Adrenal

Hypercortisolism

Hypercortisolism is a state of excess glucocorticoid activity. This section covers the HPA axis that regulates cortisol, the causes and classification of Cushing's syndrome, the diagnostic work-up, and management.

Hypothalamic–Pituitary–Adrenal (HPA) Axis

The axis runs hypothalamus → anterior pituitary → adrenal cortex, with cortisol exerting negative feedback on the top two levels.

• CRH (corticotropin-releasing hormone) — produced by the hypothalamus; acts on the corticotropic cells of the anterior pituitary to make ACTH. Secretion is under tight control of the hypothalamic suprachiasmatic nucleus and follows a circadian rhythm: cortisol is highest in the mornings and reaches its nadir at approximately 11 PM. Even small perturbations of this physiologic rhythm are considered pathologic.
• ACTH — has two functions: it stimulates production of glucocorticoids and androgens by the adrenal cortex, and it plays a critical role in maintaining adrenal cortical vitality. The most abundant cortical product is the androgens. Without ACTH (e.g. when its secretion is suppressed by exogenous steroid intake), all but the mineralocorticoid (aldosterone)-producing cells of the adrenal cortex atrophy. Secretion is stimulated by three factors: CRH (most important), oxytocin, and vasopressin.
• Negative feedback — glucocorticoids act on the hypothalamus and pituitary to inhibit production of CRH and ACTH.

Two clinical notes:

• Patients with hypercortisolism may be at higher risk for post-adrenalectomy adrenal insufficiency than patients with non-cortisol-secreting adrenal pathologies, because function of the contralateral gland may be suppressed.
• Stress, whether physiologic or psychologic, appears to be the most important variable in modulating activity of the HPA axis.

Pathophysiology

Cushing's syndrome is hypercortisolism secondary to excessive production of glucocorticoids by the adrenal cortex. Its causes fall into three main groups — exogenous, ACTH-dependent (endogenous), and ACTH-independent (endogenous):

Group	Share	Mechanism / key points
Exogenous	—	Most common cause of hypercortisolism in the Western world. Can cause virilization, including hirsutism, but should not elevate ketosteroid levels.
ACTH-dependent (endogenous)	85% of endogenous Cushing syndrome	Results from an increased serum ACTH level, caused by pathology extrinsic to the adrenal gland.
ACTH-independent (endogenous)	15% of endogenous Cushing syndrome; relatively rare	Caused by pathology intrinsic to the adrenal gland — unregulated overproduction of glucocorticoids by the adrenal(s), either a unilateral neoplasm or, rarely, bilateral disease.

The ACTH-dependent causes, in turn:

• Primary pituitary pathology (Cushing disease) — the most common cause (80%) of ACTH-dependent hypercortisolism.
• Ectopic ACTH production — nearly always malignant; the most common associated malignancies are bronchial carcinoid, small cell lung cancer, and less often pheochromocytoma.
• Ectopic CRH syndrome — extremely uncommon; bronchial carcinoma is the most common cause.

Subclinical Cushing syndrome is hypercortisolemia in the absence of an overt cushingoid phenotype. Surgical indications remain debated: some argue adrenalectomy should be performed only in patients who are potentially symptomatic and exhibit clinical signs (hypertension, obesity, glucose intolerance, or osteopenia), while others argue surgery should be offered to all patients to prevent the sequelae of hypercortisolism.

Hypercortisolism without Cushing's syndrome — other conditions can stimulate the HPA axis and mimic Cushing's syndrome:

• Some features of Cushing syndrome may be present: morbid obesity, glucocorticoid resistance, poorly controlled diabetes mellitus, pregnancy, depression, alcohol dependence.
• Unlikely to have any clinical features of Cushing syndrome: physical stress (hospitalization, surgery, pain), malnutrition or anorexia nervosa, intense chronic exercise, hypothalamic amenorrhea, corticosteroid-binding globulin excess (raises serum but not urine cortisol).

Diagnosis and Evaluation

History and Physical Exam

(See Campbell's 11th edition, Table 65-2, for the primary effects of glucocorticoids.)

The classic symptoms of hypercortisolism are nonspecific: central obesity, moon facies, buffalo hump, facial plethora, menstrual disturbances, hirsutism, proximal muscle weakness, easy bruisability, and abdominal striae. Cushing syndrome also produces systemic features — dyslipidemia, insulin resistance, and hypertension — similar to the highly prevalent metabolic syndrome.

