Residency · Residency · Endocrinology

Pheochromocytoma and Paraganglioma

Overview

Definitions

Pheochromocytoma (PHEO) is a catecholamine-producing tumor arising from the chromaffin cells of the adrenal medulla, accounting for 80-85% of all catecholamine-secreting tumors. Paraganglioma (PGL) refers to catecholamine-producing or non-functional tumors arising from extra-adrenal paraganglia, which are distributed along the sympathetic and parasympathetic nervous systems. Sympathetic paragangliomas, found in abdominal (with the organ of Zuckerkandl being the most common location), pelvic, and thoracic sites, are usually functional and secrete catecholamines. Parasympathetic paragangliomas, located in the head and neck region including the carotid body, jugulotympanic region, and vagal nerve, are usually non-functional and do not secrete catecholamines. These tumors are collectively referred to as PPGL (pheochromocytoma and paraganglioma) in contemporary literature.

Epidemiology

The incidence of PPGL is estimated at 2-8 per million per year, and these tumors are found in 0.1-0.6% of hypertensive patients. Peak incidence occurs between 40 and 50 years of age, with generally equal sex distribution, though SDH-related paragangliomas show a male predominance. The historical "10% rules" that once defined this disease have been rendered obsolete by modern genetic and clinical data. It is now recognized that approximately 40% of patients carry germline mutations rather than the previously cited 10%. Malignancy rates are 10-17%, bilateral disease occurs in roughly 10% overall (though much higher in MEN2 and VHL), and 15-20% of tumors are extra-adrenal. Hereditary syndromes are now recognized in up to 40% of cases, and genetic testing is recommended for all PPGL patients.

Genetics

The genetic landscape of PPGL is among the most complex of any tumor type, with three major molecular clusters identified.

Cluster 1, the pseudohypoxia pathway, includes mutations in SDHx, VHL, FH, PHD/EGLN, and HIF2A genes. These tumors are associated with extra-adrenal location, higher malignancy risk, and predominant norepinephrine or dopamine secretion. SDHB mutations carry the highest malignancy risk at 30-70%, with tumors typically presenting as extra-adrenal paragangliomas with a poor prognosis. SDHD mutations predominantly cause head and neck paragangliomas transmitted via paternal inheritance, with a lower malignancy risk. SDHA, SDHC, and SDHAF2 mutations are less common and demonstrate variable penetrance. VHL mutations cause bilateral pheochromocytomas in 50% of carriers, are characteristically norepinephrine-predominant, and carry a low malignancy risk. FH (fumarate hydratase) mutations are rare but associated with aggressive PPGLs.

Cluster 2, the kinase signaling pathway, encompasses RET, NF1, MAX, and TMEM127 mutations. These are characteristically associated with adrenal pheochromocytomas and epinephrine secretion. RET mutations (MEN2) produce bilateral pheochromocytomas in 50% of carriers, with epinephrine-predominant secretion and coexisting medullary thyroid carcinoma and hyperparathyroidism. NF1 mutations result in unilateral pheochromocytoma in 1-5% of NF1 patients.

Cluster 3, the Wnt signaling pathway, involves CSDE1 and MAML3 fusions, which are somatic. Some tumors in this cluster are associated with cortisol co-secretion.

Somatic mutations are identified in an additional 25-30% of patients without germline mutations, further emphasizing the genetic complexity of these tumors.

