Adrenal

Background

A pheochromocytoma is an endocrine tumour arising from the chromaffin cells of the adrenal gland.

• About one-third of cases are familial.
• 1–25% originate outside the adrenal gland; when extra-adrenal, the tumour is called a paraganglioma. Extra-adrenal sites include the organ of Zuckerkandl (at the bifurcation of the aorta), the sympathetic chain, and perivesical tissue.
• About 5% of incidental adrenal masses harbour a pheochromocytoma.
• Malignant pheochromocytoma can currently only be defined by the presence of clinical metastases; a number of pathologic criteria to differentiate benign from malignant disease have been proposed, but none is agreed upon.

Pathology

The specific histopathological finding is zellballen — well-defined nests of polygonal cells surrounded by fibrovascular stroma.

Hereditary Forms

Compared with sporadic cases, pheochromocytomas in familial syndromes are almost always bilateral and more frequently malignant, although clinical manifestations are similar. In VHL the risk of malignancy is low and the tumour characteristically produces norepinephrine; unlike VHL, MEN2 and NF1 predominantly produce epinephrine.

Syndrome	Clinical characteristics	Risk of pheochromocytoma	Risk of malignant disease
Multiple endocrine neoplasia type 2A	Medullary thyroid cancer, hyperparathyroidism, cutaneous lichen amyloidosis	50%	3%
Multiple endocrine neoplasia type 2B	Medullary thyroid cancer, hyperparathyroidism (rare), multiple neuromas, marfanoid body habitus	50%	3%
Von Hippel-Lindau (VHL), type 2	HIPPPEEL — CNS and/or retinal hemangioblastomas, ccRCC (increased risk) and renal cysts, pheochromocytoma, paraganglioma, pancreatic neuroendocrine tumours and cysts, epididymal cystadenoma, ear (endolymphatic sac tumour), broad ligament tumours	10–20%	5%
Neurofibromatosis type 1	Neurofibromas, café-au-lait skin spots	1%	11%
Familial paraganglioma syndrome type 4	Carotid body tumours (chemodectomas); vagal, jugular, tympanic, abdominal, thoracic paragangliomas	20%	30–50%
Familial paraganglioma syndrome type 1	Carotid body tumours (chemodectomas); vagal, jugular, tympanic, abdominal, thoracic paragangliomas	20%	<3%

Diagnosis and Evaluation

History and Physical Exam

The classic triad is headache, episodic sudden perspiration, and tachycardia. Other symptoms (12) include anxiety, sweating, palpitations, abdominal pain, chest pain, pallor, nausea, dyspnea, tremor, weight loss, flushing, and visual disturbance.

Clinical behaviour is heterogeneous because of variability in the amount and ratio of the catecholamines secreted (norepinephrine, epinephrine, dopamine):

• Norepinephrine-predominant tumours (e.g. von Hippel–Lindau syndrome) cause hypertension and sweating, through norepinephrine's vasoconstricting action on the α-adrenoreceptor.
• Epinephrine-predominant tumours (rare, usually limited to the adrenals or the organ of Zuckerkandl) cause syncope or hypotensive episodes, through epinephrine's vasodilatory action on the β2 receptor.

Agonist potency order:

• α1: epinephrine ≥ norepinephrine >> isoprenaline
• α2: epinephrine ≥ norepinephrine >> isoprenaline
• β1: isoprenaline > epinephrine = norepinephrine
• β2: isoprenaline > epinephrine >> norepinephrine
• β3: isoprenaline = norepinephrine > epinephrine

Episodic hypertensive episodes may be triggered by induction of anaesthesia, labour and delivery, instrumentation or biopsy of the tumour, strenuous physical activity, and tyramine-rich foods (red wine, chocolate, cheeses). Another serious presentation is catecholamine-induced cardiomyopathy, with congestive heart failure and cardiac arrhythmias.