Urological complications of Cushing's syndrome:

• Erectile dysfunction and decreased libido.
• Hypogonadal hypogonadism — relatively common in men with Cushing syndrome. Consider initiating a hypercortisolism work-up in men with low libido or erectile problems, low testosterone, and low gonadotropin levels.
• Urolithiasis — up to 50% of patients with Cushing syndrome have urolithiasis; stone formers with cushingoid features should also receive a hypercortisolemia evaluation.

Labs

The three most frequently performed tests for confirming hypercortisolism:

Test	Sensitivity	Specificity
Overnight low-dose dexamethasone suppression test (LD-DST)	85–90%	95–99%
Late-night salivary cortisol	92–100%	93–100%
24-hour urinary free cortisol	80–98%	45–98%

The 2011 CUA Guidelines on Incidental Adrenal Mass recommend the LD-DST. Second-line tests include the 2-day low-dose dexamethasone suppression test and midnight plasma cortisol testing.

Low-dose dexamethasone suppression test (LD-DST)

• Recommended in the evaluation of an incidental adrenal mass (2011 CUA Guidelines).
• Determines the presence of endogenous hypercortisolism, not the cause.
• A supraphysiologic 1 mg dose of dexamethasone (3–4× physiologic glucocorticoid levels) is given overnight, followed by measurement of morning serum cortisol, to test the glucocorticoid negative-feedback system.
• Without hypercortisolism: dexamethasone acts on the anterior pituitary corticotropes, suppresses ACTH production, and reduces serum cortisol.
• With endogenous hypercortisolism: dexamethasone fails to suppress cortisol production (pituitary adenomas are relatively insensitive to glucocorticoid inhibition), so serum cortisol remains elevated.
• Exogenous steroid use cannot be ruled out with this test — exogenous steroids, including the test dose, are not detected by the serum cortisol assay.

Drugs that affect the overnight LD-DST:

• Accelerate dexamethasone metabolism (CYP3A4 induction): phenobarbital, phenytoin, carbamazepine, primidone, rifampin, rifapentine, ethosuximide, pioglitazone.
• Impair dexamethasone metabolism (CYP3A4 inhibition): aprepitant/fosaprepitant, itraconazole, ritonavir, fluoxetine, diltiazem, cimetidine.
• Increase cortisol-binding globulin and may falsely elevate cortisol: estrogens, mitotane.

The LD-DST can yield up to a 50% false-positive rate in women using oral contraceptives, which raise cortisol-binding globulin and thereby increase total (but not bioavailable) cortisol.

Late-night salivary cortisol and midnight plasma cortisol demonstrate a perturbation — and in some cases complete disruption — of the diurnal variation in cortisol.

24-hour urinary free cortisol may not be sensitive for subclinical Cushing syndrome, and the Endocrine Society recommends against it for the metabolic evaluation of adrenal incidentalomas. Drugs that increase the result: carbamazepine, fenofibrate (when measured by high-performance liquid chromatography), some synthetic glucocorticoids (immunoassays), and inhibitors of 11β-hydroxysteroid dehydrogenase type 2 (licorice, carbenoxolone).

Distinguishing the cause — after confirming hypercortisolism, serum ACTH is measured to separate ACTH-independent from ACTH-dependent causes:

• Low serum ACTH → ACTH-independent pathology. Abdominal imaging is indicated to identify the adrenal source. If the adrenals are unremarkable, suspect exogenous steroids or, much less commonly, primary pigmented nodular adrenocortical disease (PPNAD) — in which the adrenal glands are normal in size and show black or brown cortical nodules.
• High serum ACTH → pituitary source (Cushing disease) or ectopic ACTH syndrome. These can be difficult to distinguish, as both pituitary and ACTH-producing tumours are often hard to localize on imaging. Direct measurement of ACTH in the inferior petrosal sinus (the downstream venous plexus draining the pituitary) after CRH stimulation is the gold-standard approach. High-dose dexamethasone suppression testing was used in the past to differentiate the two — its value is limited — on the principle that high enough doses suppress ACTH production by pituitary adenomas, whereas ectopic ACTH production continues despite the high-dose glucocorticoid.