<image>A genetic classification diagram of pheochromocytoma and paraganglioma organized by molecular cluster. Three main clusters arranged as columns. Cluster 1 (Pseudohypoxia - shown in blue): list SDHx (A, B, C, D, AF2), VHL, FH, PHD1/2, HIF2A with associated clinical features (extra-adrenal location, norepinephrine/dopamine secretion, higher malignancy risk especially SDHB). Cluster 2 (Kinase Signaling - shown in green): list RET, NF1, MAX, TMEM127 with features (adrenal location, epinephrine secretion, lower malignancy). Cluster 3 (Wnt - shown in orange): CSDE1, MAML3 with features (cortisol co-secretion). For each gene, include small icons showing typical tumor location (adrenal vs extra-adrenal), predominant catecholamine, and malignancy risk level. Include associated syndromes (MEN2, VHL, NF1, Carney-Stratakis) in callout boxes.</image>

Clinical Presentation

Classic Triad (Present in <25% of Cases)

The classic clinical triad of pheochromocytoma, present in fewer than 25% of patients, consists of severe pounding headache (60-90%), episodic generalized sweating (55-75%), and palpitations or tachycardia (50-70%). Hypertension, either paroxysmal or sustained, is present in 90-95% of patients, and orthostatic hypotension is commonly observed despite the elevated blood pressure readings, resulting from the hypovolemia caused by chronic catecholamine-induced vasoconstriction.

Other Features

Beyond the classic triad, patients may experience anxiety, panic attacks, and a sense of impending doom during catecholamine surges. Tremor and pallor -- importantly not flushing, because catecholamine-induced vasoconstriction causes pallor rather than vasodilation -- are characteristic physical findings. Weight loss from hypermetabolism, hyperglycemia or diabetes from catecholamine-induced insulin resistance and glycogenolysis, and cardiomyopathy (including catecholamine-induced Takotsubo-like cardiomyopathy, dilated cardiomyopathy, or myocarditis) may complicate the presentation. Gastrointestinal symptoms including constipation and abdominal pain can occur. Polycythemia from erythropoietin production is particularly associated with VHL-associated tumors.

Catecholamine Crisis

A catecholamine crisis represents a life-threatening emergency characterized by hypertensive emergency with systolic pressures exceeding 250 mmHg, cardiac arrhythmias, pulmonary edema, stroke, and myocardial infarction. Known triggers include anesthesia, surgical manipulation of the tumor, certain drugs (metoclopramide, glucagon, histamine, tyramine-rich foods, beta-blockers administered without prior alpha-blockade, and opioids), contrast dye, emotional stress, and urination in the specific case of bladder paraganglioma. Such crises can be rapidly fatal and require immediate management with intravenous phentolamine or nicardipine.

Incidental Discovery

In the modern era, incidental discovery has become increasingly common, with up to 50% of PPGLs now identified on cross-sectional imaging performed for unrelated indications. All adrenal incidentalomas greater than 1 cm should be biochemically screened for PPGL, regardless of the clinical presentation.

Diagnosis

Biochemical Testing

Plasma free metanephrines, measuring both metanephrine (derived from epinephrine) and normetanephrine (derived from norepinephrine), represent the preferred initial screening test. With a sensitivity of 96-99% and specificity of 89-97%, this test should be drawn with the patient supine after 20-30 minutes of rest and in a fasting state. Elevated metanephrine specifically points toward adrenal pheochromocytoma and MEN2, while elevated normetanephrine is found in most PPGLs. Measurement of 3-methoxytyramine (derived from dopamine) is important for detecting certain extra-adrenal paragangliomas, particularly those with SDHB mutations, and serves as a marker of metastatic disease.

Twenty-four-hour urine fractionated metanephrines and catecholamines offer a sensitivity of 95-97% and are useful when plasma results are borderline. Urine creatinine must be checked to confirm adequacy of the collection. Chromogranin A is elevated in 80-90% of cases but is also elevated in renal failure, PPI use, and neuroendocrine tumors, limiting its specificity.

Interpreting Results

Values exceeding 2-3 times the upper limit of normal are virtually diagnostic, with a positive predictive value exceeding 99%, and imaging should be pursued immediately. Values between 1 and 2 times the upper limit of normal require careful evaluation for false positives, repeat testing, and potentially a clonidine suppression test. Common causes of false-positive metanephrines include sympathomimetics, tricyclic antidepressants, SNRIs (particularly venlafaxine and duloxetine), MAOIs, levodopa, acetaminophen (which interferes with some assays), caffeine, obstructive sleep apnea, acute illness or stress, withdrawal states, and cocaine.

