Residency · Residency · General Surgery

Pheochromocytoma and Paraganglioma

Overview

Pheochromocytoma is a catecholamine-producing tumor arising from chromaffin cells of the adrenal medulla. Paraganglioma is an extra-adrenal catecholamine-producing tumor arising from sympathetic or parasympathetic paraganglia. The historical "rule of 10s" has been updated with current understanding: approximately 35% are hereditary, 10% are bilateral, 10% are extra-adrenal, and 10% are malignant. These tumors can cause life-threatening hypertensive crisis if unrecognized perioperatively.

Clinical Presentation

The classic triad consists of episodic headache, diaphoresis, and palpitations. Hypertension may be sustained or paroxysmal and can be severe and refractory to standard antihypertensives. Other symptoms include anxiety, pallor, tremor, weight loss, and hyperglycemia. Precipitants of crisis include anesthesia, surgery, medications (metoclopramide, opioids, tricyclic antidepressants, glucocorticoids), physical stress, and tyramine-rich foods. Some patients present as an incidentaloma on imaging.

Biochemical Diagnosis

Plasma Free Metanephrines

Plasma free metanephrines are the test of choice, with sensitivity exceeding 96% and specificity of approximately 85-89%. The test measures metanephrine (derived from epinephrine) and normetanephrine (derived from norepinephrine). Blood should be drawn with the patient supine for 30 minutes to reduce false positives. Elevation greater than 3 times the upper limit of normal is virtually diagnostic.

24-Hour Urine

A 24-hour urine collection for fractionated metanephrines and catecholamines has a sensitivity of 90-95% and is useful as a confirmatory test. Creatinine should be included to confirm adequate collection.

False Positives

Medications that can cause false positives include acetaminophen, tricyclic antidepressants, MAO inhibitors, decongestants, and labetalol (which interferes with some assays). Physiologic stress, obstructive sleep apnea, and acute illness can also elevate levels. For mildly elevated values (1.5-3 times the upper limit of normal), repeat testing or a clonidine suppression test should be considered.

Clonidine Suppression Test

The clonidine suppression test is used for borderline plasma normetanephrine elevations. Clonidine 0.3 mg is given orally, and plasma catecholamines are measured at 3 hours. A normal response shows suppression of normetanephrine and norepinephrine to normal levels. Failure to suppress confirms autonomous catecholamine secretion.

<image>Biochemical diagnostic algorithm for pheochromocytoma showing initial screening with plasma free metanephrines, confirmatory testing, and clonidine suppression test for borderline results</image>

Imaging

CT Abdomen/Pelvis

CT is the first-line imaging study after biochemical confirmation. Pheochromocytomas are typically larger than 3 cm, heterogeneous, with attenuation greater than 10 HU on unenhanced CT, and may have necrosis or hemorrhage. Sensitivity exceeds 90% for adrenal tumors.

MRI

On T2-weighted imaging, pheochromocytomas classically appear "light bulb bright" with high T2 signal, though this finding is variable. MRI is useful for paragangliomas, especially in head, neck, and pelvic locations, and is safe for pregnant patients as it avoids radiation. On chemical shift MRI, pheochromocytoma does not lose signal on out-of-phase images, which distinguishes it from a lipid-rich adenoma.

Functional Imaging

123I-MIBG scintigraphy is specific for catecholamine-producing tumors and is useful for extra-adrenal, recurrent, or metastatic disease. 68Ga-DOTATATE PET/CT has high sensitivity for paragangliomas, especially SDH-mutated tumors, and is increasingly used as first-line functional imaging. 18F-FDG PET/CT is useful for metastatic disease and SDH-mutated paragangliomas. 18F-FDOPA PET/CT has high sensitivity but limited availability.

Genetic Syndromes

Hereditary Syndromes (~35-40% of pheo/para)

MEN2A is caused by a RET mutation and includes medullary thyroid cancer, pheochromocytoma (50%), and primary hyperparathyroidism. MEN2B involves a RET mutation with MTC, pheochromocytoma, mucosal neuromas, and marfanoid habitus. Von Hippel-Lindau disease is caused by a VHL mutation and features pheochromocytoma/paraganglioma, renal cell carcinoma, hemangioblastomas, and pancreatic neuroendocrine tumors. SDH mutations (SDHx) cause paraganglioma-pheochromocytoma syndromes: SDHB carries the highest malignancy risk at 30-40%, SDHD is associated with head and neck paragangliomas (carotid body tumors), and SDHA, SDHC, and SDHAF2 are less common. NF1 (neurofibromatosis type 1) is associated with pheochromocytoma in 0.1-5.7%. MAX, TMEM127, and FH are rare predisposition genes.

