Pheochromocytoma and paraganglioma

Pheochromocytoma and paraganglioma: the must-not-miss catecholamine tumour

By Dr HB Lo, FACRRM 9 min read

Pheochromocytoma and paraganglioma (PPGL) are catecholamine-secreting tumours — rare but must-not-miss. Untreated PPGL can cause hypertensive crisis, MI, stroke, sudden death, and peripartum mortality ≈50%.

The classic triad (headache, sweating, palpitations + hypertension) has ≈90% specificity but occurs in only ≈20% of patients. Most presentations are paroxysmal hypertension, an adrenal incidentaloma, or family screening.

Plasma free metanephrines is first-line screening; levels >2× ULN are highly indicative. At least 25–40% of PPGLs are hereditary — genetic counselling and multi-gene panel testing for every confirmed patient.

An adrenaline-producing tumour that can kill during a routine blood pressure check, a dental extraction, or a Caesarean section is a diagnosis no one wants to miss. Pheochromocytoma (PCC) and paraganglioma (PGL) together — PPGL — are rare but their consequences are catastrophic when missed and entirely manageable when caught.

The incidence is approximately 0.8 per 100,000 per year. The lifetime prevalence is roughly one in 2,500 hypertensive patients. These numbers make PPGL far less common than hypertension or anxiety, but far more dangerous — and the biochemical screen is simple.

A. Core clinical — the AU general practice framework

The biology that explains the diagnosis

Chromaffin cells (in the adrenal medulla and autonomic ganglia) normally synthesise and store catecholamines — adrenaline, noradrenaline, and dopamine. PPGL tumours constitutively O-methylate catecholamines to metanephrines, which are continuously secreted into the bloodstream regardless of whether the tumour is actively releasing a catecholamine surge. This is the reason plasma free metanephrines are more sensitive than measuring catecholamines themselves: the metanephrine signal is present even between symptomatic episodes.

Adrenal PPCCs tend to secrete predominantly adrenaline (producing tachycardia and hypertension). Extra-adrenal sympathetic paragangliomas (abdomen, thorax, pelvis) tend to secrete predominantly noradrenaline (producing sustained vasoconstriction and hypertension). Head and neck paragangliomas (carotid body, jugulotympanic, vagal) are usually non-secretory.

Syndromic associations — know the common ones

At least 25–40% of PPGLs are hereditary per Muth J Intern Med 2019. The key syndromes:

  • MEN2A/B (RET mutation): adrenal PCC often bilateral; also medullary thyroid cancer and hyperparathyroidism (2A) or mucosal neuromas and marfanoid habitus (2B).
  • Von Hippel-Lindau (VHL): PCC plus retinal and CNS haemangioblastoma, renal cell carcinoma, pancreatic NET — fundoscopy should be part of the assessment of any VHL patient.
  • Neurofibromatosis 1 (NF1): PCC in approximately 5% lifetime; café-au-lait macules, axillary freckling, Lisch nodules in the iris, neurofibromas are the clue.
  • Hereditary paraganglioma syndromes (SDHB/C/D/AF2): extra-adrenal and head-neck PGL; SDHB carries approximately 40% lifetime metastatic risk and drives the most intensive surveillance requirement.

When examining a patient with suspected PPGL, look for: café-au-lait and neurofibromas (NF1); marfanoid habitus with mucosal neuromas (MEN2B); palpable neck mass with cranial nerve palsies (head-neck PGL, ask about SDHD family history); and always refer for fundoscopy in any suspected VHL patient.

Who to screen and when

Per the Endocrine Society 2014 Clinical Practice Guideline and eTG Endocrine:

  • Paroxysmal or labile hypertension with hyperadrenergic spells (headache, sweating, palpitations, pallor).
  • Resistant hypertension (BP not controlled on three agents including a diuretic).
  • Hypertensive emergency with arrhythmia, myocardial infarction, stroke, or takotsubo cardiomyopathy.
  • Any adrenal incidentaloma — regardless of size or appearance on imaging; PPGL cannot be reliably excluded by imaging characteristics alone.
  • Hypertension under age 40 years.
  • Family history of PPGL, MEN2, VHL, NF1, or SDHx mutation.
  • Hypertension in pregnancy with classic symptoms (peripartum mortality approximately 50% if undiagnosed).
  • Unexplained dilated or takotsubo cardiomyopathy.
  • Any patient who is going for elective surgery and has an unscreened adrenal mass.