Management

• ACTH-independent disease: ipsilateral adrenalectomy. Medications that block steroid-synthesis enzymes (mitotane, metyrapone, aminoglutethimide, trilostane, ketoconazole, etomidate) are used to bridge a patient to surgery or when surgical intervention is not possible.
• Cushing disease (ACTH-secreting pituitary adenoma): trans-sphenoidal surgical resection. Bilateral adrenalectomy is most often recommended when at least one attempt to treat the primary tumour has failed, and is also necessary in rare instances when hypercortisolism is life-threatening and swift definitive treatment is mandatory; lifelong mineralocorticoid and glucocorticoid replacement is then required in all patients. Patients undergoing bilateral adrenalectomy are at risk (8–29%) of progressive growth of their pituitary adenoma, producing Nelson–Salassa (Nelson) syndrome — ocular chiasm compression, oculomotor deficiencies, and rarely a rise in intracranial pressure. When counselling patients, the urologist must also warn of the rare possibility of residual functioning adrenal tissue remaining after the procedure.
• Ectopic ACTH production: resection of the ACTH-producing tumour, though primary tumour resection is possible in only 10% of patients. For patients with unresectable primary tumours or whose ACTH-producing tissue cannot be identified, bilateral adrenalectomy with lifelong replacement therapy is an excellent therapeutic option.

Hyperaldosteronism

Renin–Angiotensin–Aldosterone System (RAAS)

Under normal physiology, renin release is stimulated in a low-volume, low-salt state by:

• Low renal perfusion pressure
• Increased renal sympathetic nervous activity
• Low sodium concentration sensed by the macula densa

Renin then cleaves angiotensinogen to angiotensin I, which in turn is cleaved by angiotensin-converting enzyme (ACE) to angiotensin II.

• Angiotensin II — has two functions: it is a potent vasoconstrictor (in the kidney it constricts both efferent and afferent arterioles, with a stronger effect on the efferent), and it triggers the release of aldosterone.
• Aldosterone — produced by the zona glomerulosa of the adrenal gland. Production is stimulated by three factors: angiotensin II (most potent stimulator), elevated serum potassium and decreased serum sodium, and ACTH (much less potent); it is inhibited by atrial natriuretic peptide. The zona glomerulosa is the only region of the adrenal cortex that does not atrophy on pituitary failure. Aldosterone increases sodium reabsorption and potassium secretion in the distal nephron, and the increased sodium reabsorption raises total body volume.

Classification

Primary hyperaldosteronism — aldosterone secretion is independent of the RAAS, and renin levels are suppressed.

• Can lead to hypokalemia, hypomagnesemia, alkalosis, fluid depletion or retention, refractory hypertension, cardiac dysfunction, and arrhythmias.
• Hypernatremia does not occur, because sodium reabsorption is accompanied by water uptake, thereby maintaining isotonicity.
• Most patients are normokalemic — although hypokalemia is classically described as a common finding, only 9–37% of newly diagnosed patients are hypokalemic.
• Hypertension secondary to hyperaldosteronism carries an increased risk of end-organ damage compared with essential hypertension.

Causes of primary hyperaldosteronism (8):

Cause	Frequency	Notes
Bilateral (idiopathic) hyperplasia	60%	Less severe hypertension and less likely to be hypokalemic than aldosterone-producing adenomas
Aldosterone-producing adrenal adenoma	35%
Unilateral adrenal hyperplasia	2%
Aldosterone-producing adrenal cortical carcinoma	<1%
Ectopic aldosterone-producing tumour	<1%
Familial hyperaldosteronism type I	<1%	Aldosterone production is mediated by ACTH
Familial hyperaldosteronism type II	<1%
Familial hyperaldosteronism type III	<1%

Secondary hyperaldosteronism — elevated renin levels drive the increased aldosterone secretion. Causes of elevated renin (4): renal artery stenosis, hypovolemia (e.g. cirrhosis, heart failure), juxtaglomerular cell tumour, and fibromuscular dysplasia.

Primary Hyperaldosteronism — Diagnosis and Evaluation

Indications for screening (9)

• Unexplained hypokalemia (spontaneous or diuretic-induced)
• Hypertension with hypokalemia
• Adrenal incidentaloma with hypertension
• Resistant hypertension (3 or more oral agents with poor control)
• Early-onset hypertension (<20 years) or stroke (<50 years)
• Severe hypertension (≥160/≥110)
• Whenever considering secondary causes of hypertension (e.g. pheochromocytoma or renovascular disease)
• Evidence of target-organ damage disproportionate to the degree of hypertension
• Hypertension with a family history of primary aldosteronism

Primary hyperaldosteronism may be unmasked by diuretic-induced hypokalemia. The diagnosis is confirmed if 24-hour urinary aldosterone remains elevated after sodium loading (see below); after confirmation, a CT scan localizes the tumour.