The clonidine suppression test involves drawing plasma catecholamines before and 3 hours after oral clonidine 0.3 mg. Normal suppression is defined as norepinephrine falling more than 50% or below 500 pg/mL. Failure to suppress suggests the presence of a PPGL.

Imaging

Biochemical confirmation must precede imaging to avoid unnecessary procedures and the risks associated with imaging an unsuspected, unprepared pheochromocytoma. CT of the abdomen and pelvis with contrast is the initial imaging modality; pheochromocytomas typically measure greater than 10 HU on unenhanced CT (indicating a lipid-poor lesion), demonstrate heterogeneous enhancement, and may show necrosis or hemorrhage in larger tumors. MRI provides superior tissue characterization with the classic "light bulb" T2 hyperintensity (though this is variable) and is useful for surgical planning and detection of extra-adrenal paragangliomas.

For functional imaging and staging, 123I-MIBG scintigraphy offers high specificity (95-100%) with moderate sensitivity (80-90% for pheochromocytoma, 50-75% for paraganglioma) and is useful for confirming the functional nature of an adrenal lesion, detecting multifocal or metastatic disease, and as a prerequisite for 131I-MIBG therapy. However, 68Ga-DOTATATE PET/CT has emerged as the superior functional imaging modality, with sensitivity exceeding 90% for SDHB-related and metastatic PPGL, and is now considered first-line functional imaging at many centers. 18F-FDG PET/CT demonstrates high sensitivity for metastatic and aggressive tumors but is less specific and is useful when DOTATATE imaging is unavailable. 18F-FDOPA PET/CT has particularly high sensitivity for head and neck paragangliomas but is less widely available.

Preoperative Management (Alpha-Blockade)

Alpha-Adrenergic Blockade (Mandatory Before Surgery)

Alpha-adrenergic blockade is absolutely mandatory before surgical resection of a pheochromocytoma and must be initiated at least 10-14 days preoperatively, with some centers preferring 2-4 weeks.

Phenoxybenzamine (Dibenzyline) is a non-selective, irreversible alpha-blocker started at 10 mg twice daily and increased by 10 mg every 2-3 days, with target doses of 20-40 mg two to three times daily. Its long half-life of approximately 24 hours provides sustained alpha-blockade, though side effects include orthostatic hypotension, nasal congestion, reflex tachycardia, and fatigue.

Doxazosin, a selective alpha-1 blocker, is increasingly used as an alternative. It is started at 2 mg daily and titrated to 16-32 mg per day. Its shorter duration of action and fewer side effects compared with phenoxybenzamine have made it popular at many centers. Prazosin and terazosin are alternative selective alpha-1 blockers.

Target blood pressure goals during preoperative preparation include seated BP below 130/80 mmHg while ensuring standing BP does not fall below 90/60, a seated heart rate of 60-70 bpm and standing heart rate of 70-80 bpm, the presence of orthostatic hypotension (which indicates adequate alpha-blockade), and no ST-T wave changes on ECG.

Beta-Blockade (ONLY After Adequate Alpha-Blockade)

Beta-blockers must never be started before alpha-blockade is established, as unopposed alpha-adrenergic stimulation in the absence of beta-mediated vasodilation can precipitate a potentially fatal hypertensive crisis. Beta-blockade is introduced 2-3 days after alpha-blockade has been initiated, typically using propranolol 20-40 mg three times daily or atenolol 25-50 mg daily, with a heart rate target of 60-80 bpm.

Additional Preoperative Measures

Volume expansion through a high-sodium diet combined with 1-2 liters of intravenous saline in the 24 hours before surgery is critical because chronic catecholamine excess causes significant volume contraction, placing the patient at risk for severe intraoperative hypotension following tumor removal if not adequately volume-expanded.

