Pheochromocytoma in MRCP PACES: Recent Research Update

Pheochromocytoma is one of the MRCP PACES classics that has genuinely shifted in the last five years. New genetic insights, modern functional imaging, and a more individualised approach to preoperative alpha blockade have all changed what "complete management" looks like. PACES candidates are now expected to weave recent evidence into a confident, structured answer - particularly in Station 2 (history), Station 5 (consultation), and increasingly Station 1 (identification).

Why Pheochromocytoma Keeps Appearing in PACES

Pheochromocytoma sits at a clinical crossroads:

• It mimics common conditions (panic disorder, hyperthyroidism, essential hypertension, menopause)

• The classic episodic triad is memorable and testable

• It demands a structured, stepwise diagnostic approach that examiners can easily score

• It is a "do not miss" cause of preventable perioperative death

• Perioperative management crosses endocrinology, anaesthesia, and surgery - ideal for a Station 5 consultation

What Has Changed: The Modern Definition

The 2017 WHO reclassification and the 2023 European Society of Endocrinology (ESE) clinical practice guideline on phaeochromocytoma and paraganglioma (PPGL) have reshaped the field:

• Pheochromocytoma = tumour of chromaffin cells in the adrenal medulla

• Paraganglioma = extra-adrenal tumour (sympathetic or parasympathetic)

• Together referred to as PPGL

The single most important change for PACES: up to 30–40% of PPGLs are now recognised as hereditary, replacing the older "10% rule." This directly affects workup, counselling, and family screening.

Clinical Recognition: A PACES-Ready Approach

The Classic Triad

• Episodic headache

• Sweating (often drenching)

• Palpitations

When a patient describes a sudden, stereotyped, time-limited episode with full recovery in between, PPGL should be on the differential - especially with hypertension.

Other Clues Examiners Like

• Pallor, not flushing (flushing pushes you toward carcinoid, mastocytosis, menopause)

• Paroxysmal or sustained hypertension (5–15% are normotensive, particularly in adrenal incidentaloma cases)

• Orthostatic hypotension from volume contraction

• Anxiety, sense of impending doom

• Hyperglycaemia (catecholamine-driven)

• Cardiomyopathy (Takotsubo or dilated) - rare but worth knowing

• Family history pointing to:

  • MEN2 (medullary thyroid cancer, primary hyperparathyroidism)

  • VHL (haemangioblastomas, renal cell carcinoma)

  • NF1 (café-au-lait macules, neurofibromas, Lisch nodules)

  • SDHx familial paraganglioma syndromes

Triggers Worth Asking About

• Micturition (bladder paraganglioma)

• Anaesthesia, surgery, interventional procedures

• Pressor drugs, TCAs, SNRIs, metoclopramide, glucagon

• Tyramine-rich foods in patients on MAOIs

Diagnostic Workup: What Recent Evidence Supports

Step 1 - Biochemical Confirmation

First-line biochemistry is now unambiguous:

• Plasma free metanephrines (sensitivity ~99%) or

• 24-hour urinary fractionated metanephrines (sensitivity ~95%)

Both measure O-methylated metabolites produced continuously within the tumour, so random sampling outperforms catecholamine measurements.

Recent refinements:

• Supine sampling (≥20 minutes supine before venepuncture) is now standard, improving specificity without loss of sensitivity

• Reference ranges are assay-specific - always interpret in the local context

• Pre-analytical factors matter: caffeine, nicotine, intense exercise, and acute stress can falsely elevate results

PACES tip: Be ready to say which drugs need to be withdrawn and for how long (TCAs ≥2 weeks, SNRIs/levodopa ≥1 week). Do not stop essential antihypertensives - alpha-blockers, beta-blockers, and calcium channel blockers can usually be continued safely.

Step 2 - Imaging Once Biochemistry Is Positive

• CT adrenals (or MRI if CT contrast is contraindicated or in radiation-sensitive patients)

• MRI is preferred for extra-adrenal, head and neck, and SDH-mutated disease

• Functional imaging is increasingly first-line in higher-risk scenarios:

  • ⁶⁸Ga-DOTATATE PET/CT - high sensitivity for SDH-mutated, metastatic, or extra-adrenal disease

  • ¹⁸F-FDG PET/CT - preferred for high-grade, metastatic, or SDHB-mutated PPGL

  • ¹²³I-MIBG - useful when ¹³¹I-MIBG therapy is being considered

Step 3 - Genetic Testing

This is the biggest PACES-relevant change.

• The 2023 ESE guideline recommends offering germline genetic testing to all patients with PPGL, not just those with young onset, bilateral, extra-adrenal, or malignant disease

• Cost-effectiveness data have driven this shift

• Susceptibility genes include RET, VHL, NF1, SDHB, SDHD, SDHC, SDHA, SDHAF2, MAX, TMEM127, FH

• SDHB mutations carry a particularly high metastatic risk (up to 40–50%) and a more aggressive course

PACES tip: Be ready to discuss what a positive genetic test means for the patient and their family. Variants of uncertain significance (VUS) are common in panels - the counselling point is that a pathogenic result triggers family cascade testing and lifelong surveillance.

Preoperative Management: The Alpha Blockade Debate

Traditionally, candidates were taught "at least 14 days of phenoxybenzamine before surgery." Recent evidence has softened that position.

