Diagnosis is Pheochromocytoma.
1. Definition
Pheochromocytoma is a neuroendocrine tumor arising from chromaffin cells of the adrenal medulla, usually producing catecholamines.
Related tumors arising from extra-adrenal sympathetic or parasympathetic paraganglia are called paragangliomas.
2. Etiology and Genetics
1. Many cases are apparently sporadic.
2. Approximately 20 to 40% of pheochromocytomas and paragangliomas (PPGLs) are associated with germline pathogenic variants.
3. Important hereditary associations include:
o Multiple endocrine neoplasia type 2 (MEN2) due to RET variants
o Von Hippel-Lindau syndrome (VHL)
o Neurofibromatosis type 1 (NF1)
o Hereditary paraganglioma syndromes due to SDHx variants
o Less commonly, variants involving genes such as MAX and TMEM127
4. Because PPGLs have substantial heritability, genetic counseling and germline testing should be considered for all patients.
3. Pathophysiology
1. Tumors may produce excessive norepinephrine, epinephrine, and occasionally dopamine.
2. Catecholamine excess causes:
o Alpha-adrenergic vasoconstriction, producing hypertension
o Beta-adrenergic stimulation, contributing to tachycardia and palpitations
3. Catecholamines are metabolized to metanephrine and normetanephrine.
4. Metanephrines are produced continuously within the tumor and are therefore more reliable biochemical markers than episodically secreted catecholamines.
4. Clinical Features
4.1 Classic Presentation
1. Paroxysmal or sustained hypertension
2. Classic triad:
o Headache
o Diaphoresis
o Palpitations
Hypertension may be sustained, episodic, or occasionally absent.
4.2 Other Features
1. Tachycardia
2. Tremor
3. Anxiety or panic-like symptoms
4. Pallor
5. Weight loss
6. Hyperglycemia
7. Orthostatic hypotension
4.3 Potential Triggers of Catecholamine Release
Episodes or hypertensive crises may be precipitated by:
1. Emotional or physical stress
2. Surgery or anesthesia
3. Tumor manipulation
4. Certain medications, including:
o Tricyclic antidepressants
o Monoamine oxidase inhibitors
o Sympathomimetics
o Metoclopramide and other dopamine antagonists
o Glucocorticoids
5. Pheochromocytoma and Paraganglioma
1. Pheochromocytoma
o Arises from the adrenal medulla
o Represents approximately 80 to 85% of PPGLs
o Usually produces catecholamines
2. Paraganglioma
o Arises from extra-adrenal paraganglia
o Sympathetic paragangliomas, usually in the thorax, abdomen, or pelvis, are often catecholamine-producing.
o Parasympathetic head and neck paragangliomas are often nonsecretory.
6. Diagnosis
6.1 Biochemical Testing
Recommended first-line biochemical tests are:
1. Plasma free metanephrines
2. 24-hour urinary fractionated metanephrines
Important principles:
1. Both tests have high diagnostic sensitivity and are appropriate first-line tests.
2. Plasma free metanephrines are particularly sensitive when collected under standardized conditions.
3. For plasma testing, the patient should ideally rest supine for approximately 20 to 30 minutes before blood sampling to reduce false-positive results.
4. Metanephrines are preferred over direct catecholamine measurement because their production is more continuous.
5. Markedly elevated metanephrine concentrations strongly support the diagnosis in the appropriate clinical setting.
6.2 Anatomical Imaging
After biochemical evidence of PPGL:
1. CT of the abdomen and pelvis is commonly used for initial tumor localization.
2. MRI is useful when radiation exposure should be minimized and in selected patients with extra-adrenal, head and neck, or metastatic disease.
