"

This rule remains widely tested even though modern data has revised the numbers significantly. Know both versions.

Hereditary Syndromes Associated with Pheochromocytoma

Clinical Manifestation by Pattern

03Diagnostic Workup

The workup begins with biochemical confirmation before any imaging. This is a crucial concept: you never image first. The reason is that adrenal incidentalomas are common (found in up to 5% of abdominal CTs), and imaging alone cannot distinguish a benign non-functioning adenoma from a pheochromocytoma.

Step 1: Biochemical Testing. The best initial test is plasma free metanephrines (fractionated: metanephrine and normetanephrine). These are the O-methylated metabolites of epinephrine and norepinephrine and are produced continuously within the tumor, independent of episodic catecholamine release. This gives the test its exceptionally high sensitivity (>96%). A normal result essentially rules out the diagnosis. For this reason, it is the preferred screening test in the Endocrine Society guidelines.

A 24-hour urine collection measuring catecholamines, metanephrines, and vanillylmandelic acid (VMA) serves as a complementary or confirmatory test. The 24-hour urine is slightly less sensitive but more available in some settings.

Important note: false positives can occur with sympathomimetic drugs, tricyclic antidepressants, decongestants (pseudoephedrine), amphetamines, and acute physiologic stress. The patient should ideally be tested in a rested, supine position, having avoided interfering medications.

Step 2: Anatomical Imaging. Once biochemistry confirms catecholamine excess, obtain a CT of the abdomen and pelvis with IV contrast to localize the tumor. Pheochromocytomas are typically adrenal masses measuring 3-5 cm or larger, with heterogeneous enhancement and possible central necrosis. On unenhanced CT, pheochromocytomas typically have Hounsfield units >20 (unlike lipid-rich adenomas that are <10 HU). On MRI, the classic finding is a markedly hyperintense signal on T2-weighted imaging (the "light bulb" sign), though this is not seen in all cases.

Step 3: Functional Imaging (when needed). If CT/MRI does not reveal the tumor, or if metastatic or multifocal disease is suspected, ${}^{123}^\{123\}$I-MIBG scintigraphy is the next step. MIBG is an analog of norepinephrine and is taken up by chromaffin cells, making it highly concentrated in pheochromocytoma tissue. In patients with SDHB-related paraganglioma, ${}^{68}^\{68\}$Ga-DOTATATE PET/CT has shown superior sensitivity compared to MIBG and is increasingly the preferred modality.

Step 4: Genetic Testing. Given that up to 40-50% of pheochromocytomas have a hereditary component, current guidelines recommend genetic testing for all patients, not just those with a family history or young age of onset.

04Management and Treatment

The cardinal rule is: alpha before beta. Never give a beta-blocker alone.

The reasoning is essential to understand. A beta-blocker blocks beta-2 vasodilatory receptors in the vasculature while leaving alpha-1 vasoconstrictive effects completely unopposed. The result is loss of the compensatory vasodilation that beta-2 receptors provide, which leads to a paradoxical and potentially fatal hypertensive crisis through unopposed alpha-mediated vasoconstriction. This is one of the most commonly tested concepts in pheochromocytoma management.

Step 1: Alpha-blockade. Phenoxybenzamine is the classic agent, a long-acting, irreversible, non-selective alpha-blocker. Begin at 10 mg PO twice daily, titrating upward every 2-3 days. The target blood pressure is <120/80 mmHg while seated, with mild orthostatic hypotension (a systolic drop of about 20 mmHg on standing is expected and acceptable, but the standing systolic should remain above 80-90 mmHg). Side effects include reflex tachycardia, nasal congestion, and orthostatic hypotension. Doxazosin (a selective alpha-1 blocker) is an increasingly used alternative, starting at 1-2 mg PO daily with similar titration goals. It is less expensive and has fewer side effects.

Step 2: Beta-blockade (only after alpha-blockade). Typically added 2-3 days after starting alpha-blockade if the patient develops reflex tachycardia or has persistent tachyarrhythmias. Propranolol 10-40 mg PO three to four times daily, or atenolol 25-50 mg PO daily, are commonly used.

Step 3: Volume expansion. High-sodium diet and liberal fluids should begin after alpha-blockade is in place. This is necessary because chronic vasoconstriction has caused intravascular volume depletion; expanding the volume reduces the risk of severe postoperative hypotension once the catecholamine source is removed.

Step 4: Surgical resection. Laparoscopic adrenalectomy is the standard of care for tumors <6 cm. Open surgery may be needed for larger tumors or those with suspected invasion. Intraoperatively, anesthesiologists must be prepared for acute hypertensive surges during tumor manipulation (treated with IV phentolamine or sodium nitroprusside) and for hypotension following tumor removal (treated with aggressive IV fluid resuscitation and vasopressors).

Step 5: Postoperative follow-up. Plasma or urine metanephrines should be checked 2-6 weeks after surgery to confirm biochemical cure. Long-term follow-up is recommended for at least 10 years because recurrence can occur, particularly in hereditary cases. The Endocrine Society recommends annual biochemical screening.

Contraindication to note: In pregnant patients with pheochromocytoma, surgery is ideally performed in the second trimester. Phenoxybenzamine crosses the placenta and has been used, but data is limited; selective alpha-blockers or calcium channel blockers may be considered. Beta-blockers should also be used cautiously.

05Differential Diagnosis and Distractors

06Traps and High-Yield Pearls

The single most commonly tested pitfall on pheochromocytoma is the "alpha before beta" rule. A vignette will describe a patient with paroxysmal hypertension, and the answer choices will include a beta-blocker among the options. The student who reflexively reaches for a beta-blocker to control tachycardia will trigger a catastrophic hypertensive crisis through unopposed alpha-receptor stimulation. The correct first step in medical management is always an alpha-blocker.

The second major trap involves the diagnostic sequence. Never image before obtaining biochemistry. A vignette may present a young patient with an incidentally found adrenal mass. The temptation is to order a CT-guided biopsy, but performing a biopsy or invasive procedure on an undiagnosed pheochromocytoma can provoke a life-threatening catecholamine surge. Always obtain plasma free metanephrines first.

A third common mistake involves confusing pallor with flushing. Students often associate episodic spells with flushing (as in carcinoid syndrome). In pheochromocytoma, the skin is pale because alpha-mediated vasoconstriction shunts blood away from the cutaneous circulation. If the vignette says "flushing," think carcinoid. If the vignette says "pallor," think pheochromocytoma.

Another tested concept is the association with hyperglycemia. A patient presenting with new-onset diabetes, hypertension, and episodic spells should prompt consideration of pheochromocytoma. Catecholamines stimulate glycogenolysis and gluconeogenesis, and they also inhibit insulin secretion, producing a glucose intolerance that resolves after tumor resection.

Finally, remember that the "Rule of 10s" is now considered significantly outdated for the hereditary component. When a vignette mentions a young patient, bilateral adrenal tumors, or a family history of medullary thyroid carcinoma, renal cell carcinoma, or neurofibromas, the question is asking you to recognize a hereditary pheochromocytoma syndrome and to recommend genetic testing. SDHB mutations carry the highest malignancy risk among all hereditary causes, and this is increasingly tested.

The core competency being assessed in pheochromocytoma questions is the ability to recognize a pattern of episodic sympathetic activation, correctly sequence the biochemical workup before imaging, and safely prepare the patient for surgery by following the strict pharmacologic sequence of alpha-blockade first.