Diagnosis and Management of Pheochromocytoma

Introduction to Pheochromocytoma Diagnosis

The American Urological Association recommends screening all patients with adrenal incidentalomas displaying >10 HU on non-contrast CT or who have signs/symptoms of catecholamine excess using plasma free metanephrines or 24-hour urinary fractionated metanephrines as the initial biochemical test 1, 2

Screen for pheochromocytoma in patients with early-onset hypertension (<30 years of age) 2
Screen for pheochromocytoma in patients with resistant hypertension (BP >140/90 mmHg despite optimal doses of ≥3 antihypertensive medications including a diuretic), with a prevalence up to 4% in this population 2
Screen for pheochromocytoma in patients with paroxysmal hypertension with classic triad: headache, palpitations, and sweating ("cold sweat"), which has 90% diagnostic specificity when occurring together 2
Screen for pheochromocytoma in patients with significant blood pressure variability or pallor 2
Screen for pheochromocytoma in patients with a family history of pheochromocytoma or associated genetic syndromes (MEN2, VHL, NF1, hereditary paraganglioma syndromes) 2, 3

Measure plasma free metanephrines or 24-hour urinary fractionated metanephrines as the first-line biochemical test, with excellent diagnostic performance 1, 2, 3
Plasma free metanephrines have 96-100% sensitivity and 89-98% specificity 2
Urinary fractionated metanephrines have 86-97% sensitivity and 86-95% specificity 2
If levels are ≥4 times the upper limit of normal, results are consistent with pheochromocytoma/paraganglioma, and proceed immediately to imaging 2, 3

First-line anatomical imaging: CT or MRI of the abdomen and pelvis, with MRI preferred due to risk of hypertensive crisis with IV contrast for CT 2, 3
Include chest CT to evaluate for metastatic disease 3

Consider genetic testing in patients with family history of pheochromocytoma/paraganglioma, young age at diagnosis, bilateral or multifocal disease, or extra-adrenal location (paraganglioma) 3
Approximately 25-33% of patients with pheochromocytoma have germline mutations (NF1, VHL, SDHD, SDHB, RET) 3
SDHB mutations are associated with higher risk of aggressive behavior and metastatic disease, requiring more intensive surveillance 2

Malignancy is defined only by presence of metastatic lesions at sites where chromaffin cells are normally absent, with risk factors including tumor size ≥5 cm, extra-adrenal paraganglioma, SDHB germline mutation, elevated plasma methoxytyramine (>3x upper limit) 2, 3

Alpha-adrenergic blockade is essential before surgery, typically started 7-14 days before surgery 2
Phenoxybenzamine is started with 10 mg twice daily, increased every other day to 20-40 mg 2-3 times daily until optimal blood pressure control 2

Maintain a low threshold for multidisciplinary review by endocrinologists, surgeons, and radiologists when imaging is not consistent with a benign lesion, evidence of hormone hypersecretion exists, tumor has grown significantly during follow-up, or adrenal surgery is being considered 1, 2

123I‑MIBG scintigraphy is sufficient for sporadic, non‑metastatic pheochromocytoma and provides sensitivity comparable to PET imaging (European Association of Nuclear Medicine). [4] [5] 6
18F‑FDOPA PET offers the highest sensitivity (≈ 100 %) for head‑and‑neck paragangliomas (European Association of Nuclear Medicine). [4] [5] 7
In metastatic disease associated with SDHB germline mutations, 18F‑FDG PET demonstrates high lesion‑by‑lesion sensitivity (≈ 83 % in SDHB‑positive patients) (European Association of Nuclear Medicine). [4] [5]
Functional imaging (e.g., 18F‑FDG PET, 18F‑FDOPA PET, or alternative modalities) is recommended for patients with high‑risk features such as MIBG‑negative disease or multifocal tumors (European Association of Nuclear Medicine). [4] [5]

Genetic testing should be offered to patients diagnosed at ≤ 40 years of age (European Society of Endocrinology). 8
SDHB germline mutations confer a 31–71 % risk of malignancy and mandate extended lifelong surveillance (European Society of Endocrinology). 9

Laparoscopic adrenalectomy is the preferred treatment for pheochromocytoma and is usually curative (National Comprehensive Cancer Network). 10
Open adrenalectomy is reserved for lesions suspicious for malignancy—characterized by irregular/inhomogeneous morphology, lipid‑poor appearance, or size > 3 cm with multi‑hormonal secretion (National Comprehensive Cancer Network). 10

Patients with a PASS (Pheochromocytoma of the Adrenal gland Scaled Score) ≥ 4 require intensified follow‑up (European Society of Endocrinology). 8
Tumors ≥ 5 cm in greatest dimension are considered high‑risk and merit closer monitoring (European Society of Endocrology). 8
Carriers of SDHB mutations are classified as high‑risk and should undergo lifelong, more frequent surveillance (European Society of Endocrinology). 8