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Pheochromocytoma - Comprehensive PG Medicine Notes

Definition & Overview

1. Can cause fatal hypertensive crises despite standard treatment

2. 10% are malignant at diagnosis

3. Specific therapy is curative
4. 40% are familial - affects family members

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The Classic "Rule of 10s" (Robbins)

Note: The classic "10% rule" now applies mainly to sporadic cases. Familial disease has much higher rates of bilaterality and malignancy. - Robbins & Kumar Basic Pathology

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Anatomy & Location

• ~90% in or adjacent to the adrenal medulla
• Extra-adrenal sites: organ of Zuckerkandl (at aortic bifurcation or origin of inferior mesenteric artery), carotid body, urinary bladder, thorax
• Bladder paraganglioma causes classic micturition headache and syncope (episodic symptoms triggered by urination + painless hematuria)
• Campbell Walsh Wein Urology - Most extra-adrenal tumors are in or near the organ of Zuckerkandl

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Genetics and Familial Syndromes

Key Syndromes

• Café-au-lait spots + neurofibromas → NF1
• Retinal hemangiomas → VHL
• Marfanoid habitus + submucosal neuromas → MEN2B
• Port wine stains, subungual fibromas, ash-leaf patches, adenoma sebaceum → Tuberous sclerosis

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Pathogenesis

1. RET, NF1 - enhance growth factor receptor signaling
2. VHL, SDH subunits, EPAS1/HIF2A - increased activity of hypoxia-inducible factors (HIFs)

• Robbins & Kumar Basic Pathology

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Morphology (Pathology - Robbins)

• Range from small circumscribed lesions to large hemorrhagic masses (several kg)
• Cut surface: yellow-tan, well-defined; compress adjacent adrenal gland
• Larger lesions: hemorrhagic, necrotic, cystic
• Chromaffin reaction: fresh tissue turns dark brown with potassium dichromate - reacts with catecholamines

• Polygonal to spindle-shaped chromaffin cells in small nests ("zellballen pattern") separated by rich vascular network
• Cytoplasm: finely granular (catecholamine granules)
• Granules highlighted by silver stains (Grimelius)
• EM: membrane-bound electron-dense granules containing catecholamines

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Clinical Features

Classic Triad (found in ~95% of cases in large series):

1. Headache (pulsating, severe)
2. Sweating (profuse, generalized)
3. Palpitations/Tachycardia

Hypertension Patterns:

• Sustained hypertension - most common
• ~2/3 also have paroxysmal episodes on top of sustained hypertension
• ~10% have purely paroxysmal hypertension
• ~10% are normotensive (often incidentalomas)

Paroxysmal Episodes ("Spells"):

Full Symptom Spectrum (Goldman-Cecil):

Exam trap: Flushing is NOT typical of pheochromocytoma. Flushing occurs in carcinoid, mastocytosis, menopause.

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When to Suspect Pheochromocytoma (Goldman-Cecil Indications):

1. Hyperadrenergic spells (nonexertional palpitations, diaphoresis, headache, tremor, pallor)
2. Resistant hypertension
3. Familial syndrome (MEN2, NF1, VHL) predisposing to PPGL
4. Family history of pheochromocytoma
5. Hypertension + diabetes
6. Pressor response during anesthesia, surgery, or angiography
7. Onset of hypertension before age 20 years
8. Idiopathic dilated cardiomyopathy
9. Incidentally discovered adrenal mass (incidentaloma)

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Biochemical Diagnosis

First-Line Test:

Second-Line / Confirmatory:

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Imaging / Localization

CT Scan (First-Line for Localization):

• Sensitivity 90-100%
• Pheochromocytoma on non-contrast CT: HU >10 (commonly 40-50 HU; unlike benign adenomas which are <10 HU due to lipid content)
• Vigorous early contrast enhancement with <60% washout in venous phase
• Appearance: homogeneous (small) or heterogeneous/necrotic/cystic (large)

MRI (Preferred in Pregnancy, Children, Contrast Allergy):

• Classic finding: Bright (hyperintense) on T2-weighted images - "light bulb sign" - due to high vascularity and water content
• Higher sensitivity than CT for extra-adrenal paragangliomas
• Not affected by radiation (important in pediatrics and pregnancy)