A normal blood pressure does not exclude PPGL. Dopamine-secreting paragangliomas can be nearly normotensive.

History

  • The spell pattern: paroxysmal onset, duration (minutes to hours), associated symptoms (headache, sweating, palpitations, pallor, tremor, anxiety). How frequent? What triggers them?
  • Triggers to document specifically: exertion, abdominal pressure, foods (aged cheese, red wine, fermented products), medications (beta-blockers, opioids, metoclopramide, IV contrast).
  • Blood pressure pattern: consistently elevated, paroxysmal, or orthostatic hypotension between episodes (reflecting catecholamine-induced volume contraction).
  • Constitutional features: unexplained weight loss, glucose intolerance or new diabetes, hypercalcaemia (PTHrP-secreting tumour).
  • Family history: early hypertension, adrenal tumours, medullary thyroid cancer, renal cell carcinoma, head-neck masses, retinal haemangioma. Draw a three-generation pedigree.
  • Pregnancy: current or planned; catastrophic risk if PPGL unrecognised.

Examination

  • Blood pressure supine and standing (orthostatic hypotension between spells = catecholamine-induced volume contraction).
  • Pallor during or just after a spell (vasoconstriction); not flushing (which points to carcinoid syndrome or rosacea).
  • Tachycardia, irregular pulse.
  • Carefully note syndromic features (café-au-lait, axillary freckling, neurofibromas, Lisch nodules, mucosal neuromas, marfanoid habitus, palpable neck mass, retinal haemangioma).
  • Abdominal palpation: perform gently and briefly — palpation of a PPGL can provoke a catecholamine surge. A palpable abdominal mass is rare but significant.
  • Cardiovascular: evidence of catecholamine cardiomyopathy (gallop, cardiac murmur from new mitral regurgitation in takotsubo).

Biochemical screening

Plasma free metanephrines (LC-MS/MS preferred over immunoassay) — collected supine after 30 minutes of rest, fasting, no caffeine or exercise on the day. MBS 66635 for plasma fractionated metanephrines. Most major Australian pathology laboratories offer this.

24-hour urinary fractionated metanephrines — equivalent diagnostic accuracy; useful where plasma sampling is impractical; requires acid-preserved collection. MBS 66628.

Drugs that interfere and should be washed out for five to seven days before testing where safe to do so: tricyclic antidepressants, MAOIs, levodopa, sotalol, labetalol, paracetamol (some assays). Flag medication history on the request form.

Interpretation per Endocrine Society 2014:

  • Below the upper reference limit: PPGL effectively excluded (excellent negative predictive value).
  • Borderline (up to 2× upper reference): repeat under standardised conditions; consider clonidine suppression test at specialist assessment.
  • More than 2× upper reference limit: PPGL highly likely → imaging.
  • Predominant 3-methoxytyramine elevation suggests dopamine-secreting paraganglioma (SDHB mutation, head-neck PGL).

B. Evidence appraisal — management principles

Localisation imaging — after biochemical confirmation

Imaging is ordered only after biochemical confirmation. Imaging without biochemistry generates false-positive results and exposes patients to unnecessary intervention.

  • CT abdomen and pelvis with contrast (MBS 56501) — first-line for adrenal lesions; sensitivity approximately 90%; characteristic features include heterogeneous enhancement, high attenuation unenhanced (>10 HU), and slow contrast washout.
  • MRI abdomen (MBS 63507) — preferred in pregnancy, head-neck PGL, paediatric cases, and ongoing surveillance to reduce cumulative radiation.
  • Ga-68 DOTATATE PET (MBS 61632) — preferred functional imaging for SDHB metastatic disease, head-neck PGL, multifocal disease, and staging.
  • ¹⁸F-FDG PET — for SDHB metastatic disease and dedifferentiated tumours.