Calcium channel blockers, particularly nicardipine and amlodipine, serve as adjunctive or alternative agents for patients intolerant of alpha-blockers, and intravenous nicardipine is also useful for intraoperative blood pressure management. Metyrosine (alpha-methyl-para-tyrosine) inhibits tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis. Dosed at 250 mg four times daily, it is used for refractory preoperative hypertension, though its side effects of sedation, depression, and extrapyramidal symptoms, along with limited availability, restrict its use.

Intraoperative Management

Intraoperative management requires arterial line and central venous access monitoring. Intravenous phentolamine and nitroprusside must be immediately available for hypertensive crises during tumor manipulation, with intravenous nicardipine infusion increasingly preferred for intraoperative blood pressure control. A short-acting beta-blocker such as esmolol should be available for tachyarrhythmias. Drugs that must be avoided include histamine-releasing agents (atracurium, morphine), indirect sympathomimetics, and metoclopramide. Following tumor resection, hypotension is common and managed with volume resuscitation and, if needed, vasopressors such as norepinephrine or vasopressin, avoiding indirect agents.

<image>A preoperative management timeline for pheochromocytoma surgery. Show a horizontal timeline spanning from diagnosis to surgery day. Week 1-2: Start alpha-blockade (phenoxybenzamine 10 mg BID, titrate up every 2-3 days; or doxazosin starting 2 mg daily). Day 3-5 after alpha start: Add beta-blockade (propranolol 20 mg TID) only after adequate alpha-blockade - include a red warning box "NEVER beta-block before alpha-blockade." Week 2-3: High-sodium diet for volume expansion; optimize blood pressure targets (show target values: seated BP <130/80, standing BP not <90/60, HR 60-70). Day before surgery: IV saline 1-2L for volume loading. Surgery day: show intraoperative setup with arterial line, IV phentolamine/nicardipine available, avoid triggers. Post-surgery: monitor for hypotension and hypoglycemia. Use timeline format with icons and checkboxes.</image>

Surgical Management

Adrenalectomy

Laparoscopic adrenalectomy is the standard approach for tumors smaller than 6-8 cm, offering minimally invasive access with low morbidity. Open adrenalectomy is reserved for large tumors exceeding 6-8 cm, locally invasive tumors, or cases with suspected malignancy. Cortical-sparing (partial) adrenalectomy is an important consideration for bilateral pheochromocytomas in MEN2 or VHL, as it preserves cortical function and avoids the need for lifelong steroid replacement. However, the recurrence risk of 10-15% in the remaining adrenal tissue mandates lifelong catecholamine surveillance. Robotic-assisted adrenalectomy is increasingly used and may offer advantages for large tumors.

Post-Operative Monitoring

Hypotension is common in the first 24-48 hours postoperatively and requires aggressive intravenous fluid resuscitation with vasopressors if needed. Hypoglycemia, resulting from the abrupt cessation of catecholamine-mediated glycogenolysis following tumor removal, is an underappreciated complication; glucose should be monitored every 4-6 hours for 24 hours. Adrenal insufficiency may occur if bilateral adrenalectomy was performed or if cortical-sparing surgery left insufficient reserve, requiring hydrocortisone stress dosing perioperatively. Biochemical follow-up with plasma metanephrines at 2-6 weeks postoperatively confirms successful resection when values normalize.

Malignant PPGL

Defining Malignancy

There are no reliable histological criteria to distinguish benign from malignant PPGL; malignancy is defined exclusively by the presence of metastases, specifically chromaffin tissue found at non-chromaffin sites including bone, liver, lungs, and lymph nodes. The PASS (Pheochromocytoma of the Adrenal Gland Scaled Score) and GAPP (Grading System for Adrenal Pheochromocytoma and Paraganglioma) scoring systems attempt to predict malignant potential but have limited accuracy. The strongest risk factors for malignancy include SDHB mutation (the most powerful predictor, with malignancy rates of 30-70%), extra-adrenal location, large tumor size exceeding 5 cm, and dopamine secretion as indicated by elevated 3-methoxytyramine.