Functional Imaging (for metastatic/recurrent/extra-adrenal):

• ¹²³I-MIBG (meta-iodobenzylguanidine) scintigraphy - MIBG is taken up by chromaffin cells; whole-body scan for metastatic disease. Also used therapeutically with ¹³¹I-MIBG.
• ¹⁸F-FDG-PET - for SDHB-related and malignant disease
• ¹⁸F-DOPA PET - high sensitivity
• ¹⁸F-Fluorodopamine PET - high sensitivity for adrenal lesions

Adrenal Venous Sampling: NOT useful for pheochromocytoma (unlike primary hyperaldosteronism).

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Management

Preoperative Preparation (Critical!)

Beta-blocker alone before alpha-blockade = unopposed alpha-adrenergic stimulation = hypertensive crisis and peripheral ischemia (dangerous)

Step-by-Step:

1. Alpha-blockade x 7-10 days preoperatively
   • Phenoxybenzamine (drug of choice) - irreversible, non-selective alpha-blocker
     • Start 10 mg once or twice daily, increase by 10-20 mg every 2-3 days
     • Final dose: typically 20-100 mg/day
   • Alternatives: selective alpha-1 blockers - doxazosin (start 1 mg at bedtime), prazosin, terazosin
   • Target BP: <120/80 seated; systolic >90 standing
2. High-sodium diet (≥5000 mg/day) from day 2-3 of alpha-blockade - to expand catecholamine-contracted blood volume
3. Beta-blockade - add only after adequate alpha-blockade, only if HR >80 bpm
   • Use propranolol or atenolol
4. Calcium channel blockers - useful adjunct; also as alternative in patients who cannot tolerate alpha-blockers
5. Volume expansion before surgery

Target parameters preoperatively:

• Seated BP <120/80 mmHg
• Standing systolic BP >90 mmHg
• HR 60-80 bpm seated, 70-80 bpm standing
• No ST changes on ECG for 1 week preop
• No more than 1 paroxysm per week

Surgical Treatment: Definitive Cure

• Open adrenalectomy for large (>6 cm), locally invasive, or suspected malignant tumors
• Partial adrenalectomy possible in familial bilateral cases to preserve adrenal cortical function

• Hypertensive episodes: IV nitroprusside, phentolamine, nitroglycerin, nicardipine (rapid onset, short half-life)
• Tachyarrhythmias: IV labetalol or esmolol
• After tumor removal: aggressive fluid resuscitation (sudden loss of vasomotor tone → hypotension)

• Monitor for hypotension - use phenylephrine + aggressive fluids
• Correct electrolyte abnormalities and hypoglycemia
• Some patients remain hypertensive postoperatively (essential or renovascular HTN)
• Persistent hypoglycemia can occur (rebound hyperinsulinism)

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Malignant Pheochromocytoma

• Defined by presence of metastases, not histology
• Metastatic sites: lymph nodes, liver, lung, bone
• More common in extra-adrenal tumors (up to 20%), SDHB mutations (high risk)
• Treatment options for malignant/metastatic disease:
  • ¹³¹I-MIBG therapy (if MIBG-avid tumor)
  • Chemotherapy: CVD regimen (cyclophosphamide + vincristine + dacarbazine)
  • Sunitinib (tyrosine kinase inhibitor) - recent evidence
  • External beam radiotherapy (for bone metastases)
  • Stereotactic radiosurgery for paragangliomas

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Differential Diagnosis

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Follow-Up

• Lifelong annual biochemical follow-up (even after apparently complete resection)
• Biochemistry (plasma/urine metanephrines) 2-6 weeks postoperatively as baseline, then annually
• Recurrence rate: ~10% after 5 years; up to 17% at 10 years
• Genetic counseling and cascade testing of first-degree relatives

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High-Yield Exam Points Summary

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Recent evidence note: A 2025 meta-analysis (PMID 40214691) on partial adrenalectomy for pheochromocytoma showed favorable surgical outcomes, supporting its use in bilateral/familial cases to preserve cortical function. Core diagnostic and management principles remain consistent with Endocrine Society guidelines.