In a primary‑care patient with suspected pheochromocytoma, how urgently should I arrange referral to an endocrinology or hypertension specialist for further evaluation?

Urgency of Referral for Suspected Pheochromocytoma in Primary Care

All patients with suspected pheochromocytoma should be referred urgently—within 1-2 weeks—to endocrinology or a hypertension specialist, as unrecognized tumors can cause life-threatening hypertensive crises, myocardial infarction, stroke, or sudden death. 1

Clinical Context Determining Urgency

The urgency of referral depends on the clinical presentation and biochemical findings, but all cases warrant prompt specialist evaluation given the potentially fatal complications:

Immediate/Emergent Referral (Same Day to 48 Hours)

• Patients presenting with severe hypertensive episodes, chest pain, cardiac arrhythmias, or signs of hypertensive crisis require immediate specialist consultation or emergency department evaluation. 1
• Patients with the classic triad of severe episodic headache, palpitations, and diaphoresis have 90% diagnostic specificity and should be referred emergently for biochemical testing. 1
• Any patient with an incidentally discovered adrenal mass and hypertensive symptoms requires urgent referral before any biopsy or intervention, as unrecognized pheochromocytoma can precipitate fatal hypertensive crisis. 1

Urgent Referral (Within 1-2 Weeks)

• Patients with resistant hypertension (BP >140/90 mmHg despite ≥3 antihypertensive medications including a diuretic) should be referred within 1-2 weeks, as pheochromocytoma prevalence reaches 4% in this population. 1
• Young patients (<30 years) with new-onset hypertension warrant urgent referral, as early-onset hypertension is a key screening indicator. 1
• Patients with paroxysmal hypertension accompanied by any classic symptoms (headache, palpitations, sweating, pallor) should be referred within 1-2 weeks. 1
• Any patient with a family history of pheochromocytoma or hereditary syndromes (MEN2, VHL, NF1, SDHx mutations) requires urgent specialist evaluation. 1

Primary Care Actions Before Referral

While arranging urgent specialist referral, primary care physicians should initiate the following:

Biochemical Testing

• Order plasma free metanephrines (sensitivity 96-100%, specificity 89-98%) or 24-hour urinary fractionated metanephrines (sensitivity 86-97%, specificity 86-95%) immediately upon suspicion. 1
• For plasma testing, ideally collect from an indwelling venous catheter after the patient has been supine for 30 minutes to minimize false positives, though this can be bypassed in urgent situations with repeat testing under ideal conditions if marginally elevated. 1
• Ensure interfering medications are avoided prior to testing, including tricyclic antidepressants and monoamine oxidase inhibitors, though common antihypertensives do not affect results with modern LC-MS/MS analysis. 1

Critical Safety Measures

• Never initiate beta-blockade alone before alpha-blockade in suspected pheochromocytoma, as this can precipitate severe hypertensive crisis due to unopposed alpha-adrenergic stimulation. 1
• Avoid any procedures that can trigger catecholamine release until pheochromocytoma is excluded, including contrast-enhanced CT (use MRI preferentially) and fine needle biopsy of adrenal masses. 1
• Do not order imaging before biochemical confirmation, as unrecognized pheochromocytomas can cause life-threatening hypertensive crises during procedures. 1

Interpretation of Biochemical Results and Referral Timing

Markedly Elevated Results (≥4 Times Upper Limit of Normal)

• Results ≥4 times the upper limit of normal are diagnostic for pheochromocytoma/paraganglioma and require immediate specialist referral (within 24-48 hours) for imaging localization and preoperative management. 1

Moderately Elevated Results (2-4 Times Upper Limit of Normal)

• Results 2-4 times the upper limit warrant urgent specialist referral within 1 week, with repeat testing in 2 months and consideration of genetic testing. 1

Marginally Elevated Results (1-2 Times Upper Limit of Normal)

• Marginally elevated results require referral within 1-2 weeks for repeat testing under ideal conditions (supine, indwelling catheter) or clonidine suppression testing if clinical suspicion remains high. 1
• The clonidine suppression test has 100% specificity and 96% sensitivity for distinguishing true pheochromocytoma from false-positive elevations. 1

High-Risk Features Requiring Expedited Referral

Certain features mandate more urgent specialist evaluation due to increased risk of malignancy and complications:

• SDHB germline mutations carry up to 70% risk of metastatic disease and require immediate specialist referral for intensive surveillance protocols. 2
• Extra-adrenal paragangliomas (any location outside the adrenal gland) require urgent referral as they carry higher malignancy risk. 1
• Tumors ≥5 cm on imaging require expedited referral due to higher metastatic potential. 1
• Plasma methoxytyramine >3-fold above upper limit indicates higher malignancy risk and warrants urgent specialist evaluation. 1

Common Pitfalls to Avoid

• Do not delay referral while waiting for biochemical test results if clinical suspicion is high based on the classic triad or severe symptoms—refer urgently and order testing simultaneously. 1
• Do not assume normal blood pressure excludes pheochromocytoma, as up to 50% of patients remain normotensive or have only paroxysmal hypertension. 3
• Do not order CT with IV contrast before biochemical exclusion of pheochromocytoma, as contrast can precipitate hypertensive crisis—use MRI preferentially. 1
• Do not dismiss family history as irrelevant, as approximately 35% of pheochromocytomas are hereditary with autosomal dominant inheritance. 1

Multidisciplinary Team Discussion

All patients with suspected or proven pheochromocytoma should be discussed in a multidisciplinary expert team meeting at the time of initial diagnosis, involving endocrinology, surgery, anesthesiology, and radiology. 2