Pheochromocytoma and Paraganglioma: How Doctors Find Them, Genetic Testing Every Patient Needs, and Why Treatment Timing Matters

Research-informed explainer — last updated April 12, 2026

Pheochromocytomas and paragangliomas are rare hormone-secreting tumors that can cause life-threatening hypertensive crises if unrecognized — and up to 40% are linked to inherited gene mutations, making genetic testing essential for every patient diagnosed. Knowing how these tumors are found, what tests confirm them, and why surgery must be carefully prepared will help patients navigate a diagnosis that can be alarming but is highly treatable when caught in time.

This article is informed by William Young, MD, Tyson Family Endocrinology Clinical Professor and Chair of Endocrinology at Mayo Clinic in Rochester, Minnesota, who led the Endocrine Society's foundational clinical practice guideline for pheochromocytoma and paraganglioma (2,701 citations) and authored the landmark NEJM review on the incidentally discovered adrenal mass (1,092 citations) and a 2019 NEJM review (675 citations); Richard Auchus, MD, at the University of Michigan Medical Center, co-author of the Cancer Cell comprehensive molecular characterization of these tumors (762 citations); Mouhammed Habra, MD, Professor and Chief of Endocrine Neoplasia at MD Anderson Cancer Center, whose work covers current and future treatments for malignant disease (176 citations) and a phase II pembrolizumab trial (67 citations); Tobias Else, MD, at the University of Michigan, who published on somatic ATRX mutations in pheo/para (184 citations); and Beverly Biller, MD, Professor of Medicine at Harvard Medical School and Massachusetts General Hospital, whose adrenal biochemistry expertise underpins the differential diagnosis framework.

What are these tumors and where do they appear?

Pheochromocytomas arise from the adrenal medulla — the inner portion of the adrenal gland. Paragangliomas arise from similar chromaffin cells located outside the adrenal gland, anywhere from the skull base to the pelvis. Together they are called PPGLs. Both tumor types can secrete catecholamines — epinephrine, norepinephrine, and dopamine — producing surges that raise blood pressure to dangerous levels. Annual incidence is approximately 2–8 per million people.

The classic symptoms — and why they are missed

The triad of pounding headache, sweating, and heart palpitations occurring in episodes is classic, but fewer than half of patients have this complete picture. Many present with resistant hypertension, incidentally discovered adrenal masses on imaging done for unrelated reasons, or even with no symptoms at all. The NEJM 2019 review (675 citations) emphasizes that symptoms are "protean and common, but the tumors are rare" — making the diagnosis easy to miss without a high index of suspicion.

How diagnosis is confirmed biochemically

The Endocrine Society guideline recommends measuring plasma free metanephrines or 24-hour urinary fractionated metanephrines as the initial biochemical test. The Mayo Clinic comparison study (502 citations) found plasma fractionated metanephrines achieved 97% sensitivity for pheochromocytoma, compared with 90% for combined urinary metanephrines and catecholamines. The tradeoff is specificity: plasma testing had 85% specificity versus 98% for urinary testing. Many centers now use plasma testing as the first step given its superior sensitivity, with confirmatory urinary testing when results are borderline.

Several medications — tricyclic antidepressants, acetaminophen, and some decongestants — can cause false-positive results. Patients should discuss all current medications with their endocrinologist before testing.

Imaging: CT first, then functional scans

Once biochemistry is positive, CT of the abdomen and pelvis is recommended as the initial imaging modality. MRI is preferred when radiation exposure needs to be minimized or when metastatic disease is suspected. For metastatic disease, ¹²³I-MIBG scintigraphy or FDG-PET can identify sites of spread that CT misses.

The genetic testing every patient needs

The comprehensive molecular characterization published in Cancer Cell (762 citations), in which Dr. Auchus was a co-author, demonstrated that 35–40% of PPGL patients carry germline mutations in one of more than 15 identified susceptibility genes. Historically, genetic testing was reserved for young patients or those with family history. Current Endocrine Society guidelines now recommend germline genetic testing for all patients regardless of age or family history.

The most critical genes to test include:

• SDHx genes (SDHA, SDHB, SDHC, SDHD): associated with extra-adrenal paraganglioma and higher malignancy risk
• SDHB: particularly linked to metastatic disease; negative prognosis
• VHL, RET, NF1, TMEM127, MAX: each carrying distinct risk profiles for associated syndromes

Knowing a patient's germline status guides surveillance of other tumors (e.g., clear-cell renal cell carcinoma in VHL), informs family member testing, and shapes surgical decision-making. Dr. Else's work on somatic ATRX mutations (184 citations) showed that ATRX loss predicts a telomere-lengthening phenotype associated with metastatic potential, adding another layer to risk stratification.

Pre-operative preparation: the most critical step

Surgery is the definitive treatment, but uncontrolled catecholamine release during anesthesia or tumor manipulation can provoke hypertensive crisis, stroke, or cardiac arrhythmia. Alpha-adrenergic blockade — typically phenoxybenzamine or a selective alpha-1 blocker — must be started 10–14 days before surgery, followed by beta-blockade only after adequate alpha-blockade is established. Liberal salt and fluid intake helps restore volume. This preparation is not optional; surgery performed without it carries significant mortality risk.

Malignant disease: a changing landscape

Roughly 10–17% of pheochromocytomas and 25–30% of paragangliomas are metastatic. The SDHB mutation is the strongest predictor. Dr. Habra's work at MD Anderson outlined existing options including ¹³¹I-MIBG therapy, chemotherapy with cyclophosphamide-vincristine-dacarbazine (CVD), and everolimus — and a phase II trial of pembrolizumab (67 citations) showed partial responses in some patients with progressive metastatic disease, suggesting a role for immunotherapy in selected cases.

Questions to ask your doctor

• Should I have plasma free metanephrines or 24-hour urinary fractionated metanephrines tested first, and does my current medication list affect the result?
• What imaging will be used to locate the tumor, and is functional scanning needed in my case?
• Will I undergo germline genetic testing, and what genes will be included in the panel?
• How long do I need to take alpha-blockers before surgery, and what should I expect from that medication?
• Is my tumor at any risk of being malignant based on its location, size, or genetic results?
• If a family member needs to be tested, which specialist should they see?

The bottom line

Pheochromocytoma and paraganglioma are rare but recognizable tumors whose surgical cure depends on biochemical confirmation, careful imaging, and mandatory pre-operative alpha-blockade. Because up to 40% of cases have a hereditary basis, comprehensive germline genetic testing is now standard for every patient — not just those with a family history. Timely diagnosis and proper surgical preparation are the two factors that most reliably prevent a life-threatening crisis.