Biopsy of a suspected PPGL should be avoided — it can provoke a catecholamine crisis.

Pre-operative preparation — mandatory in every functional PPGL

Pre-operative alpha-blockade is mandatory for all functional PPGLs, started 10–14 days before surgery. Without it, manipulation of the tumour during surgery triggers a catecholamine crisis with potentially fatal haemodynamic instability.

Alpha-blockade — two options per eTG and AMH:

  • Phenoxybenzamine: 10 mg twice daily, titrating up by 10 mg every two to three days to a total of approximately 1 mg/kg/day in divided doses. Non-selective irreversible blockade; smooth intra-operative haemodynamics. Available via Special Access Scheme (SAS) only — not on PBS; access through hospital pharmacy or compounding pharmacy.
  • Doxazosin (selective α₁): 2 mg increasing to 8–16 mg per day. PBS General Schedule — widely available, cheaper, fewer side effects (less nasal congestion, less severe postural hypotension). Comparable haemodynamic outcome to phenoxybenzamine in non-comparative studies.

Target blood pressure on alpha-blockade: below 130/80 mmHg supine and standing systolic above 90 mmHg (some postural fall is acceptable and expected — it confirms adequate blockade). Nasal congestion and warmth are signs of adequate alpha-blockade.

High-sodium diet plus ≥2.5 L fluid per day — start from day three of alpha-blockade to reverse catecholamine-induced volume contraction and prevent post-tumour-removal hypotension.

Beta-blockade (after alpha is established) — for reflex tachycardia (heart rate >100) or arrhythmia: atenolol 25–50 mg per day or propranolol 20–40 mg three times daily. Never before alpha-blockade — unopposed alpha stimulation causes hypertensive crisis.

Calcium channel blockers (nifedipine SR, amlodipine) are a useful addition for residual blood pressure elevation or in patients who cannot tolerate alpha-blockers.

Surgery

Laparoscopic adrenalectomy is first-line for most PPCCs under 8 cm. Open adrenalectomy is required for large (>8 cm), invasive, or suspected malignant lesions. Cortical-sparing adrenalectomy should be discussed for bilateral hereditary PPCCs to preserve residual cortical function and avoid lifelong steroid replacement.

Surgery should be performed at a high-volume centre with experienced PPGL anaesthetists. Failure to communicate the PPGL diagnosis to the procedural team before any procedure (including dental work) is a recognised medico-legal risk.

Post-operative monitoring and surveillance

Plasma metanephrines at two to six weeks post-operatively to confirm biochemical cure. If levels remain elevated, further imaging is required to identify residual or metastatic disease. Annual plasma metanephrines and blood pressure monitoring continue lifelong, because metachronous recurrence (a new PPGL years after the first) occurs in approximately 5–15%, and is higher in hereditary syndromes.

Genetic testing — for every confirmed PPGL

Every confirmed PPGL patient should be offered multi-gene panel germline testing and referral to a clinical genetics service, regardless of family history and regardless of patient age. Per Muth 2019, at least 25–40% carry a pathogenic germline variant; this proportion is higher in younger patients and those with extra-adrenal, bilateral, or malignant tumours. Identification of the variant drives lifelong surveillance protocols for the patient and enables predictive testing for at-risk first-degree relatives. Clinical genetics services at major Australian hospitals provide both pre-test and post-test counselling. MBS 73292 is rebatable for eligible heritable endocrine or cancer indications.

C. Australian operations

GP role in PPGL:

  • Recognise and screen (order plasma free metanephrines for appropriate patients).
  • Ensure safe antihypertensive choices during workup — doxazosin or amlodipine are the safest options; avoid beta-blocker monotherapy until PPGL is excluded.
  • Refer urgently to endocrinology with positive or borderline biochemistry.
  • Coordinate family screening and genetic counselling referral.
  • Support lifelong surveillance post-curative resection, including annual plasma metanephrines and blood pressure review.
  • Mental Health Care Plan for anxiety, panic, and hereditary cancer distress.

Endocrinology centres with PPGL MDT: all major tertiary hospitals in Australia — Royal Melbourne, Royal Prince Alfred (Sydney), Princess Alexandra (Brisbane), Royal Adelaide, Sir Charles Gairdner (Perth), Royal Hobart.

