Pheochromocytoma: Symptoms, Diagnosis, Treatment, and When to Suspect It

What pheochromocytoma and paraganglioma mean

Pheochromocytomas and paragangliomas are often grouped as PPGL. A pheochromocytoma begins in chromaffin cells of the adrenal medulla. A paraganglioma begins in related tissue outside the adrenal gland, including along sympathetic chains in the chest, abdomen, or pelvis and in parasympathetic tissue of the head and neck. Some head-and-neck paragangliomas do not produce clinically important catecholamine excess.

These tumors are not the same as disorders of the adrenal cortex. Addison disease involves inadequate adrenal cortical hormones. Cushing syndrome involves excess cortisol. Primary aldosteronism involves excess aldosterone. A person with an adrenal mass can still require assessment for more than one hormone pattern, but the symptoms and biochemical tests are different. The current European adrenal-incidentaloma guideline uses imaging phenotype and targeted hormone evaluation to determine which lesions need additional workup [3].

PPGLs are important despite being uncommon because uncontrolled catecholamine release can affect the heart, blood vessels, brain, and metabolism. The newer disease model also treats every PPGL as having some potential to metastasize rather than relying on the old idea that a fixed percentage is simply "benign" or "malignant" [4]. Metastatic disease is established by tumor in a site where normal chromaffin tissue is absent, not by one microscopic feature alone.

Symptoms and clinical patterns

The best-known symptom cluster is headache, sweating, and palpitations. Other possible features include tremor, pallor, chest or abdominal discomfort, anxiety-like spells, nausea, weight loss, heat intolerance, or marked changes in blood pressure. Hypertension may be sustained, episodic, or absent at a routine office measurement. Orthostatic symptoms can coexist with hypertension because chronic catecholamine exposure can reduce circulating volume and alter vascular responses.

Symptoms are not diagnostic by themselves. Panic disorder, arrhythmias, migraine, medication effects, obstructive sleep apnea, hyperthyroidism, hypoglycemia, and other conditions can produce overlapping spells. Conversely, an incidentally found tumor or a tumor detected through hereditary surveillance may cause few symptoms. Older diagnostic research found the complete symptom triad more specific than any one symptom but not sensitive enough to rule disease out when absent [14].

Potential triggers include anesthesia, surgery, direct tumor manipulation, major physiologic stress, and some medications. A suspected catecholamine crisis is an emergency, especially when severe hypertension or hypotension occurs with chest pain, shortness of breath, neurological symptoms, altered mental status, or signs of organ injury. It should not be managed through an outpatient dosing checklist.

Who should be evaluated

Testing is considered when the pretest probability is meaningful. Examples include:

• spells compatible with catecholamine excess, especially with blood-pressure elevation;
• an adrenal mass whose imaging features are not clearly benign;
• a prior pheochromocytoma or paraganglioma;
• a pathogenic variant or hereditary syndrome associated with PPGL;
• a close relative with an associated hereditary syndrome;
• otherwise unexplained severe, resistant, episodic, or labile hypertension when the clinical pattern raises suspicion.

An adrenal mass does not automatically mean pheochromocytoma. The 2023 European guideline changed older one-size-fits-all incidentaloma practice: a homogeneous adrenal lesion with unenhanced CT attenuation of 10 Hounsfield units or less has a very low likelihood of pheochromocytoma, while other imaging phenotypes can warrant metanephrine assessment [3]. This distinction matters because unnecessary testing in a very low-risk setting produces false positives, anxiety, and avoidable imaging.

Metanephrine testing

The Endocrine Society recommends plasma free metanephrines or urinary fractionated metanephrines for initial biochemical testing [1]. Metanephrines are useful because tumors produce them continuously, even when catecholamine release and symptoms are episodic. Direct catecholamine measurement alone is generally a less reliable screening strategy.

Collection conditions materially affect interpretation. For plasma testing, the 2023 biochemical review emphasizes appropriate reference intervals and collection after fully supine rest [2]. Acute illness, pain, physical stress, posture, sleep apnea, withdrawal states, and several medications can increase sympathetic activity or interfere with an assay. A clinician and laboratory should review those factors rather than asking a patient to stop prescribed medicine without supervision.

A result above the laboratory range is not automatically a tumor diagnosis. The size and pattern of elevation, clinical probability, collection conditions, renal function, and laboratory method determine the next step. Modest elevations often call for a carefully repeated test after correct preparation and review of interferences. Marked, internally consistent elevations in a high-risk patient may justify proceeding to localization imaging. Clonidine suppression or additional analytes may help selected cases, but neither is a universal second test [2].

Normal results obtained with a sensitive method and correct collection make a catecholamine-producing PPGL unlikely in most clinical settings. Important exceptions include very small tumors, some head-and-neck paragangliomas, dopamine-predominant tumors, and tumors found through hereditary surveillance. Those cases need specialist interpretation rather than a blanket reassurance or automatic scan.

Imaging after biochemical assessment

For most patients with symptoms suggesting a secreting PPGL, anatomic localization starts after clear biochemical evidence [1]. CT provides detailed anatomy and attenuation characteristics. MRI avoids ionizing radiation and can be useful for pregnancy, children, head-and-neck disease, contrast limitations, and selected hereditary surveillance. No single MRI signal or washout value proves or excludes PPGL.

Functional imaging is selected according to tumor location, biochemical phenotype, genetic background, metastatic risk, and the treatment being considered. Options include somatostatin-receptor PET, fluorodopa PET, FDG PET, and MIBG imaging. A systematic review found high lesion detection with gallium-labeled somatostatin-receptor PET, but performance varies by molecular subtype and clinical setting [9]. A modern imaging review therefore recommends phenotype-specific choices rather than declaring one scan best for every patient [8].