What Has Changed

• Duration of alpha blockade is now individualised, not a fixed two-week ritual

• Recent meta-analyses have not shown a clear mortality benefit of 14 days over 7 days in non-metastatic disease

• The choice of agent is no longer rigid - selective alpha-1 blockers are widely used in many centres

• However, adequate alpha blockade before any invasive procedure remains non-negotiable

A PACES-Ready Approach

1. Start an alpha-1 selective blocker (doxazosin or prazosin) or phenoxybenzamine

2. Titrate over 2–3 weeks to BP target (seated <130/80, standing systolic >90)

3. Only add a beta-blocker once alpha blockade is established - to avoid unopposed alpha stimulation and hypertensive crisis

4. Encourage high salt and fluid intake to restore intravascular volume

5. Add a calcium channel blocker (amlodipine, nifedipine) if needed

6. Consider metyrosine in catecholamine-resistant hypertension or to shorten preoperative preparation

Phenoxybenzamine vs Selective Alpha-1 Blockers

• Phenoxybenzamine: non-selective, irreversible - more hypotension, reflex tachycardia, nasal congestion

• Doxazosin/prazosin: selective, reversible - better tolerated, historically thought to be less cardioprotective

• Recent prospective work suggests doxazosin is non-inferior to phenoxybenzamine for intraoperative haemodynamic stability in low-risk patients, and is now considered acceptable first-line in many centres

Surgical and Postoperative Care

• Laparoscopic adrenalectomy is standard for most tumours <6 cm without local invasion

• Open surgery for large (>6 cm), invasive, or extra-adrenal disease

• Partial (cortical-sparing) adrenalectomy may be considered in hereditary bilateral disease to avoid lifelong steroid dependence

• Postoperative hypotension is common due to sudden catecholamine withdrawal - careful fluid titration and occasionally noradrenaline

• Hypoglycaemia can occur in the first 24–48 hours - check glucose regularly

• Lifelong biochemical surveillance, with frequency guided by genotype

Metastatic PPGL: Recent Therapeutic Updates

A brief mention in PACES is often enough, but recent developments are worth knowing:

• Tyrosine kinase inhibitors (cabozantinib, sunitinib) - meaningful activity in progressive metastatic disease

• PRRT (peptide receptor radionuclide therapy) with ¹⁷⁷Lu-DOTATATE for somatostatin-receptor positive metastatic disease

• Belzutifan (HIF-2α inhibitor) for VHL-associated PPGL

• Temozolomide-based chemotherapy for aggressive SDHB-mutated disease

• Circulating tumour DNA is under investigation for monitoring minimal residual disease

How to Approach a PACES Pheochromocytoma Station

History (Station 2 / 5)

• Detailed symptom timeline: frequency, duration, triggers, recovery

• Episodic vs sustained features

• Family history - be specific, ask about adrenal, thyroid, kidney, neurological conditions, sudden death in young relatives

• Past medical history: paroxysmal AF, "anxiety disorder," unexplained hypertensive episodes during surgery or pregnancy

• Drug history including OTC and supplements

Examination

• Blood pressure both arms, lying and standing

• Pulse, rhythm

• Fundoscopy (look for hypertensive retinopathy)

• Cardiovascular exam (LVH, signs of coarctation in young patients)

• Abdominal exam (rarely a palpable mass, but check for succussion splash or other findings)

• Skin: café-au-lait macules, neurofibromas, mucosal neuromas (MEN2B)

• Thyroid (MEN2 association)

• Spine (VHL-associated haemangioblastoma screening if relevant)

Investigations You Should Offer

• Plasma or 24h urinary fractionated metanephrines

• Chromogranin A as an adjunct neuroendocrine marker

• CT/MRI adrenals

• Functional imaging (⁶⁸Ga-DOTATATE PET/CT) if indicated

• Genetic counselling and germline panel testing

• MEN2 screen: calcitonin, serum calcium/PTH

• VHL screen: ophthalmology review, MRI brain and spine, renal surveillance

Management Discussion

• Initiate alpha blockade with appropriate titration

• Volume expansion with high salt and fluid intake

• Optimise BP and HR before surgery

• MDT discussion (endocrinology, endocrine surgery, anaesthesia, genetics)

• Surgery at an experienced centre

• Genetic counselling and family cascade testing if a pathogenic variant is identified

• Lifelong biochemical and imaging surveillance

• Patient education on steroid sick day rules if bilateral adrenalectomy

Differential Diagnosis Pearls for PACES

Key Take-Home Messages for PACES

1. Think of PPGL in any paroxysmal, stereotyped, autonomic episode with hypertension.

2. Plasma or urinary fractionated metanephrines are first-line biochemistry; sample supine when possible.

3. ⁶⁸Ga-DOTATATE PET/CT is now often first-line functional imaging in metastatic, hereditary, or extra-adrenal disease.

4. Offer genetic testing to all patients with PPGL - this is a 2023 guideline change, not an option.

5. Alpha blockade before surgery is non-negotiable; beta-blockade only after.

6. Duration and choice of alpha blocker are individualised rather than rigidly 14 days of phenoxybenzamine.

7. Recognise postoperative complications - hypotension, hypoglycaemia, and the need for lifelong follow-up.

8. MDT, family screening, and survivorship care are part of the modern management plan.

9. Pallor (not flushing) with paroxysmal symptoms is a strong PACES-relevant clue.

Recent Guidelines to Anchor Your Reading

• ESE Clinical Practice Guideline on PPGL (2023 update)

• ESMO/EURACAN Clinical Practice Guidelines for metastatic PPGL (2023)

• Endocrine Society Scientific Statement on PPGL (2014, with subsequent working group updates)

• NICE Hypertension Guideline (NG136) - relevant for identifying when to consider PPGL

Pheochromocytoma remains a high-yield PACES case, and the recent shift toward universal genetic testing, modern functional imaging, and individualised preoperative care has changed what a complete answer looks like. Read the ESE 2023 guideline once, rehearse the workup algorithm out loud, and the case becomes far more straightforward than the volume of information suggests.