Labs

• Aldosterone-to-renin ratio (ARR) — the screening test for primary hyperaldosteronism. Measure a morning (8–10 AM) plasma aldosterone concentration (PAC) and plasma renin activity (PRA). An ARR > 20 (some suggest > 30) with a concomitant aldosterone concentration > 15 ng/mL indicates hyperaldosteronism; standard thresholds have not been established, owing to laboratory variability.
• Before screening, hypokalemia should be corrected and all contraindicated medications discontinued. Patients can continue most antihypertensives, but potassium-sparing diuretics (amiloride, triamterene) and especially mineralocorticoid receptor blockers (spironolactone, eplerenone) alter the RAAS and affect results — stop these approximately 6 weeks before testing.
• 50–70% of patients with a positive screen are diagnosed with primary aldosteronism after confirmatory testing. Most confirmatory tests assess suppression of aldosterone after sodium loading — loading decreases plasma renin and aldosterone production in patients without autonomous aldosterone secretion. The oral sodium loading test gives a high-sodium diet for 3 days, followed by 24-hour urine measurement of aldosterone, sodium, and creatinine.

Imaging

• Cross-sectional abdominal imaging should be performed in all patients with primary aldosteronism who are potential surgical candidates.
• Aldosterone-producing adenomas appear as a unilateral, low-density, non-enhancing lesion of < 10 Hounsfield units.
• Lateralization cannot be based on CT alone. Patients with confirmed primary aldosteronism should undergo adrenal vein sampling to establish lateralization when adrenalectomy is being considered. Exceptions: patients <40 years with a clear unilateral adenoma and a normal contralateral gland on imaging, and patients suspected of having an ACC.
• Adrenal vein sampling is specifically indicated when there is bilateral disease, micronodular disease <1 cm, normal adrenal imaging, or a unilateral adrenal nodule >1 cm and age more than 40 years.

Genetic screening

Given the rarity of familial primary hyperaldosteronism, genetic screening should not be performed in all patients. Consider it in patients with a family history of primary aldosteronism, early age of onset (<20 years), or a family history of cerebrovascular accidents at a young age.

Management

The role of surgery depends on the cause.

• Surgically correctable causes (4): aldosterone-producing adrenal adenoma, unilateral adrenal hyperplasia, ectopic aldosterone-secreting tumour, and aldosterone-producing adrenal cortical carcinoma. In patients with confirmed lateralizing aldosterone secretion, adrenalectomy should be considered. Given the small size of aldosterone-producing adenomas, most patients are candidates for laparoscopic adrenalectomy; an open procedure may be recommended when aldosterone hypersecretion is associated with an ACC.
• Not correctable by surgery (4): bilateral adrenal hyperplasia and familial hyperaldosteronism types I, II, and III. Treat medically with mineralocorticoid receptor antagonists (spironolactone, eplerenone) — also indicated for patients who are not surgical candidates.

Pheochromocytoma

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.
• The classic (imperfect) rule of 10s: 10% bilateral, 10% extra-adrenal, 10% malignant, 10% familial, and 10% paediatric.

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.

Adrenal Insufficiency

Pathophysiology

Adrenal insufficiency is classified as primary or secondary.

• Primary — also known as Addison's disease (named after the British physician who described it in 1856). In the Western world, the most frequent cause is autoimmune adrenalitis.
• Secondary — pituitary/hypothalamic failure.

Because aldosterone secretion does not depend primarily on ACTH, the zona glomerulosa continues to function appropriately in secondary adrenal insufficiency; mineralocorticoid deficiency is therefore present only in primary adrenal insufficiency.

Diagnosis and Evaluation

The diagnosis of primary adrenal insufficiency is primarily made on clinical grounds, with a high index of suspicion from the history, physical, and labs.

History and Physical

Clinical manifestations: anorexia, abdominal pain, weakness, weight loss, fatigue, hypotension, salt craving, and hyperpigmentation of the skin (in primary adrenal insufficiency).

Labs

Diagnosis is confirmed by measurements of morning serum cortisol and ACTH; patients with primary adrenal insufficiency also exhibit abnormal aldosterone and renin levels. Confirmatory testing assesses the adrenal response to ACTH stimulation (the corticotropin test).

Management

• Adrenal hormonal repletion.
• Post-operative adrenal crisis — any patient who has undergone ipsilateral partial or radical nephrectomy and is undergoing contralateral renal or adrenal surgery is at risk. Obtaining old operative or pathology reports and examining cross-sectional imaging for the presence or absence of adrenal tissue are essential in this setting. In a patient with suspected post-operative adrenal crisis, consider 2 mg dexamethasone or 100 mg hydrocortisone.

