# Pheochromocytoma

Evaluate patients with paroxysmal or resistant hypertension, catecholamine spells, adrenal incidentaloma, or relevant family history using properly collected fractionated metanephrines; localize only after biochemical evidence, then provide alpha blockade, volume expansion, and expert surgical planning for functional disease.

**Clinical question:** How should clinicians confirm, localize, genetically assess, and prepare a patient with suspected functional pheochromocytoma for definitive treatment?

Updated: 2026-09-16T00:30:34.290968+00:00

## What matters in practice
- Test for pheochromocytoma/paraganglioma in resistant or paroxysmal hypertension, catecholamine spells, adrenal incidentaloma, or a positive family history; use plasma metanephrines collected supine with an indwelling cannula or 24-hour urinary fractionated metanephrines. [5][8]
- Do not use anatomic imaging as the first routine diagnostic step: obtain CT or MRI of the abdomen and pelvis after biochemical testing supports pheochromocytoma/paraganglioma. [5][8]
- All functional pheochromocytomas and sympathetic paragangliomas require preoperative alpha-adrenergic blockade; pair blockade with a high-sodium diet to reduce perioperative hemodynamic complications. [18][20]
- Assess hereditary disease because pheochromocytoma may occur with RET-associated MEN2, VHL disease, NF1, and hereditary paraganglioma syndromes; SDHB pathogenic variants warrant genotype-informed surveillance planning. [3][11][12]

## Who requires biochemical testing for pheochromocytoma

Target testing to clinical patterns with meaningful pretest probability.

Screen patients with resistant hypertension; paroxysmal hypertension or hypertensive crisis superimposed on sustained hypertension; episodic headache, sweating, palpitations, pallor, or marked blood-pressure lability; an adrenal incidentaloma; or a first-degree family history of pheochromocytoma or paraganglioma. Orthostatic hypotension and cutaneous neurofibromatosis findings, including café-au-lait macules and neurofibromas, further increase suspicion. [5][8]

In adults with cyanotic congenital heart disease, episodic tachycardia or hypertension should trigger screening with plasma fractionated metanephrines and 24-hour urinary fractionated metanephrines because chronic hypoxemia is associated with increased pheochromocytoma/paraganglioma prevalence in this population. [6]

During hypertensive emergency or an urgent preoperative assessment, proceed promptly with adrenal or paraganglionic imaging when rapid tumor identification is clinically necessary, while obtaining biochemical testing because metanephrine results may not be immediately available. [9]
- Do not frame testing as a routine hypertension screen: pheochromocytoma/paraganglioma accounts for approximately 0.1% to 0.6% of secondary-hypertension evaluations. [5][8]
- A known hereditary syndrome or family clustering should lower the threshold for biochemical evaluation and genetic assessment. [1][3][12]

*Clinical triggers that change the threshold for pheochromocytoma/paraganglioma testing. [5][6][8]*

| Presentation | Next diagnostic action | Finding that reinforces suspicion |
| --- | --- | --- |
| Resistant hypertension or episodic crisis on sustained hypertension | Order plasma metanephrines under standardized supine conditions or 24-hour urinary fractionated metanephrines. [5][8] | Marked blood-pressure lability or recurrent spells. [5][8] |
| Adrenal incidentaloma | Obtain plasma or 24-hour urinary fractionated metanephrines before management decisions. [5][8] | Hypertension, tachycardia, or catecholamine-type symptoms. [5][8] |
| Family history or syndromic phenotype | Obtain biochemical testing and arrange hereditary-risk assessment. [1][3][12] | Multiple tumors, head-and-neck paragangliomas, NF1 skin findings, or relatives with pheochromocytoma/paraganglioma. [3][12] |
| Cyanotic congenital heart disease with episodic tachycardia or hypertension | Measure plasma and 24-hour urinary fractionated metanephrines. [6] | Chronic cyanosis with new episodic adrenergic symptoms. [6] |

## Choose and collect metanephrine testing correctly

Collection conditions determine whether a metanephrine result can direct imaging.

Use either plasma metanephrines obtained under standardized conditions or 24-hour urinary fractionated metanephrines as the initial biochemical evaluation. For plasma testing, collect with the patient supine and an indwelling intravenous cannula in place; this is the specified standard-condition approach in hypertension guidance. [5][7][8]

A positive biochemical result should lead to localization with CT or MRI of the abdomen and pelvis. In patients whose disease distribution requires broader staging or localization, Ga-DOTATATE PET/CT is included as an imaging option in contemporary hypertension guidance. [7]

Interpret testing in the clinical context rather than using imaging alone to establish functional disease. Pheochromocytomas and sympathetic paragangliomas can produce catecholamines causing episodic tachycardia and hypertension, whereas some paragangliomas may be detected as masses or through hereditary surveillance. [6][16]
- If plasma sampling was not performed supine with an indwelling cannula, repeat testing under standard conditions before acting on a discordant or borderline clinical result. [5][8]
- Use CT or MRI of the abdomen and pelvis as the first anatomic localization study after biochemical evidence is obtained. [5][8]
- Use Ga-DOTATATE PET/CT when functional imaging is needed for lesion localization or disease mapping. [7]

