Pheochromocytoma Clinical Overview

I. The "On-Call" Snapshot

Clinical Significance in Malaysia: This is a rare but critical diagnosis. You will see it in exams more than in the ward, but missing it can lead to perioperative mortality or a catastrophic hypertensive crisis. It is a key reversible cause of secondary hypertension in the young.

High-Yield Definition: A catecholamine-secreting neuroendocrine tumour arising from chromaffin cells of the adrenal medulla. An extra-adrenal tumour is termed a paraganglioma. (Source: Endocrine Society Clinical Practice Guideline, 2014).

Clinical One-Liner: The "10% tumour" that causes episodic headaches, sweating, and palpitations with wild, difficult-to-control blood pressure.

II. Etiology & Risk Factors

Etiology: Arises from chromaffin cells of the sympatho-adrenal system. While most are sporadic, up to 40% are now known to be hereditary.

Risk Factors (Primarily Genetic Syndromes):

• Multiple Endocrine Neoplasia Type 2 (MEN 2A & 2B): Due to RET proto-oncogene mutation.

• Von Hippel-Lindau (VHL) Syndrome: VHL gene mutation.

• Neurofibromatosis Type 1 (NF1): NF1 gene mutation. Look for the café-au-lait spots.

• Hereditary Paraganglioma Syndromes: Due to succinate dehydrogenase (SDHx) gene mutations.

III. Quick Pathophysiology

The tumour autonomously synthesises and secretes excessive catecholamines (norepinephrine, epinephrine, dopamine). This leads to massive, unregulated stimulation of adrenergic (α and β) receptors throughout the body. The episodic nature of symptoms is due to intermittent tumoural catecholamine release, which can be triggered by pressure, stress, or medications.

IV. Classification

• Anatomical:

  • Pheochromocytoma: Intra-adrenal tumour.

  • Paraganglioma: Extra-adrenal tumour (can be anywhere along the sympathetic chain).

• Biochemical:

  • Noradrenergic: Secretes predominantly norepinephrine. Typically causes sustained hypertension.

  • Adrenergic: Secretes predominantly epinephrine. More likely to cause episodic symptoms, tachycardia, and systolic hypertension.

V. Clinical Assessment

🚩 Red Flags & Immediate Actions

• Labile/Refractory BP (>180/120 mmHg) with end-organ damage (chest pain, confusion, SOB): Pheochromocytoma crisis.

  • Action: Immediate HDU/ICU admission. Urgent IV anti-hypertensives (phentolamine, sodium nitroprusside). Consult seniors immediately.

  • Reason: High risk of MI, stroke, ARDS, or multi-organ failure.

• Hyperthermia, altered mental status, haemodynamic instability:

  • Action: As above. Aggressive cooling and supportive care.

  • Reason: Represents multi-systemic effects of extreme catecholamine excess.

History

• Key Diagnostic Clues (Classic Triad):

  • Episodic Headache (severe, throbbing)

  • Diaphoresis (profuse, drenching sweats)

  • Tachycardia/Palpitations

  • (The presence of all three during a hypertensive episode is highly specific).

• Symptom Breakdown by Frequency:

  • Common (>50%): Hypertension (sustained or paroxysmal), headache, sweating, palpitations, anxiety/sense of impending doom.

  • Less Common (10-50%): Pallor, nausea, chest or abdominal pain, tremor, fatigue.

  • Rare (<10%): Weight loss, visual disturbances, constipation (from opiates produced by tumour).

• Pertinent Negatives:

  • Absence of the classic triad during a symptomatic spell.

  • No family history of pheochromocytoma or related syndromes.

  • No history of spells induced by anaesthesia, surgery, or specific drugs (e.g., beta-blockers, TCAs).

Physical Examination (OSCE Approach)

• General Inspection: Patient may be normal between spells. During an attack, they may appear pale, anxious, and profusely sweaty. Look for stigmas of genetic syndromes (e.g., café-au-lait macules in NF1, marfanoid habitus in MEN2B).

• Vitals:

  • Hypertension: Can be severe.

  • Orthostatic Hypotension: Common due to catecholamine-induced intravascular volume contraction. A key clinical clue.

  • Tachycardia.

• Disease-Specific Examination:

  • Cardiovascular: Assess for signs of hypertensive heart disease (e.g., displaced apex beat, S4 gallop).

  • Abdomen: Palpation is generally avoided due to the theoretical risk of provoking catecholamine release, although this is rare.

• Differentiating Disease Stage:

  • Early / Asymptomatic: May be an incidental finding on imaging ("incidentaloma").

  • Symptomatic / Paroxysmal: Patient experiences classic spells.

  • Crisis / Complicated: Patient presents with end-organ damage as listed under Red Flags.

• Clinical Pearl: Unexplained hypertension in a young patient, or a hypertensive crisis precipitated by beta-blocker monotherapy, should make you think of pheochromocytoma. Beta-blockade without alpha-blockade leads to unopposed α-receptor stimulation, worsening vasoconstriction and BP.

VI. Diagnostic Workflow

Differential Diagnosis

1. Hyperthyroidism:

   • Points For: Sweating, palpitations, anxiety, hypertension.

   • Points Against: Lacks the severe episodic headaches. Usually has goitre, proptosis, or a persistent fine tremor.

   • How to Differentiate: Thyroid Function Test (TFT).

2. Panic Disorder / Anxiety:

   • Points For: Episodic palpitations, sense of impending doom, sweating.

   • Points Against: Severe hypertension (>180/110) during an attack is less common.

   • How to Differentiate: Biochemical testing for metanephrines is definitive.

3. Carcinoid Syndrome:

   • Points For: Episodic symptoms (flushing).