Malignant Adrenal Tumours

Pathogenesis

Adrenal cortical carcinoma (ACC) is classified as sporadic or genetic.

• Sporadic — the cause remains unknown.
• Genetic — syndromes associated with ACC (6): Li-Fraumeni, Beckwith-Wiedemann, Lynch, Carney complex, MEN-1, and McCune-Albright.

Diagnosis and Evaluation

History and Physical Exam

Symptoms can be secondary to local or systemic disease burden and/or hypersecretion of adrenal hormones; ACCs with hormone hypersecretion are characterized as functional. Most ACCs are functional at presentation, and the most common hormone secreted is cortisol.

Laboratory

Evaluating the functional status of tumours suspicious for ACC is essential — for making the diagnosis, for considering postoperative cortisol replacement, and for using tumour-secreted hormones as markers during postoperative surveillance. Assess for excesses of glucocorticoid, mineralocorticoid, catecholamine, sexual steroid, and steroid precursor.

Imaging

In incidentally detected adrenal tumours, size is a relative indicator of malignancy:

Tumour size	Risk of malignancy
< 4 cm	5%
> 4 cm	10%
> 6 cm	25%

Given this relationship, adrenal tumours > 4–6 cm are currently recommended for surgical excision. ACCs tend to be larger than benign adrenal tumours, averaging 10–12 cm at presentation.

Radiographic characteristics of ACC on CT (5): irregular borders, heterogeneous enhancement, increased enhancement (mean 39 HU vs 8 HU for adenoma), calcifications, and necrotic areas with cystic degeneration.

MRI signal characteristics:

Lesion	T1	T2
Normal adrenal gland	Uniform intermediate signal, slightly less intense than liver and renal cortex	Difficult to distinguish from retroperitoneal fat (intracellular lipid in the gland)
Myelolipoma	Bright	Intermediate
ACC	Isointense to liver or spleen; marked uptake on gadolinium-enhanced images	Intermediate to increased intensity
Pheochromocytoma	—	Classically bright ("light bulb" sign, best on fat-suppression sequences) — now known to be neither specific nor sensitive enough to be diagnostic; interpret with caution

Other

Percutaneous needle biopsy is usually not performed before surgical excision, owing to a clinically unacceptable risk of needle-tract seeding. In surgically resectable disease, biochemical and radiographic evaluation should be enough to justify extirpation.

Pathology

Modified Weiss criteria (5) — mnemonic "Necrotic ACC Metastasizes":

• Necrosis
• Abnormal mitoses
• Cytoplasm (clear cells comprising ≤25% of the tumour)
• Capsular invasion
• Mitotic rate > 5 per 50 high-power fields

Score = (2× mitotic-rate criterion) + (2× clear-cytoplasm criterion) + abnormal mitoses + necrosis + capsular invasion; a score of 3 or more suggests malignancy.

Traditional Weiss criteria: abnormal mitoses, mitotic rate >5/hpf, diffuse architecture of tumour cells, clear cells ≤25%, capsular/sinusoidal/venous invasion, Fuhrman grade 3–4, and necrosis.

Management

Multimodal treatment — surgical resection, radiation therapy, and systemic chemotherapy — is often necessary.

• Mitotane — an oral synthetic derivative of the insecticide dichlorodiphenyltrichloroethane (DDT) and the most commonly used chemotherapeutic agent for ACC. It inhibits several adrenal-cortex enzymes: the cholesterol side-chain cleavage enzyme (P450scc, CYP11A1), 11β-hydroxylase (CYP11B1), 18-hydroxylase (aldosterone synthase, CYP11B2), and 3β-hydroxysteroid dehydrogenase (3β-HSD) to a lesser extent.

Prognosis

Despite aggressive surgical resection, ACC carries a high rate (60–80%) of recurrent disease.

• Factors associated with recurrence-free survival: tumour size, nodal status, T stage, functional activity, and capsular invasion. Local and systemic adjuvant therapy is often administered despite no clear evidence of improved survival.
• Factors associated with overall survival: margin status (most important), tumour size, nodal status, and metastases.

Metastatic disease to the adrenals is common: in patients with a history of previous malignancy, >50% of newly discovered adrenal lesions are metastatic — nevertheless, metabolic work-up is recommended. Bilateral and bulky disease (>4 cm) is necessary to produce biochemical evidence of adrenal insufficiency. Current imaging modalities, supplemented by adrenal biopsy when necessary, can frequently differentiate metastases from a primary adrenal tumour.