Imaging before biochemical confirmation can discover unrelated lesions and complicate interpretation. The exception is when imaging is already required for an emergency or another clinical reason. Any adrenal procedure, including biopsy, should be planned only after a secreting pheochromocytoma has been considered because tumor manipulation can provoke dangerous hemodynamic changes.

Genetics is part of routine PPGL care

PPGL has one of the strongest inherited components among solid tumors. Pathogenic germline variants are found in up to roughly 40% of affected people across cohorts, involving genes such as SDHB, SDHD, VHL, RET, NF1, MAX, TMEM127, FH, and others [5]. Family history alone misses carriers.

Guidelines therefore recommend considering genetic testing for every person with confirmed PPGL [1,10]. This is not merely a label. A result can change the search for multifocal disease, the imaging strategy, recurrence surveillance, the assessment of metastatic risk, and testing offered to relatives. Pretest counseling should cover the difference between a pathogenic variant, a negative panel, and a variant of uncertain significance. A variant of uncertain significance should not be treated as proof of a hereditary syndrome.

Preparing for surgery

Complete surgical resection is the main curative treatment for localized disease. Preparation requires an experienced team because catecholamine release can cause extreme blood-pressure swings during induction, tumor handling, or vessel ligation. The plan may include an alpha-adrenergic blocker, salt and fluid optimization, other blood-pressure medicines, and later heart-rate control. Beta blockade must not be started as unopposed initial therapy in a catecholamine-secreting tumor because it can worsen vasoconstriction.

Exact drug, dose, target, timing, and monitoring depend on secretory phenotype, baseline pressure, orthostatic symptoms, cardiac function, pregnancy, kidney function, and the planned operation. In a randomized multicenter trial, phenoxybenzamine and doxazosin produced similar time outside the prespecified intraoperative blood-pressure range, while phenoxybenzamine improved one hemodynamic-instability score without a demonstrated difference in clinical outcomes [6]. A 2025 expert Delphi process also documented substantial variation among specialist centers, reinforcing that a universal online dosing schedule is inappropriate [7].

The operation may be minimally invasive or open depending on size, location, invasion, metastatic concern, prior operations, and surgeon expertise. Cortical-sparing surgery can be considered in selected hereditary or bilateral cases to preserve adrenal function, but it can leave a higher local recurrence risk. Pathology, postoperative biochemistry, genetics, and the operative findings all inform follow-up.

What happens after surgery

Early monitoring focuses on blood pressure, volume status, glucose, and complications specific to the operation. Biochemical testing after recovery assesses whether excess hormone production has resolved. Persistent elevation can reflect residual disease, metastatic disease, testing too early, or another source of interference and deserves structured reassessment.

Recurrence estimates differ because cohorts contain different genetic risks and follow-up periods. A systematic review estimated about 0.98 new events per 100 person-years after apparently complete surgery, with higher risk associated with syndromic disease and paraganglioma [13]. The European follow-up guideline recommends annual plasma or urinary metanephrines, at least 10 years of follow-up for all operated patients, and lifelong annual follow-up for higher-risk patients such as those who are young or have a hereditary disorder, large tumor, or paraganglioma [10].

Follow-up is not identical for everyone. A nonsecretory tumor may require scheduled imaging because biochemistry cannot reliably reveal recurrence. A pathogenic variant may dictate surveillance of other organs. New symptoms, a rising biochemical marker, or a new family finding can change the plan.

A practical evidence-based pathway

Step 1: establish why PPGL is being considered. Record the symptom pattern, blood-pressure behavior, adrenal imaging phenotype, family history, and prior tumors. This determines pretest probability and prevents indiscriminate testing.

Step 2: obtain the right biochemical test under the right conditions. Use plasma free or urinary fractionated metanephrines. Match plasma collection posture to the laboratory reference interval and document acute illness, stress, and relevant medicines.

Step 3: interpret magnitude and context, not a binary flag. Repeat a modest elevation under improved conditions when appropriate. Escalate a convincing result rather than ordering a broad collection of unselected scans.

Step 4: localize and stage with phenotype-directed imaging. CT or MRI defines anatomy. Functional imaging is chosen for extra-adrenal, multifocal, hereditary, recurrent, or metastatic disease and for radiopharmaceutical treatment planning.

Step 5: involve genetics and an experienced treatment team. Confirmed PPGL should prompt genetic counseling and multidisciplinary planning. Surgery for a secreting tumor requires coordinated endocrine, anesthesia, and surgical preparation.

Step 6: document biochemical status and a long-term surveillance plan. The discharge plan should identify who orders annual testing, whether imaging is scheduled, which findings trigger earlier reassessment, and whether relatives need counseling.

Advanced or metastatic disease

Advanced PPGL is heterogeneous. Some tumors grow slowly and primarily require control of catecholamine effects; others progress and threaten organs. Treatment can include surgery or ablation for selected sites, radionuclide therapy chosen by imaging uptake, systemic therapy, or observation with structured surveillance. Decisions belong in a center familiar with PPGL because genotype, pace, symptoms, distribution, and prior therapy all matter.

Systemic treatment options changed in 2025. In the LITESPARK-015 phase 2 trial, 72 people with locally advanced or metastatic PPGL not amenable to curative treatment received the HIF-2 alpha inhibitor belzutifan [11]. The FDA approved belzutifan for adults and children age 12 years and older with locally advanced, unresectable, or metastatic PPGL, based on a 26% objective response rate and a median response duration of 20.4 months in the approval dataset [12]. This is an oncology treatment with important risks and monitoring requirements, not a substitute for initial diagnostic or surgical care.