Phaeochromocytoma is a rare, catecholamine-secreting neuroendocrine neoplasm originating from chromaffin cells within the adrenal medulla 2,3. Although representing fewer than 0.2% of hypertensive patients, its recognition is paramount due to the potential for fatal cardiovascular complications induced by profound surges of circulating epinephrine and norepinephrine 2,4. Most tumours are sporadic, but approximately 30-40% are linked to familial hereditary cancer syndromes, necessitating comprehensive genetic screening and multidisciplinary management 2.
1. Etiology & Risk Factors
- Sporadic Genetic Alterations: Approximately 60% of cases arise without a known inherited familial predisposition, typically manifesting in adults aged 30 to 50 years.
- Familial Syndromes (Genetic Mutations): Up to 40% of phaeochromocytomas are hereditary, associated with autosomal dominant cancer predisposition syndromes including Multiple Endocrine Neoplasia type 2 (MEN 2A and MEN 2B driven by RET proto-oncogene mutations), von Hippel-Lindau (VHL) syndrome (VHL gene mutations), and Neurofibromatosis type 1 (NF1, NF1 gene mutations) 2.
- Paraganglioma-Phaeochromocytoma Syndromes: Mutations involving genes encoding subunits of the succinate dehydrogenase mitochondrial complex (specifically SDHA, SDHB, SDHC, and SDHD, along with SDHAF2) significantly increase predisposition to extra-adrenal paragangliomas and malignant phaeochromocytomas 5. Additional rare susceptibility genes include TMEM127, MAX, and EPAS1 (HIF2A).
- Precipitating Triggers of Crises: Endogenous or exogenous stressors—such as physical exertion, surgical manipulation, trauma, general anesthesia, childbirth, or administration of specific provocative agents (e.g., opioids, metoclopramide, tricyclic antidepressants)—can trigger massive catecholamine dumping 4.
2. Pathophysiology
Chromaffin cells of the adrenal medulla derive from the embryonic neural crest and synthesize catecholamines from the amino acid tyrosine 3,7. Tyrosine is hydroxylated to DOPA via tyrosine hydroxylase (the rate-limiting step), decarboxylated to dopamine, and subsequently hydroxylated within storage vesicles to form norepinephrine. In the adrenal medulla, phenylethanolamine N-methyltransferase (PNMT)—induced by high local cortisol concentrations from the adrenal cortex—catalyses the methylation of norepinephrine into epinephrine 3,7.
Unlike normal adrenal medullary tissue, phaeochromocytoma cells exhibit impaired vesicular storage and augmented constitutive or episodic exocytosis of catecholamines. These vasoactive amines spill directly into the sinusoidal vasculature, precipitating systemic activation of alpha-1, alpha-2, beta-1, and beta-2 adrenergic receptors 2,3. Activation of vascular alpha-1 receptors drives severe arterial vasoconstriction, elevating systemic vascular resistance and blood pressure 3. Concurrently, stimulation of cardiac beta-1 receptors induces positive inotropy, chronotropy, and dromotropy, manifesting clinically as tachycardia and palpitations 2. Chronic supraphysiological catecholamine exposure results in catecholamine-induced cardiomyopathy, focal myocardial necrosis, contraction band necrosis, interstitial fibrosis, and down-regulation of peripheral adrenergic receptors 2.
3. Clinical Presentation & Classic Clinical Signs
- History & Cardinal Symptoms: The classical presentation features paroxysmal spells characterized by the triad of episodic severe headache, profuse diaphoresis, and tachycardia accompanied by marked hypertension 2,3. These attacks typically last from 15 minutes to several hours, occurring with increasing frequency over time. Additional symptoms include severe anxiety, tremulousness, pallor, chest pain, abdominal pain, nausea, and weight loss 2.
- Physical Examination & Named Clinical Signs: Sustained or paroxysmal hypertension is universally present in the vast majority of symptomatic patients 2,3. Orthostatic hypotension may occur secondary to contracted intravascular volume resulting from chronic intense peripheral vasoconstriction. Paradoxical blood pressure responses to specific drugs or physical palpation of the abdomen (diagnostic tumor provocation) can elicit dramatic acute hypertensive surges 3. Retinal examination may reveal hypertensive retinopathy during acute crises 2.