Benign Adrenal Tumours

Adenomas

The most common primary adrenal tumour; incidence increases with age.

Diagnosis and evaluation — the vast majority (93%) are metabolically silent. The essential task in evaluating a small adrenal mass is to differentiate the non-functional benign adenoma from functional or malignant lesions.

Management:

• Functional adenoma — should undergo resection in an acceptable surgical candidate.
• Non-functional adenoma — size and growth characteristics dictate management (as described in the adrenal-mass work-up). Adenomas that are initially metabolically inert are unlikely (<2%) to gain function; despite this low rate of "metabolic transformation," the most recent NIH-convened consensus statement suggests that annual metabolic hormonal screening for the first 3–4 years after diagnosis is prudent.

Oncocytoma

Extremely rare. Although predominantly benign, a proportion can exhibit malignant potential. On imaging, adrenal oncocytic lesions lack the central stellate scar often seen in renal oncocytomas. Because the diagnosis is nearly always made on surgical resection, evaluation and treatment follow the same strategy as that of other adrenal masses.

Myelolipoma

Rare, benign, metabolically silent lesions with tissue components identical to healthy bone marrow. In most cases, diagnosis can be made accurately on cross-sectional imaging — usual CT enhancement is between -30 and -140 Hounsfield units. The NIH consensus panel on adrenal incidentaloma concluded that myelolipoma can be regarded as an exception to the mandatory metabolic work-up of a newly discovered adrenal mass. Classically asymptomatic myelolipomas are treated conservatively; surgery is indicated only for extremely large or symptomatic lesions.

Ganglioneuroma

Extremely rare benign neuroectodermal neoplasms that tend to occur in the young and are composed of ganglion and Schwann cells. They can grow extremely large and have a propensity to encase vessels without impinging on the vessel lumen.

Cysts

Four types of adrenal cyst have been described: pseudocysts, endothelial cysts, epithelial cysts, and parasitic cysts. 7% of adrenal cysts are associated with malignancy — all of which were pseudocysts — so observation must be done with caution. Although the majority of adrenal cysts are benign and non-functional, routine endocrinologic evaluation should be performed to exclude active lesions.

Diagnosis and Evaluation of Adrenal Mass

Background

An incidental adrenal mass is an adrenal lesion >1 cm discovered on radiologic examination performed for reasons other than to investigate primary adrenal disease. Exclusions to the definition: known malignancy or high suspicion of a malignant process (the mass has a high likelihood of being a metastatic deposit), and clinically overt disease.

Differential Diagnosis

The differential diagnosis of an incidental adrenal mass (10):

• Malignant (3): adrenal cortical carcinoma, metastasis, sarcoma.
• Benign (7): pheochromocytoma, adenoma (functional vs non-functional), oncocytoma, cyst, myelolipoma, ganglioneuroma, abscess.

About 20% of incidental adrenal masses are found to be potential surgical lesions. (See Campbell's 11th edition, Table 65-15, for characteristics of incidental adrenal masses from a systematic review of published series.)

Workup at a Glance

Per the 2011 CUA guidelines, ALL incidental adrenal masses (excluding myelolipomas, hemorrhages, and cysts) initially require a comprehensive work-up — clinical, radiologic, and hormonal — to distinguish benign from malignant, and non-functioning from hyperfunctioning, tumours.

• Labs (3): low-dose dexamethasone suppression test or 24-hour urinary cortisol (rule out hypercortisolism); 24-hour urinary metanephrines and/or catecholamines (rule out pheochromocytoma); and, in hypertensive patients, the aldosterone-to-renin ratio (rule out hyperaldosteronism).
• Imaging (1): unenhanced CT; if attenuation ≥ 10 HU, obtain contrast-enhanced CT with adrenal washout.

History and Physical Exam

Most patients are asymptomatic. Screen for signs and symptoms of adrenal hyperfunction:

• Hypercortisolism (9): central obesity, moon facies, buffalo hump, facial plethora, menstrual disturbances, hirsutism, proximal muscle weakness, easy bruisability, and abdominal striae. Systemic manifestations include dyslipidemia, insulin resistance, and hypertension.
• Hyperaldosteronism: hypertension — classified as elevated (SBP 120–129, DBP <80 mm Hg), stage 1 (SBP 130–139, DBP 80–89 mm Hg), or stage 2 (SBP ≥140, DBP ≥90 mm Hg).
• Pheochromocytoma (3): headache, episodic sudden perspiration, tachycardia.
• Adrenal sex steroid hypersecretion and adrenal malignancy.