Labs

Metanephrine / catecholamine testing

• The enzyme phenylethanolamine-N-methyltransferase (PNMT) catalyzes the conversion of norepinephrine to epinephrine and is relatively unique to the adrenal medulla (the brain and organ of Zuckerkandl also express it). This localization explains why the adrenal gland is the primary source of systemic epinephrine, despite chromaffin cells elsewhere in the sympathetic nervous system.
• Pheochromocytomas produce catecholamines (dopamine, norepinephrine, epinephrine) in varying amounts, and release into the bloodstream is often paroxysmal. Metanephrines are the methylated metabolites of catecholamines: O-methylation (catalyzed by COMT) of norepinephrine produces normetanephrine, and of epinephrine produces metanephrine — together known as the metanephrines.
• Conversion of catecholamines to metanephrines within pheochromocytomas is an uninterrupted process, so plasma metanephrine concentration is much more sensitive for detecting pheochromocytoma than measuring the (often paroxysmal) rises in plasma catecholamines.
• In the past, urinary and serum catecholamines were the mainstay, but had only moderate sensitivity and specificity and have largely been replaced by metanephrines. Urinary catecholamine measurement is nevertheless still recommended in conjunction with urinary fractionated metanephrine testing.
• Plasma fractionated metanephrines and 24-hour urinary fractionated metanephrines and catecholamines are the mainstay biochemical tests. Plasma fractionated metanephrines are used primarily when the index of suspicion is high; 24-hour urinary fractionated metanephrines when it is low.

Guideline recommendations:

• 2011 CUA Incidental Adrenal Mass: screen with 24-hour urinary fractionated metanephrines and/or catecholamines.
• 2014 Endocrine Society (most recent as of October 2019): plasma free metanephrines or 24-hour urinary fractionated metanephrines.
• 2019 AUA Update: initial screening with plasma free metanephrines; urinary fractionated metanephrines are an alternative, with slightly lower diagnostic sensitivity.

"Fractionated" means the laboratory report details not only the amount of each compound type (e.g. metanephrines) but also the relative concentrations of each compound (e.g. normetanephrine vs metanephrine).

Pre-test conditions:

• Draw the blood sample after placing an IV cannula, dimming the room lights, and having the patient lie supine for 30 minutes, having minimized any pain or anxiety. Counsel patients to avoid caffeine for at least 24 hours beforehand.
• Acetaminophen can produce a false positive (cross-reactivity in the assay) and should be stopped at least 5 days before testing. Tricyclic antidepressants and phenoxybenzamine should also be stopped, as they cause false positives. Usual antihypertensive therapy can be continued. Although β-blockade can potentially cause a false positive, the current recommendation is to stop it only on repeat testing.

Vanillylmandelic acid (VMA) testing

VMA is the primary end-metabolite of catecholamines. The sympathetic nervous system lacks PNMT and so cannot produce epinephrine, contributing only normetanephrine (from norepinephrine) to the serum, not metanephrine (from epinephrine). Indeed, > 90% of metanephrine and ≥ 20% of normetanephrine in the bloodstream derive from the adrenal medulla (PNMT is also present in the brain and organ of Zuckerkandl). Consequently the rise in VMA — the combined end-metabolite of norepinephrine and epinephrine — with a pheochromocytoma is much less dramatic than the rise in metanephrines, so the sensitivity of urine VMA is low; its specificity, however, is high, especially in non-familial cases.

Oral clonidine testing

Used to distinguish suspected pheochromocytoma from essential hypertension in patients with minimally elevated plasma catecholamines. Patients with pheochromocytoma usually have elevated plasma catecholamines but can rarely present with normal or mildly elevated levels. With clonidine, patients with essential hypertension experience a significant drop in norepinephrine (suppression of sympathetic production), whereas those with pheochromocytoma do not.