Genetic Testing

Genetic testing is recommended for all patients with pheochromocytoma or paraganglioma. Testing should be prioritized based on clinical features: bilateral pheochromocytoma suggests MEN2 or VHL, extra-adrenal or paraganglioma location suggests SDHx mutations, malignant disease suggests SDHB, and young age raises suspicion for any hereditary syndrome.

<image>Diagram showing the major hereditary syndromes associated with pheochromocytoma and paraganglioma including MEN2, VHL, and SDHx mutations with their characteristic clinical features</image>

Preoperative Management

Alpha-Adrenergic Blockade

Alpha-adrenergic blockade is mandatory before surgery, initiated a minimum of 10-14 days preoperatively. Goals are blood pressure below 130/80 mmHg seated, systolic blood pressure above 90 mmHg standing, and heart rate 60-70 bpm seated. Phenoxybenzamine is a non-selective, irreversible alpha-blocker started at 10 mg twice daily and titrated up to 20-40 mg two to three times daily. Side effects include orthostatic hypotension, nasal congestion, and reflex tachycardia, and its long duration of action may contribute to postoperative hypotension. Selective alpha-1 blockers (doxazosin, prazosin, terazosin) are shorter acting and may cause less postoperative hypotension, with growing evidence from systematic reviews supporting equal efficacy. Doxazosin is typically started at 2 mg daily and titrated to 8-16 mg daily.

Beta-Blockade

Beta-blockade is added only after adequate alpha-blockade is established, as beta-blockers alone cause unopposed alpha-stimulation and worsen hypertension. It is indicated for tachycardia or arrhythmias, with propranolol, atenolol, or metoprolol as options.

Volume Expansion

A high-salt diet and liberal fluid intake during the alpha-blockade period are recommended because chronic vasoconstriction leads to contracted intravascular volume. Volume expansion reduces the risk of postoperative hypotension.

Calcium Channel Blockers

Nicardipine or amlodipine can be used as adjuncts or alternatives, and are useful for patients who cannot tolerate alpha-blockers. Some centers use calcium channel blockers as the primary preoperative agent.

Metyrosine (alpha-methyltyrosine)

Metyrosine inhibits catecholamine synthesis by blocking tyrosine hydroxylase. It is reserved for refractory hypertension or very large tumors. Side effects include sedation, depression, and crystalluria.

Surgical Management

Laparoscopic Adrenalectomy

Laparoscopic adrenalectomy is the standard approach for pheochromocytoma smaller than 6-8 cm without local invasion. Either a lateral transabdominal or posterior retroperitoneoscopic approach may be used. Tumor manipulation should be minimized as it stimulates catecholamine release. Early ligation of the adrenal vein reduces catecholamine surges during manipulation. Insufflation pressure may compress the IVC and reduce venous return, requiring communication with the anesthesia team.

Open Adrenalectomy

Open adrenalectomy is indicated for large tumors (greater than 8-10 cm), suspected malignancy, local invasion, or IVC involvement. A midline or subcostal approach is used. En bloc resection is performed if the tumor is locally invasive.

Intraoperative Management

Invasive arterial monitoring via an arterial line and central venous access are required. Short-acting antihypertensives must be available: phentolamine (alpha-blocker) for IV bolus during hypertensive surges, nitroprusside or nicardipine as IV infusions for sustained hypertension, esmolol for tachyarrhythmias, and magnesium sulfate as an antiarrhythmic and vasodilator. Histamine-releasing agents, indirect-acting sympathomimetics, and metoclopramide must be avoided. After tumor removal, hypotension is expected due to loss of the catecholamine surge combined with chronic volume depletion, and treatment involves volume resuscitation with crystalloid or colloid and vasopressor support (norepinephrine, phenylephrine) if needed. Hypoglycemia from rebound hyperinsulinism after catecholamine removal requires close glucose monitoring.