Labs

(See the 2011 CUA Incidental Adrenal Mass Guideline.)

• Hypercortisolism — assessed by the overnight low-dose (1 mg) dexamethasone suppression test (sensitivity 85–90%, specificity 95–99%). The 24-hour urine free cortisol (sensitivity 80–98%, specificity 45–98%) may be used for screening, with the 1 mg test used to differentiate Cushing's from subclinical Cushing's syndrome if the 24-hour cortisol is elevated.
• Pheochromocytoma — assessed by 24-hour urine metanephrines and catecholamines. Fractionated plasma metanephrines is a newer test that may be more sensitive but less specific, so its use should be reserved for confirmatory testing rather than primary screening. Plasma metanephrine testing may not be widely available outside select centres, so 24-hour urinary metanephrines is suggested for initial screening.
• Hyperaldosteronism — assessed in hypertensive patients by the upright plasma aldosterone-to-renin ratio (ARR).
  • Pre-testing: mineralocorticoid receptor blockers (e.g. spironolactone) and some diuretics — potassium-sparing (amiloride, triamterene) and potassium-wasting (furosemide, HCTZ, indapamide) — should be discontinued at least 4 weeks before the ARR. If results are non-diagnostic and hypertension can be controlled with relatively non-interfering antihypertensives, withdraw other potentially interfering medications (ACE inhibitors, ARBs, renin inhibitors, dihydropyridine calcium channel antagonists, β-blockers, central α-2 agonists, NSAIDs) for at least 2 weeks before a repeat ARR. Patients should liberalize salt intake leading up to the test for accurate results (acute fluctuations in dietary sodium are reported not to affect ARR accuracy).
  • Normokalemia occurs in up to 50% of patients with hyperaldosteronism, although it has traditionally been associated with hypertension and hypokalemia.
• Adrenal sex steroid hypersecretion — routine testing of incidentalomas for sex hormones is not currently recommended; hypersecretion by adrenal masses (especially incidentalomas) is exceedingly rare and typically presents with concomitant clinical symptoms (feminization or virilization). Assessed with (2): serum DHEA-S and 24-hour urine 17-ketosteroids.

Confirmatory hormonal testing for all positive screening tests is recommended, to limit false positives and unnecessary surgery.

Imaging

• CT — unenhanced CT is the first test. Myelolipoma, cysts, and hemorrhages have distinct features; CT is the most easily interpreted test for intracellular lipid, and adenomas typically contain a greater proportion of intracellular fat than malignant incidentalomas. Attenuation of a region of interest over a mass on unenhanced CT:
  • <10 HU — diagnostic for an adrenal adenoma (high intracytoplasmic lipid content); this cutoff has ≈70% sensitivity and 98% specificity. About 30% of adenomas show attenuation >10 HU owing to lower lipid content — these "atypical" or "lipid-poor" adenomas are indistinguishable from non-adenomas on non-contrast density alone.
  • >10 HU — obtain contrast-enhanced CT with washout, which has excellent sensitivity and specificity for differentiating adenomas from non-adenomatous incidentalomas. A single-phase enhanced CT is limited, as post-contrast attenuation of adenomas and non-adenomas overlaps considerably.
• Phases of an adrenal CT study (3): non-contrast 5-mm images through the adrenal; enhanced (1-minute post-bolus); and 15-minute washout imaging.
• Washout indicative of adenoma: absolute percent washout > 60% ([enhanced − delayed] / [enhanced − unenhanced] × 100%), or relative percent washout (RPW) > 40% ([enhanced − delayed] / [enhanced] × 100%). Lipid-poor adenomas wash out identically to lipid-rich adenomas; RCC and HCC metastases may show washout similar to lipid-poor adenomas.
• Characteristics of pheochromocytoma and malignant processes (5): size >3 cm, heterogeneous texture, increased vascularity, attenuation >10 HU on unenhanced CT, and decreased contrast washout at 10–15 minutes.
• MRI — chemical-shift MRI uses the lipid-rich property of most adenomas to differentiate benign from malignant, but CT with washout is the gold standard and is better than chemical-shift MRI for identifying adenomas.
• Ultrasound — a suboptimal modality for detecting and characterizing adrenal lesions.
• Functional imaging / PET — limited role for diagnosing pheochromocytoma (most are accurately diagnosed with cross-sectional imaging and metabolic evaluation). 2-[18F] FDG-PET can be useful for detecting metastasis in patients with a history of malignancy, as metabolically active lesions typically show increased FDG uptake versus benign lesions.