Imaging

• 18F-FDG PET (fluorine-18 fluorodeoxyglucose positron emission tomography) — the gold-standard modality for definitive staging. Superior test characteristics to CT, MRI, and metaiodobenzylguanidine (MIBG) scintigraphy, with better accuracy than 123I-MIBG in nearly all patients, especially for identifying metastatic disease.
• MIBG — uses a small-molecule analogue of norepinephrine; high specificity but low sensitivity for diagnostic disease identification. Useful when a suspected pheochromocytoma cannot be localized or when metastatic disease is suspected.
• In the most common, urologically relevant scenario — a solitary adrenal mass on cross-sectional imaging with a biochemical evaluation indicative of pheochromocytoma — MIBG or 18F-FDG PET may be safely omitted, as these functional studies only confirm what is already known and do not alter management. However, for large (>5 cm) tumours, MIBG or 18F-FDG PET is likely prudent to assess for metastatic disease before surgery and counsel the patient appropriately.
• MRI — distinct low signal intensity on T1-weighted imaging and high signal intensity on T2-weighted imaging.
• CT — on unenhanced CT, pheochromocytomas are typically > 10 HU (mean ≈35 HU) given their rich vascularity and low lipid content, helping differentiate them from lipid-rich adenomas. If the lesion is not an adenoma, an adrenal-mass-protocol CT with IV contrast evaluates tumour washout: benign lesions wash out >50% on delayed imaging, whereas pheochromocytoma, adrenocortical carcinoma, and metastatic tumours do not. Pheochromocytomas usually measure >10 HU on unenhanced CT and >100 HU on contrast imaging, and are often well-circumscribed with or without necrotic or cystic elements. Any evaluation of an adenoma should still include plasma free metanephrines to rule out pheochromocytoma.

Genetic Counselling

Investigation for familial syndromes is warranted in patients younger than 50 years with a significant family history, an extra-adrenal pheochromocytoma (hereditary paraganglioma syndrome), or bilateral/multifocal tumours. If a mutation is identified, screening should also be offered to asymptomatic at-risk family members.

Management

Pheochromocytoma is a surgical disease — complete resection of the tumour is advised whenever possible. No level 1 evidence exists regarding optimal preoperative or perioperative management.

General principles (4):

• Preoperative cardiology or anaesthesia consultation, given the risk of cardiomyopathy; preoperative cardiac work-up (electrocardiography, echocardiography) and assessment of hypertension-induced end-organ dysfunction are indicated.
• Restoration of intravascular volume.
• Preoperative medications (α-blockade followed by β-blockade).
• A monitored bed postoperatively.

Restoration of intravascular volume

The most important component of preoperative management. Most centres admit patients the day before surgery and initiate aggressive IV fluid resuscitation.

Preoperative medications

All patients with pheochromocytoma and an abnormal metabolic evaluation undergo preoperative catecholamine blockade — including those without blood-pressure elevation or classic symptoms — because catecholamine release during intraoperative tumour manipulation can cause hazardous blood-pressure elevation and cardiac arrhythmias. (Recent data suggest preoperative α-blockade may not be necessary in normotensive, asymptomatic patients.)

α-Blockade — helps with both haemodynamic and glucose control.

• Phenoxybenzamine — the most common α-blocker used for preoperative catecholamine blockade. An irreversible, non-selective α-receptor blocker; intraoperative catecholamine surges typically do not override it, because reversal requires synthesis of new receptor molecules. Its non-selective nature may cause tachycardia (β-adrenergic blockade may then be necessary), and prolonged postoperative hypotension and CNS effects such as somnolence may be expected. Started 7–14 days before surgery — typically at 10 mg twice daily with stepwise increases of 10–20 mg every 2–3 days to a final dose of 1 mg/kg if tolerated, with blood-pressure checks at least 3 times daily. The last dose is usually given the night before surgery, and the next morning's dose is withheld to minimize prolonged hypotension after tumour resection.
• Newer selective, competitive α1-adrenergic blockers (doxazosin, prazosin, terazosin) obviate the drug-induced need for β-blockade.
• If phenoxybenzamine is not effective, start metyrosine (blocks catecholamine biosynthesis by inhibiting conversion of tyrosine to L-dopa), generally added for extensive disease with large catecholamine increases.
• Acute hypertensive attacks can also be treated with a short-acting α-blocker such as phentolamine.