### When a mass is found before biochemical confirmation

An adrenal incidentaloma is itself an indication for plasma or urinary fractionated metanephrine testing. If urgent surgery or severe hypertension accelerates the workup, obtain biochemical testing while using imaging to identify an adrenal or extra-adrenal lesion. [5][8][9]

*Testing sequence for suspected pheochromocytoma/paraganglioma. [5][7][8][9]*

| Clinical situation | First test | Result-driven next step |
| --- | --- | --- |
| Stable outpatient with compatible symptoms, resistant hypertension, family history, or incidentaloma | Plasma metanephrines under supine standardized conditions with an indwelling IV cannula, or 24-hour urinary fractionated metanephrines. [5][8] | If biochemical evidence supports disease, obtain CT or MRI of the abdomen and pelvis. [5][8] |
| Cyanotic congenital heart disease with episodic tachycardia or hypertension | Plasma fractionated and 24-hour urinary fractionated metanephrines. [6] | Localize biochemical disease with cross-sectional imaging. [5][8] |
| Need for broader functional imaging | CT or MRI-based localization plus Ga-DOTATATE PET/CT when indicated. [7] | Use mapped distribution to plan operative or advanced-disease management. [7] |
| Hypertensive emergency or urgent preoperative concern | Obtain blood free and urinary fractionated metanephrine testing while expediting imaging when tumor identification is urgent. [9] | Avoid unplanned lesion manipulation until catecholamine-producing tumor risk has been addressed. [18][20] |

## Identify hereditary pheochromocytoma and paraganglioma

Genotype changes family counseling and surveillance strategy.

Pheochromocytoma may occur as part of RET-associated multiple endocrine neoplasia type 2, von Hippel-Lindau disease, neurofibromatosis type 1, and hereditary paraganglioma syndromes. Multiple head-and-neck paragangliomas, multiple pheochromocytomas, or a family history should prompt hereditary-risk assessment rather than being labeled nonsyndromic. [3][12]

Germline VHL mutation can underlie familial pheochromocytoma, as illustrated by affected first-degree relatives and VHL c.298T→C in a reported family. [1] SDHB pathogenic-variant carriers require structured surveillance planning; tumor size and age at first diagnosis have been reported as independent predictors of metastatic behavior and survival in SDHB-related pheochromocytoma/paraganglioma. [11]

Metastatic pheochromocytoma/paraganglioma is defined by metastasis to non-chromaffin tissue or local invasion, not by primary-tumor histology alone. This distinction should redirect care toward disease mapping, germline assessment, and multidisciplinary treatment planning. [9]
- Document a three-generation history of pheochromocytoma, paraganglioma, MEN2-associated disease, VHL manifestations, and NF1 features before genetic counseling. [3][12]
- Prioritize genetic evaluation in patients with malignant or metastatic pheochromocytoma/paraganglioma. [2]
- For SDHB-associated disease, integrate age at diagnosis and primary-tumor size into metastatic-risk discussions and surveillance intensity. [11]

*Hereditary patterns that change evaluation and follow-up. [1][2][3][11][12]*

| Pattern | Gene or syndrome association | Clinical implication |
| --- | --- | --- |
| Familial pheochromocytoma | VHL disease can present with germline VHL mutation and affected relatives. [1][3] | Evaluate the patient and at-risk relatives through a hereditary cancer/endocrine pathway. [1][3] |
| Pheochromocytoma with syndromic phenotype | MEN2/RET, VHL, NF1, and hereditary paraganglioma syndromes. [3][12] | Genetic assessment informs surveillance and family testing. [3][12] |
| SDHB pathogenic variant | Hereditary paraganglioma/pheochromocytoma predisposition. [11] | Plan radiologic surveillance; incorporate tumor size and age at first diagnosis into risk assessment. [11] |
| Metastatic or malignant disease | Genetic testing should be proposed. [2] | Use disease extent and genotype to guide specialized management. [2][11] |

## Prepare functional disease for surgery without provoking crisis

Biochemically functional tumors require adrenergic preparation before resection.

Refer patients with functional pheochromocytoma or sympathetic paraganglioma for planned resection after preoperative alpha-receptor blockade. Endocrine Society guidance recommends preoperative blockade for all functional tumors to prevent perioperative complications, with a high-sodium diet as part of preparation. [20] A perioperative review similarly states that all pheochromocytoma and sympathetic paraganglioma patients should receive alpha-receptor blockade before surgery. [18]

Begin alpha-adrenergic blockade 1 to 2 weeks before surgery when elective resection is planned. [23] Do not proceed directly to tumor manipulation or nonurgent surgery without catecholamine-directed preparation, because intraoperative hemodynamic instability is the central preventable risk. [18][20][24]