Treatment of Metastatic PPGL

High-specific-activity 131I-MIBG therapy (Azedra) is FDA-approved for MIBG-avid metastatic or recurrent PPGL. It achieves an objective response rate of approximately 25% with symptomatic improvement in roughly 70% of patients. Confirmation of tumor uptake on 123I-MIBG scintigraphy is required before treatment, and side effects include myelosuppression and hypothyroidism (necessitating thyroid blockade with potassium iodide).

177Lu-DOTATATE (Lutathera) targets DOTATATE-avid tumors and has emerging evidence supporting its use in metastatic PPGL, currently employed off-label. The CVD chemotherapy regimen (cyclophosphamide, vincristine, dacarbazine) achieves response rates of approximately 35-55% and is used for rapidly progressive disease. Temozolomide, an oral alkylating agent, is particularly effective in SDHB-mutated PPGL with response rates of 33-40%, and MGMT methylation status may predict response. Tyrosine kinase inhibitors including sunitinib and cabozantinib have shown some responses in refractory disease. External beam radiation is useful for symptomatic bone metastases. Belzutifan, an HIF-2alpha inhibitor, is FDA-approved for VHL-associated PPGL and has an emerging role in treatment.

Surveillance

All PPGL patients require lifelong follow-up because delayed recurrence and metastasis may occur decades after initial treatment. Annual plasma metanephrines along with imaging based on the genetic risk profile constitute the surveillance framework. SDHB carriers require annual biochemical screening and imaging every 1-2 years even if no tumor has been identified.

Key Clinical Pearls

• Genetic testing is recommended for ALL patients with PPGL regardless of family history; up to 40% have germline mutations that affect surveillance, family screening, and malignancy risk
• SDHB mutation carriers have the highest risk of malignant PPGL (30-70%); extra-adrenal location and dopamine secretion (elevated 3-methoxytyramine) are additional malignancy risk factors
• Alpha-blockade MUST be initiated at least 10-14 days before surgery and BEFORE beta-blockade; starting a beta-blocker without alpha-blockade can precipitate a fatal hypertensive crisis from unopposed alpha-adrenergic stimulation
• Plasma free metanephrines are the most sensitive screening test (96-99%); a normal result in a symptomatic patient essentially excludes PPGL; mildly elevated results (1-2x ULN) should be carefully evaluated for false positives before proceeding to imaging
• 68Ga-DOTATATE PET/CT has emerged as the superior functional imaging modality for paragangliomas, metastatic disease, and SDHB-related tumors, largely replacing 123I-MIBG for initial staging
• Post-resection hypoglycemia is an underappreciated complication; monitor glucose closely for 24 hours after surgery as catecholamine-driven glycogenolysis ceases abruptly

References

1. Lenders JWM, et al. "Pheochromocytoma and Paraganglioma: An Endocrine Society Clinical Practice Guideline." J Clin Endocrinol Metab. 2014;99(6):1915-1942.
2. Neumann HPH, et al. "Pheochromocytoma and Paraganglioma." N Engl J Med. 2019;381(6):552-565.
3. Patel D, et al. "Update on Pheochromocytoma and Paraganglioma from the SSO Endocrine and Head and Neck Disease Site Working Group." Ann Surg Oncol. 2020;27(5):1548-1555.
4. Nolting S, et al. "Personalized Management of Pheochromocytoma and Paraganglioma." Endocr Rev. 2022;43(2):199-239.
5. Jimenez C, et al. "Current and Future Treatments for Malignant Pheochromocytoma and Sympathetic Paraganglioma." Curr Oncol Rep. 2013;15(4):356-371.

Read this lecture as Markdown