β-Blockade

• Must be given with caution in patients with myocardial depression, and should never be started before appropriate α-blockade — in the absence of α-blockade, β-antagonists potentiate the action of epinephrine on α1 receptors (blocking β2-mediated arteriolar dilation), causing hypertension. Selective β1-adrenoreceptor blockers such as atenolol and metoprolol are therefore usually preferred.
• May be added when (2): systolic blood pressure is <100 mmHg, or tachycardia/reflex tachycardia develops.

Calcium channel blockers — some studies report that sole use of a calcium channel blocker is sufficient for safe resection, avoiding the reflex tachycardia and postoperative hypotension seen with phenoxybenzamine; this strategy should be reserved for patients who are normotensive with paroxysmal hypertension and a normal baseline blood pressure. Usually 2 weeks of preoperative calcium channel blockade is sufficient.

Monitored bed postoperatively

In the immediate postoperative period, consider overnight ICU admission for active monitoring. If phenoxybenzamine was used for α-blockade, hypotension is common given the agent's lasting effects. Moreover, in a high-catecholamine state, α2-adrenoreceptor stimulation inhibits insulin release; withdrawal of this adrenergic stimulus after tumour resection may cause rebound hyperinsulinemia and subsequent hypoglycemia.

Post-operative follow-up

• Repeat metabolic testing ≈2 weeks after adrenalectomy to document normalization of catecholamine levels.
• Postoperative cross-sectional imaging is reasonable to document tumour resection and healing of the resection bed; subsequent imaging is guided by biochemical testing.
• Annual biochemical follow-up is mandatory for all patients with resected pheochromocytoma, and lifelong screening for recurrence is recommended (10-year recurrence rates as high as 16%); no consensus on follow-up protocols exists.
• In a patient with persistent hypertension 2–3 months after adrenalectomy, residual tumour elsewhere in the body must be considered: measure plasma free metanephrines first, and if abnormal, an MIBG scan may help identify the lesion's location.

Special Scenarios

Hereditary pheochromocytoma — for patients with MEN-2 and VHL, the risk of malignancy is low whereas the risk of bilateral disease is significant, so partial cortical-sparing adrenalectomy has been advocated to avoid lifelong hormonal replacement and its associated morbidity.

Malignant pheochromocytoma — can currently only be defined by the presence of clinical metastases (several pathologic criteria to differentiate benign from malignant disease have been proposed, but none is agreed upon). Therapy for metastatic disease is largely palliative. Surgical metastasectomy of resectable disease is the standard of care, though little evidence shows it prolongs survival or relieves symptoms better than medical treatment with α/β-blockade and α-methyl-p-tyrosine. Chemotherapy is used primarily when MIBG therapy has failed or when tumours do not take up MIBG on initial imaging.

Pheochromocytoma in pregnancy — in late-term pregnancy, treat with α-adrenergic blockade (phenoxybenzamine) until the fetus reaches maturity to manage the hypertension; then perform caesarean section and tumour resection in one operation. The patient should not undergo the stress of vaginal delivery.

Self-Test

1. Where can extra-adrenal pheochromocytomas originate? The organ of Zuckerkandl (aortic bifurcation), the sympathetic chain, and perivesical tissue.

2. List the clinical manifestations of a pheochromocytoma. The classic triad — headache, episodic sweating, tachycardia — plus anxiety, palpitations, abdominal pain, chest pain, pallor, nausea, dyspnea, tremor, weight loss, flushing, and visual disturbance.

3. What laboratory test do the CUA guidelines recommend to rule out pheochromocytoma? 24-hour urinary fractionated metanephrines and/or catecholamines.

4. What is the gold-standard imaging for pheochromocytoma? 18F-FDG PET (for definitive staging).

5. List the hereditary forms of pheochromocytoma. MEN2A, MEN2B, von Hippel–Lindau type 2, neurofibromatosis type 1, and familial paraganglioma syndromes types 1 and 4.

6. Describe the key aspects of pre- and post-operative management. α-blockade for 7–14 days before surgery (± a deferred β-blocker if the patient develops tachycardia); restoration of intravascular volume, considering admission the day before surgery; and postoperative ICU admission to monitor for hypotension, hyperinsulinemia, and resulting hypoglycemia.