Bilateral Pheochromocytoma

Bilateral pheochromocytoma is associated with hereditary syndromes, particularly MEN2 and VHL. Cortical-sparing adrenalectomy preserves the adrenal cortex to avoid lifelong steroid dependence but carries a recurrence risk of 10-15% in the remnant and requires close biochemical surveillance. Total bilateral adrenalectomy is performed when cortical-sparing is not feasible and necessitates lifelong glucocorticoid and mineralocorticoid replacement.

<image>Intraoperative monitoring setup for pheochromocytoma surgery showing arterial line tracing with hemodynamic fluctuations during tumor manipulation and stabilization after adrenal vein ligation</image>

Paraganglioma Surgery

Paraganglioma surgery is location-dependent and may involve retroperitoneal, pelvic, head/neck, or bladder tumors. Head and neck paragangliomas, including carotid body tumors, are often non-functional (parasympathetic). They are classified by the Shamblin system: type I is localized, type II partially encases vessels, and type III encases the carotid artery. Surgical excision requires careful vascular control, and preoperative embolization may reduce bleeding. Bladder paraganglioma is treated with partial cystectomy and may cause hypertensive crisis during micturition. Functional paragangliomas require the same preoperative alpha-blockade as pheochromocytoma.

Malignant Pheochromocytoma/Paraganglioma

There are no reliable histologic criteria for distinguishing benign from malignant pheochromocytoma on pathology. Malignancy is defined by the presence of metastases in distant chromaffin-negative sites, including bone, liver, lung, and lymph nodes. Risk factors for malignancy include SDHB mutation, large tumor size, and extra-adrenal location. The PASS score (Pheochromocytoma of the Adrenal Gland Scaled Score) of 4 or greater suggests malignant potential, though it is not universally adopted. Treatment includes surgical debulking, 131I-MIBG therapy, chemotherapy (CVD regimen: cyclophosphamide, vincristine, dacarbazine), targeted therapy (sunitinib), and peptide receptor radionuclide therapy (177Lu-DOTATATE for somatostatin receptor-positive tumors).

Postoperative Follow-Up

Plasma or urine metanephrines should be checked at 2-4 weeks postoperatively to confirm biochemical cure. If normal, annual biochemical screening should continue for at least 10 years, and lifelong for hereditary syndromes. Genetic counseling and testing should be provided for all patients and at-risk family members. Screening for associated tumors in hereditary syndromes, such as MTC in MEN2 and renal cell carcinoma in VHL, is essential.

Clinical Pearls

A patient with a suspected pheochromocytoma must never be operated on, biopsied, or anesthetized without adequate alpha-blockade, as the consequences can be fatal. Beta-blockade must always be added after alpha-blockade, never before, because beta-blockers alone cause unopposed alpha-stimulation and worsen hypertension. Genetic testing is recommended for all patients with pheochromocytoma or paraganglioma, as up to 40% harbor germline mutations. SDHB mutation carries the highest malignancy risk, and these patients need lifelong surveillance. After tumor removal, hypotension and hypoglycemia should be anticipated, and aggressive volume resuscitation and glucose monitoring are essential. Cortical-sparing adrenalectomy for bilateral pheochromocytoma in MEN2 and VHL avoids lifelong steroid dependence but requires close surveillance for recurrence. The diagnosis of malignant pheochromocytoma can only be made by demonstrating metastatic disease, not by histologic features.

References

• Lenders JW, et al. Pheochromocytoma and paraganglioma: An Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab. 2014;99(6):1915-1942.
• Pacak K, et al. Pheochromocytoma: Recommendations for clinical practice from the First International Symposium. Nat Clin Pract Endocrinol Metab. 2007;3(2):92-102.
• Neumann HPH, et al. Pheochromocytoma and paraganglioma. N Engl J Med. 2019;381(6):552-565.
• Buitenwerf E, et al. Efficacy of alpha-blockers on hemodynamic control during pheochromocytoma resection: A randomized controlled trial. J Clin Endocrinol Metab. 2020;105(7):e2381-e2391.
• Fishbein L, et al. Comprehensive molecular characterization of pheochromocytoma and paraganglioma. Cancer Cell. 2017;31(2):181-193.

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