Adrenal biopsy

• Currently not recommended for the routine work-up of an adrenal incidentaloma. Its role is limited: modern imaging in clinical context affords superb diagnostic capability, adenomas cannot be reliably differentiated from adrenal carcinomas histologically, and biopsy carries risks.
• Should be pursued if the diagnosis remains equivocal and the biopsy result will influence management — most useful in patients with primary malignancies that may have recurred in the adrenal gland and whose management will be affected.
• Always exclude the possibility of pheochromocytoma before biopsy, to avoid potentially life-threatening hemorrhage and hypertensive crisis.

Management

Two options: adrenalectomy or observation.

Adrenalectomy — indications (11)

• Size ≥ 4 cm (except myelolipoma) — most adrenocortical carcinomas are >4 cm, and masses >6 cm should be considered malignant until proven otherwise. Management of 4–6 cm masses is controversial, but in otherwise healthy individuals masses >4 cm should be resected; radiologically benign masses >4 cm may be followed in patients who are not prime surgical candidates. Benign adenoma incidence increases with age, so lesions in younger patients (even <4 cm) warrant greater caution than similar lesions in older patients, whereas >4 cm lesions in older patients with significant comorbidities may be better served by observation.
• Size increase > 1 cm on follow-up imaging — current recommendation is to resect, though the incidence of malignancy among these patients is low.
• Adrenal hyperfunction — some patients with primary aldosteronism may be managed medically (especially poor surgical candidates). Clinically silent hyperfunction is debated: any lesion exhibiting silent pheochromocytoma (hormonal and radiologic signs without clinical symptoms) should be surgically removed after adequate adrenergic blockade, given the life-threatening complications. Surgery may be elected for younger patients with subclinical Cushing syndrome, or those with new-onset, medically resistant, or deteriorating disease from cortisol excess; the remainder are followed and offered surgery if they develop clinical signs of Cushing's.
• Imaging suggestive of malignancy (e.g. lipid-poor, heterogeneous, irregular borders, infiltrating surrounding structures), regardless of size.
• Extremely large and/or symptomatic cyst or myelolipoma.
• Isolated adrenal metastasis (multidisciplinary decision-making required).
• During renal surgery for RCC if the adrenal is abnormal or not visualized because of large renal tumour size, or there is vein thrombus to the level of the adrenal vein.
• Failed neurosurgical treatment of Cushing disease, necessitating bilateral adrenalectomy.
• Select patients with ectopic ACTH syndrome, requiring bilateral adrenalectomy.
• ACTH-independent macronodular adrenal hyperplasia (AIMAH).
• Primary pigmented nodular adrenocortical disease (PPNAD).

(The first four are consistent with the CUA Incidental Adrenal Mass Guidelines.)

Observation

• Myelolipomas, hemorrhages, and cysts do not necessarily require further evaluation. Non-functioning adenomas (typically <4 cm) and masses not deemed resectable at initial diagnosis should undergo clinical, hormonal, and radiological surveillance. There is no consensus on the proper follow-up methodology.
• Surveillance proposed in the 2011 CUA Guidelines:
  • Hormonal: annual clinical and hormonal testing for up to 4 years. There is no agreement on the best mechanism and frequency, but it should include the same screening tests used at primary evaluation.
  • Radiographic (depends on lesion characteristics ± size): benign-appearing masses — <1 cm: consider no further follow-up or enrolment in a clinical trial; 1–2 cm: first scan at 12 months if the clinical picture warrants; 2–4 cm: first scan at 12 months. Radiologically suspicious lesions not initially removed — any size: first scan at 3–6 months, with further imaging directed by clinical judgment (consider 1–3 assessments within the first 2 years).
• Tumours that remain stable on imaging and annual hormonal evaluation may be considered for discharge from follow-up after 4 years.

Adrenal Mass Algorithm (Traffic-Light System)

A simplified scoring schema integrates three parameters — imaging feature, size, and metabolic work-up — each assigned a colour, with management driven by the combination of colours.

A. Imaging feature

• Lipid-rich → Green
• Lipid-poor → Purple

B. Size

• <4 cm → Green
• ≥4 cm → Purple

C. Metabolic work-up

• Silent → Green
• Subclinical → Purple
• Functional → Red

Management rules:

• All Green → no follow-up.
• One Purple → follow-up.
• Two Purple or one Red → surgical resection.