Metyrosine is an adjunct for selected surgical candidates with troublesome or persistent catecholamine symptoms despite blockade. A cited preoperative regimen starts metyrosine at 250 mg orally every 8 to 12 hours; dosing and duration are individualized to catecholamine burden. [19][21][22] Use it as an adjunct rather than a substitute for alpha blockade. [20][22]
- Start alpha blockade before any beta blockade; beta blockade without prior alpha blockade is not an acceptable substitute for alpha-receptor preparation. Alpha- and beta-blockade are described as perioperative measures, with phenoxybenzamine used for alpha blockade. [22]
- Add a high-sodium diet during preoperative preparation as recommended for functional tumors. [20]
- Use an experienced anesthesia and surgical team with intensive perioperative monitoring for malignant or complex pheochromocytoma/paraganglioma surgery. [24]

### Perioperative endpoint and postoperative risk

Plan for postoperative hemodynamic support after resection. Reported paraganglioma cases required transient norepinephrine for postoperative hypotension, illustrating the need for monitored recovery after catecholamine withdrawal and tumor removal. [16]

*Preoperative sequence for a functional pheochromocytoma or sympathetic paraganglioma. [18][19][20][22][23][24]*

| Step | Action | Purpose or escalation |
| --- | --- | --- |
| 1. Confirm functional disease and localize | Use fractionated metanephrine testing, then CT or MRI-based localization. [5][8] | Establish operative target and catecholamine-related perioperative risk. [18][20] |
| 2. Initiate alpha blockade | Begin alpha-receptor blockade before surgery; elective preparation is commonly started 1-2 weeks preoperatively. [18][20][23] | Reduce perioperative catecholamine-mediated complications. [18][20] |
| 3. Expand intravascular volume | Use high-sodium dietary preparation with blockade. [20] | Mitigate perioperative hemodynamic instability. [20] |
| 4. Address persistent catecholamine symptoms | Consider metyrosine 250 mg orally every 8-12 hours as an adjunct in surgical candidates when indicated. [19][21][22] | Individualize duration and dose to catecholamine burden. [21] |
| 5. Operate with specialized monitoring | Use an experienced surgical and anesthesia team with intensive perioperative monitoring. [24] | Prepare for postoperative hypotension and vasopressor support if needed. [16] |

## Recognize metastatic disease and redirect management

Metastasis changes the objective from localized resection alone to genotype-informed disease control.

Classify pheochromocytoma/paraganglioma as malignant when metastasis is present in non-chromaffin tissue or when there is local invasion. [9] This finding warrants comprehensive anatomic and functional disease mapping, germline testing, and referral to a multidisciplinary endocrine oncology center. [2][7][11]

Molecular subtypes include pseudohypoxia, kinase-signaling, and Wnt-altered groups. Cluster 1 alterations involving SDHx, VHL, FH, EPAS1, and EglN/PHD2 activate hypoxia-inducible pathways; this biology has therapeutic relevance because HIF2alpha inhibition with belzutifan has been described as recently approved monotherapy for metastatic pheochromocytoma/paraganglioma after phase 2 trials. [10]

SDHx alterations have been associated with temozolomide response in small retrospective metastatic-disease series. [10] Treatment selection for metastatic disease should therefore incorporate germline and tumor molecular findings rather than rely on primary location alone. [10][11]
- Obtain genetic testing in metastatic or malignant pheochromocytoma/paraganglioma. [2]
- Use Ga-DOTATATE PET/CT as an available functional imaging modality when mapping disease extent is needed. [7]
- Treat reported belzutifan use for metastatic pheochromocytoma/paraganglioma as an advanced-disease, genotype-informed decision in a specialized oncology setting. [10]

*Advanced-disease decisions in pheochromocytoma/paraganglioma. [2][7][9][10][11]*

| Finding | Interpretation | Next action |
| --- | --- | --- |
| Metastasis to non-chromaffin tissue or local invasion | Defines malignant disease. [9] | Map extent, obtain genetic testing, and coordinate multidisciplinary management. [2][7][11] |
| SDHB pathogenic variant | Associated with a surveillance-intensive hereditary-risk phenotype; tumor size and age at diagnosis inform metastatic-risk assessment. [11] | Use genotype-informed surveillance and counseling. [11] |
| Pseudohypoxia-pathway alteration | Includes SDHx, VHL, FH, EPAS1, and EglN/PHD2 alterations with HIF pathway activation. [10] | Consider molecularly directed options through specialist oncology care. [10] |
| SDHx-altered metastatic disease | Temozolomide responses have been reported in small retrospective series. [10] | Discuss systemic therapy options in a multidisciplinary setting. [10] |

## References
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3. Germ-Line Mutations in Nonsyndromic Pheochromocytoma — www.nejm.org — https://www.nejm.org/doi/full/10.1056/NEJMoa020152
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8. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines — www.jacc.org — https://www.jacc.org/doi/10.1016/j.jacc.2017.11.005
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11. Management of phaeochromocytoma and paraganglioma in patients with germline SDHB pathogenic variants: an international expert Consensus statement | Nature Reviews Endocrinology — www.nature.com — https://www.nature.com/articles/s41574-023-00926-0
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## Editorial note

Prepared from cited clinical literature using Astra's research workflow. Verify recommendations against current guidance and patient-specific factors.