4. Diagnostic Workup & Interpretation (Laboratory, Imaging & ECG/Pathology)
| Diagnostic Modality / Test | Expected Clinical & Radiological / Laboratory Finding |
|---|---|
| Gold-Standard Investigation | Measurement of plasma free metanephrines or 24-hour urinary fractionated metanephrines and catecholamines, demonstrating elevations exceeding 3 to 4 times the upper limit of normal 2. |
| Laboratory Panel | Elevated urinary and plasma levels of metanephrine and normetanephrine (metabolites produced continuously within tumour cells via catechol-O-methyltransferase). Mild secondary hyperglycaemia may occur due to catecholamine inhibition of insulin secretion and enhanced glycogenolysis 2,3. |
| Imaging / Radiology (X-ray, US, CT, MRI) | Adrenal multiphasic CT with IV contrast demonstrating a well-circumscribed, highly vascular, heterogeneous mass often >3 cm with cystic/necrotic areas. Abdominal MRI shows characteristic high signal intensity on T2-weighted sequences ("light-bulb" hyperintensity) 2. Functional imaging with 68Ga-DOTATATE PET/CT or 123I-MIBG scintigraphy is utilized for metastatic or extra-adrenal disease detection 2,5. |
| ECG / Histopathology / Procedural | Electrocardiogram may reveal left ventricular hypertrophy, ST-segment changes, T-wave inversions, or arrhythmias (e.g., atrial fibrillation, ventricular tachycardias) during paroxysms. Histopathology demonstrates Zellballen architecture with polygonal chief cells embedded in a rich capillary network, positive for synaptophysin, chromogranin A, and S100 protein in sustentacular cells 4. |
5. Staging, Classification & Clinical Scoring Systems
| Criterion / Stage / Score Component | Clinical Threshold, Points & Management Implication |
|---|---|
| WHO Histological Classification | All phaeochromocytomas are considered potentially malignant by the World Health Organization; true malignancy is defined strictly by the presence of metastases in non-chromaffin tissue (e.g., lymph nodes, bone, liver, lungs) rather than histological atypia 2,4. |
| PASS Score (Pheochromocytoma of the Adrenal Gland Scaled Score) | Histopathological scoring system where a score <4 suggests benign behaviour, whereas a score ≥4 indicates aggressive potential and increased risk of metastatic recurrence 4. |
| GAPP Score (Grading system for Adrenal Phaeochromocytoma and Paraganglioma) | Combines histological features, Ki-67 index, and catecholamine biochemical phenotype to stratify metastatic risk into low, intermediate, and high risk categories 4. |
6. Differential Diagnosis
| Differential Condition | Distinguishing Clinical, Biochemical & Imaging Features |
|---|---|
| Essential Hypertension with Panic Attacks / Anxiety | Normal baseline and paroxysmal metanephrine levels; episodes lack the characteristic triad of profuse diaphoresis, severe headache, and profound tachycardia 2,3. |
| Thyrotoxicosis | Characterised by suppressed TSH, elevated free T3/T4, weight loss despite increased appetite, fine tremor, and heat intolerance; normal plasma/urinary metanephrines 2. |
| Drug-Induced Hypertension / Sympathomimetic Toxicity | Clear history of exogenous agent exposure (e.g., cocaine, amphetamines, decongestants, monoamine oxidase inhibitor interactions); biochemical testing clarifies baseline profiles 2,4. |
| Obstructive Sleep Apnea (OSA) | Episodic nocturnal hypertension and morning headaches linked to upper airway collapse during sleep; confirmed via polysomnography with normal interictal metanephrines 2. |
7. Management & Treatment Protocol
- Initial Stabilization & Resuscitation: Immediate admission to a monitored clinical setting during acute crises. Management requires cessation of all offending trigger substances and rapid blood pressure control using intravenous agents (e.g., phentolamine, sodium nitroprusside, or nicardipine) 2,4.
- First-Line Medical / Pharmacological Therapy (with exact adult dosing): Pre-operative alpha-adrenergic blockade must be initiated 10 to 14 days prior to surgery to normalise blood pressure, expand contracted intravascular volume, and prevent intraoperative hypertensive crises 2,4.
- Phenoxybenzamine (Non-selective, non-competitive alpha-blocker): Initial adult dose of 10 mg orally twice daily, titrated upwards by 10–20 mg every few days until blood pressure is controlled and mild orthostatic hypotension is achieved (typical daily dose 40–120 mg divided twice daily) 2,4.
- Doxazosin or Prazosin (Selective alpha-1 blockers): Alternative options with lower incidence of postoperative hypotension. Doxazosin initiated at 1–2 mg orally daily, titrated up to 8–16 mg daily 4.
- High-Sodium Diet and Fluid Loading: Initiated 3–4 days after commencing alpha-blockade to reverse catecholamine-induced vasoconstriction-mediated blood volume contraction and prevent severe profound post-resection hypotension 2,4.
- Beta-Adrenergic Blockade: Introduced strictly only after effective alpha-blockade has been established for at least 48–72 hours (e.g., Propranolol 10–40 mg orally TID or Metoprolol 25–50 mg BID) to control reflex tachycardia and tachyarrhythmias. Never administer beta-blockers initially, as unopposed alpha-receptor vasoconstriction precipitates life-threatening hypertensive crises 2,4.
- Surgical / Interventional Indications: Definitive treatment is complete surgical resection, preferably via minimally invasive laparoscopic adrenalectomy for small-to-moderate tumours, or open radical resection for large, invasive, or malignant tumours 2,4.
8. Complications & Prognosis
- Acute Complications: Hypertensive crisis, acute myocardial infarction, acute heart failure, stress-induced (Takotsubo) cardiomyopathy, stroke, malignant cardiac arrhythmias, and intraoperative shock following tumour devascularisation 2,4.
- Prognosis: Patients with completely resected benign phaeochromocytomas enjoy an excellent long-term prognosis with normal life expectancy and normalized blood pressure in approximately 50-75% of cases 2,6. Prognosis is guarded in metastatic disease, which carries a 5-year survival rate ranging from 35% to 60% 2. Lifelong biochemical and clinical surveillance is mandatory due to the risk of local recurrence or metachronous extra-adrenal paragangliomas, particularly in patients harbouring germline genetic mutations 5,6.
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