PBS access for pre-operative medications: doxazosin is PBS General Schedule. Phenoxybenzamine is not PBS-listed for PPGL; it requires SAS Category B access through hospital pharmacy. Atenolol, propranolol, and calcium channel blockers are PBS General Schedule.

NeuroEndocrine Cancer Australia (NECA) provides patient support resources and maintains a network of specialist neuroendocrine tumour centres across Australia.

GPCCMP (MBS 965/967): eligible for post-surgical surveillance and comorbidity management. Allied health commonly required includes dietitian (high-Na diet pre-op, post-op nutrition recovery, cardiovascular risk post-catecholamine exposure), exercise physiologist (rehabilitation), psychologist (anxiety, panic, hereditary cancer distress).

Medico-legal flags: driving fitness where there is sustained hypertension or syncope risk (Austroads standards); pre-procedure communication of PPGL diagnosis to proceduralists; documentation of family screening obligations.

D. Special populations

Pregnancy: undiagnosed PPGL in pregnancy carries peripartum mortality approaching 50%. In any pregnant patient with hypertension and classic symptoms, plasma free metanephrines should be requested without delay. Phenoxybenzamine and doxazosin are used in pregnancy under specialist oversight. Timing of surgery (ideally second trimester) versus medical control to term is a complex specialist decision. Caesarean delivery is generally preferred over vaginal delivery (which involves Valsalva) in known PPGL.

Metastatic PPGL: approximately 10–15% of PPGLs develop metastatic disease (most common in SDHB mutation carriers, approximately 40% lifetime risk). Management requires a multidisciplinary neuroendocrine team. Options include surgical debulking, radiofrequency ablation, external beam radiotherapy for bone metastases, ¹⁷⁷Lu-DOTATATE PRRT (Section 100 HSD; limited current PBS access for PPGL), sunitinib, and CAPTEM chemotherapy.

Children and adolescents: PPGL in children is more commonly hereditary than in adults. Refer immediately for genetic testing and paediatric endocrinology involvement. Pre-pubertal presentation warrants assessment for VHL, SDHx, and NF1.

When to escalate

Refer urgently (same day, to emergency) for:

  • Suspected hypertensive crisis with classic PPGL symptoms — intravenous phentolamine or sodium nitroprusside is required, not oral antihypertensives alone
  • Catecholamine storm during any procedure in a patient with an unscreened adrenal mass
  • Known or suspected PPGL in pregnancy with acute hypertensive emergency

Refer urgently (within 48 hours) to endocrinology for:

  • Plasma free metanephrines >2× upper reference limit
  • Symptomatic paroxysmal hypertension with any adrenal mass on imaging
  • Pregnant patient with elevated metanephrines

What this article is and is not

This is general health information drawn from the Endocrine Society 2014 PPGL guideline, European Society of Endocrinology ENS@T 2023 guideline, Therapeutic Guidelines (eTG), and Australian Medicines Handbook. It does not constitute personal medical advice. All confirmed or suspected PPGL requires specialist endocrinology and surgical assessment. Pre-operative preparation and genetic counselling must be coordinated by experienced specialists.

For Australian patient information: NeuroEndocrine Cancer Australia (NECA), HealthDirect, Centre for Genetics Education NSW.

For hereditary cancer genetic support: state familial cancer centres at major Australian hospitals.

Sources cited

  1. Endocrine Society PPGL CPG 2014 (Lenders J Clin Endocrinol Metab)
  2. European Society of Endocrinology ENS@T 2023
  3. Muth A et al. Hereditary PPGL. J Intern Med 2019
  4. Therapeutic Guidelines (eTG) — Endocrine
  5. Australian Medicines Handbook
  6. NPS MedicineWise
  7. NeuroEndocrine Cancer Australia (NECA)
  8. Centre for Genetics Education NSW
  9. HealthDirect — pheochromocytoma

Frequently asked questions

  • What are the typical spells of pheochromocytoma like?