6.3 Functional Imaging
Functional imaging is not required in every patient. It is selected according to:
1. Tumor location
2. Genotype
3. Suspected multifocal disease
4. Recurrent disease
5. Suspected or confirmed metastatic disease
6. Whether radionuclide therapy is being considered
Options include:
1. Somatostatin receptor PET/CT, such as 68Ga-DOTATATE PET/CT
2. 123I-MIBG scintigraphy
3. 18F-FDG PET/CT in selected patients
6.4 Biopsy
Percutaneous biopsy of a suspected pheochromocytoma should not be performed until PPGL has been biochemically excluded, because tumor manipulation may provoke severe catecholamine release and a potentially life-threatening hypertensive crisis.
7. Management
7.1 Preoperative Preparation
Patients with a catecholamine-secreting PPGL generally require preoperative adrenergic blockade.
1. Alpha-adrenergic blockade is initiated first.
o Phenoxybenzamine
o Selective alpha-1 blockers such as doxazosin
2. Alpha blockade is usually established for approximately 7 to 14 days before surgery, with treatment individualized according to blood pressure and symptoms.
3. High sodium intake and adequate fluid intake, if not contraindicated, are commonly used after alpha blockade to correct catecholamine-associated volume contraction and reduce postoperative hypotension.
4. Beta blockers may be added only after adequate alpha blockade when clinically significant tachycardia persists.
5. Starting a beta blocker before alpha blockade can cause unopposed alpha-adrenergic vasoconstriction and severe hypertension.
7.2 Definitive Treatment
1. Surgical resection is the definitive treatment for most localized pheochromocytomas.
2. Minimally invasive adrenalectomy is preferred for most localized adrenal pheochromocytomas when oncologically appropriate.
3. Open surgery may be required for large, invasive, or otherwise surgically complex tumors.
8. Complications
Catecholamine excess can cause:
1. Hypertensive crisis
2. Cardiac arrhythmias
3. Acute coronary syndrome or myocardial injury
4. Stroke
5. Catecholamine-induced cardiomyopathy
6. Acute heart failure
7. Multiorgan dysfunction in severe pheochromocytoma crisis
9. Follow-Up
1. In functioning PPGLs, plasma free or urinary fractionated metanephrines should be measured approximately 2 to 6 weeks after recovery from surgery to confirm biochemical remission.
2. Annual biochemical surveillance is generally recommended after resection.
3. All patients should undergo follow-up for at least 10 years because recurrent or metastatic disease may occur after apparently successful surgery.
4. Lifelong annual surveillance is recommended for higher-risk patients, including those with:
o Hereditary disease
o Paraganglioma
o Large tumors
o Younger age at diagnosis
o Multifocal or recurrent disease
o Other features associated with increased metastatic risk
10. Key Clinical Insight
Episodic headache + diaphoresis + palpitations + hypertension + elevated plasma free or urinary fractionated metanephrines + adrenal mass = pheochromocytoma.
In this patient, the classic catecholamine-associated triad, paroxysmal symptoms, hypertension, elevated urinary fractionated metanephrines, and adrenal mass strongly establish the diagnosis of pheochromocytoma.
References
1. Tanabe A, Katabami T, Hashimoto S, et al. Japan Endocrine Society Clinical Practice Guideline for the Diagnosis and Management of Pheochromocytoma and Paraganglioma 2025. Endocr J. 2026;73(1):115-157. doi:10.1507/endocrj.EJ25-0165.
2. Lenders JWM, Kerstens MN, Amar L, et al. Genetics, diagnosis, management and future directions of research of phaeochromocytoma and paraganglioma: a position statement and consensus of the Working Group on Endocrine Hypertension of the European Society of Hypertension. J Hypertens. 2020;38(8):1443-1456. doi:10.1097/HJH.0000000000002438.
3. Plouin PF, Amar L, Dekkers OM, et al. European Society of Endocrinology Clinical Practice Guideline for long-term follow-up of patients operated on for a phaeochromocytoma or a paraganglioma. Eur J Endocrinol. 2016;174(5):G1-G10. doi:10.1530/EJE-16-0033.
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