   • Points Against: Flushing in carcinoid is typically red and associated with diarrhoea and bronchospasm. Pheochromocytoma causes pallor.

   • How to Differentiate: 24-hour urinary 5-HIAA.

Investigations Plan

The rule is: BIOCHEMICAL CONFIRMATION before LOCALISATION.

• Bedside / Initial (First 15 Mins):

  • ECG: Look for sinus tachycardia, SVT, or signs of ischaemia.

  • Capillary Blood Glucose: May be elevated due to catecholamine effects.

• First-Line Labs (Biochemical Diagnosis):

  • Plasma free metanephrines: Highest sensitivity. The preferred initial test if available.

  • 24-hour urinary fractionated metanephrines and catecholamines: High specificity. Requires meticulous collection and patient instruction to avoid interfering substances (caffeine, bananas, TCAs, decongestants).

• Imaging (For Localisation, only after biochemical proof):

  • First-line: CT of abdomen and pelvis with contrast.

  • Second-line: MRI is preferred for children, pregnant women, or if there is an allergy to CT contrast.

  • Functional Imaging: 123I-MIBG Scintigraphy or 68Ga-DOTATATE PET/CT if CT/MRI is negative or to detect metastatic disease.

VII. Staging & Severity Assessment

• Severity is assessed clinically based on BP levels, frequency of spells, and evidence of end-organ damage.

• Staging is primarily for malignant disease using the TNM system. Histological scoring systems like the PASS score (Pheochromocytoma of the Adrenal gland Scaled Score) can help predict malignant potential but are not definitive.

VIII. Management Plan

A. Principle of Management:

Medical optimisation to block the effects of catecholamines, followed by definitive surgical resection of the tumour.

B. Immediate Stabilisation (The ABCDE Plan for Pheo Crisis):

• A/B: High-flow oxygen.

• C: IV access x2. Cautious IV fluids. For severe hypertension, use an IV alpha-blocker like phentolamine or a vasodilator like sodium nitroprusside.

• D: Monitor GCS.

• E: Manage hyperthermia with cooling blankets.

• Goal: Admit to HDU/ICU. Avoid pure beta-blockers.

C. Definitive Treatment (The Ward Round Plan):

• Pre-operative Medical Preparation (Essential for 10-14 days):

  1. Alpha-Blockade: The cornerstone of preparation.

     • Phenoxybenzamine (non-competitive, long-acting): Start 10mg BD, titrate up.

     • Alternatively, selective alpha-1 blockers (e.g., Prazosin, Doxazosin).

     • Target: BP <130/80 mmHg seated with evidence of orthostasis (systolic BP drop >10-20 mmHg on standing), which indicates effective blockade.

  2. High Sodium Diet & Fluid Intake: To restore intravascular volume.

  3. Beta-Blockade:

     • MUST be started ONLY AFTER effective alpha-blockade is achieved.

     • Used to control reflex tachycardia.

     • Use Propranolol or a cardioselective agent like Metoprolol.

• Surgical Treatment:

  • Adrenalectomy (usually laparoscopic) is the definitive cure. Requires an experienced surgeon and anaesthetist.

• Post-Operative Management:

  • Monitor for hypotension (due to abrupt cessation of catecholamines) and hypoglycaemia (due to rebound insulin secretion).

  • Usually managed in HDU for the first 24 hours.

D. Long-Term & Discharge Plan:

• Annual biochemical screening (plasma or urine metanephrines) for life to detect recurrence.

• Genetic counselling and testing for patient and family members, especially if young or with bilateral disease.

• Lifelong steroid replacement if bilateral adrenalectomy was performed.

IX. Complications

• Immediate: Hypertensive crisis, catecholamine-induced cardiomyopathy, MI, CVA, arrhythmias, ARDS.

• Short-Term (Post-Op): Hypotension, hypoglycaemia, surgical bleeding.

• Long-Term: Recurrence (benign or malignant), metastasis (~10-15% of cases are malignant).

X. Prognosis

• Benign Pheochromocytoma: Excellent prognosis after complete resection. 5-year survival >95%.

• Malignant/Metastatic Pheochromocytoma: Variable prognosis. 5-year survival is approximately 50-60%.

• Key Prognostic Factors: Presence of metastases, tumour size >5cm, extra-adrenal location.

XI. How to Present to Your Senior

Use the SBAR format.

"Dr., for your review, a 34-year-old gentleman in Bed 5.

• Situation: Admitted for investigation of refractory hypertension. He just had a spell of severe headache and palpitations, BP shot up to 220/125 mmHg.

• Background: Has a 6-month history of these episodes. Otherwise fit and well. No significant family history.

• Assessment: My primary concern is a pheochromocytoma crisis. The clinical triad is present.

• Recommendation: I have administered a stat dose of IV Labetalol but BP is not responding well. I think we need to consider an alpha-blocker like phentolamine. I have sent off blood for plasma metanephrines and plan to start a 24-hour urine collection. Request your urgent review to guide further management in HDU."

XII. Summary & Further Reading

Top 3 Takeaways:

1. Suspect in any patient with the classic triad (episodic headache, sweating, palpitations) and labile hypertension.

2. The diagnostic sequence is absolute: Biochemistry first, then imaging.

3. The pre-operative management rule is non-negotiable: Alpha-blockade, then beta-blockade.

Key Resources:

• Primary Guideline: Endocrine Society Clinical Practice Guideline on Pheochromocytoma and Paraganglioma (2014). (Still the landmark guide).

• UpToDate: "Pheochromocytoma and paraganglioma in adults"

• Amboss: "Pheochromocytoma"