    Catecholamine spells are characteristically paroxysmal — abrupt onset over minutes, lasting minutes to hours, then resolving. During a spell: severe pounding headache, profuse sweating, a sense of the heart racing or pounding, pallor (not flushing), anxiety or a sense of impending doom, and very high blood pressure. Between spells, the blood pressure may be elevated or may normalise, and the patient can feel completely well. Triggers include: physical exertion, abdominal palpation (examining the abdomen can provoke a crisis), certain medications (beta-blockers given without prior alpha-blockade, opioids such as morphine, metoclopramide, tricyclics, sympathomimetics, intravenous contrast agents), tyramine-rich foods (aged cheese, red wine, salami, broad beans, fermented soy), and anaesthesia. Many patients are investigated for panic attacks or anxiety disorder for years before the diagnosis is made.

  • Which patients should be screened for pheochromocytoma?

    The Endocrine Society 2014 guideline recommends screening in: anyone with hyperadrenergic spells (paroxysmal headache, sweating, palpitations, pallor); resistant hypertension that is difficult to control on three agents; hypertensive emergency — particularly if accompanied by arrhythmia, myocardial infarction, stroke, or takotsubo cardiomyopathy; any adrenal incidentaloma regardless of size or appearance; family history of PPGL or syndromic conditions (MEN2, Von Hippel-Lindau, neurofibromatosis 1, SDHx mutations); hypertension in pregnancy with classical symptoms; hypertension under 40 years; and unexplained dilated or takotsubo cardiomyopathy. The key principle is that a normal blood pressure does not exclude PPGL — some tumours secrete predominantly dopamine and can be nearly normotensive.

  • What blood test is used to screen for pheochromocytoma?

    Plasma free metanephrines (metanephrine and normetanephrine measured by liquid chromatography–mass spectrometry, LC-MS/MS) is the first-line test, with sensitivity 96–100% and specificity 85–95%. The test must be collected supine after 30 minutes of rest, fasting, without recent caffeine, exercise, or stress. A number of medications interfere — tricyclics, MAOIs, levodopa, labetalol, and sotalol should be washed out for five to seven days where possible. If plasma sampling is impractical, 24-hour urinary fractionated metanephrines has equivalent diagnostic accuracy. Levels greater than twice the upper reference limit are highly indicative of PPGL and should prompt imaging. Mildly elevated levels warrant repeat testing under strictly standardised conditions and consideration of a clonidine suppression test at specialist assessment.

  • Why must beta-blockers never be given first for pheochromocytoma hypertension?

    In an unblocked PPGL, catecholamines cause simultaneous alpha (vasoconstriction) and beta (vasodilation, cardiac) effects that partly counteract each other. If a beta-blocker is given first — blocking the beta-mediated vasodilation — unopposed alpha-adrenergic vasoconstriction takes over, causing a sudden severe rise in blood pressure that can be life-threatening. This is a well-documented iatrogenic cause of hypertensive crisis in undiagnosed PPGL. The safe order of blockade is always alpha first, then beta: alpha-blockade (phenoxybenzamine or doxazosin) must be established for 10–14 days before any beta-blocker is added, and only then to control reflex tachycardia. Until a PPGL is excluded, avoid starting or increasing a beta-blocker as the sole antihypertensive in a patient with paroxysmal hypertension or classic symptoms.

  • Is pheochromocytoma hereditary and should family members be tested?

    Yes — at least 25–40% of PPGLs are caused by a germline (inherited) mutation, and this rate is higher in younger patients, those with bilateral or extra-adrenal tumours, and those with malignant disease. The most important genes are SDHA, SDHB, SDHC, SDHD, RET (MEN2), VHL, and NF1. SDHB mutations carry the highest metastatic risk (approximately 40% lifetime) and require the most intensive lifelong surveillance. All confirmed PPGL patients should be referred to a clinical genetics service for counselling and multi-gene panel testing, regardless of family history — because the family history is not known until the first case is diagnosed. First-degree relatives of a confirmed germline mutation carrier should also be offered predictive testing.

Source quality

Sources grouped by evidence tier. AU primary tier first; international where AU is silent or lagging; named-author reconstruction where guidelines have not yet caught up. How tiers work.