1

ADRENAL

Alireza Ghoreifi, MD

Urologist

Mashhad University of Medical Sciences

PHEOCHROMOCYTOMA

EPIDEMIOLOGY

Incidence: 1 to 2 per 100,000 annually

It is responsible for only approximately 0.5%

of cases of hypertension.

Among patients with incidental adrenal

masses, approximately 5% will have a

pheochromocytoma.

Some 1% to 25% of pheochromocytomas are

extra-adrenal (paraganglioma). They arise from

paraganglia, a network of chromaffin-producing

neural crest tissue that anatomically parallels

the sympathetic and parasympathetic ganglia.

CLINICAL CHARACTERISTICS

Paroxysmal hypertension is the classic

presenting symptom in patients with

pheochromocytoma but only documented in

approximately 30% to 50% of patients. The

remainder of patients demonstrate persistently

elevated blood pressure, and a minority are

entirely normotensive.

The triad of headache, episodic sudden

perspiration, and tachycardia is a classic

hallmark of pheochromocytoma.

More than 20% of patients can be asymptomatic.

DIAGNOSTIC TESTS

Imaging:

1. CT Scan:

A. well-circumscribed lesions

B. an attenuation of greater than 10 HU on

unenhanced CT (mean ≈35 HU): Given their

rich vascularity and low lipid content. This

property affords the ability to differentiate

them from lipid-rich adenomas.

C. Furthermore, pheochromocytomas can be

distinguished from lipid-poor adenomas using CT

contrast washout strategies.

2. MRI:

is an excellent imaging modality for

characterizing adrenal lesions.

differentiation of pheochromocytoma from adenoma

centers on an assessment of the lesion’s lipid content.

Unlike lipid-rich adenomas, pheochromocytomas do

not exhibit signal dropout on out-of-phase

sequences.

Classically, bright signal intensity on T2-weighted

imaging termed the “light bulb” sign was believed

to be diagnostic for pheochromocytoma. It is now

clear that this imaging characteristic is neither

specific nor sensitive enough to secure a diagnosis

and must be interpreted with caution

FUNCTIONAL IMAGING

MIBG scan: MIBG is a small-molecule analogue of norepinephrine

and is the preferred radiographic agent, affords a high sensitivity (83% to 100%) and superb specificity (95% to 100%) for identification of pheochromocytoma.

Indications:

a. extra-adrenal, metastatic or recurrent lesions

b. to localize diseases in patients with biochemical evidence of pheochromocytoma but negative cross-sectional imaging.

c. for large (>5 cm) tumors is likely prudent in order to assess for presence of metastatic disease prior to surgery and thereby counsel the patient appropriately.

d. in cases where metabolic workup of an adrenal mass reveals exclusive excess of norepinephrine and normetanephrine, but not epinephrine or metanephrine.

BIOCHEMICAL EVALUATION

METANEPHRINE TESTING.

O-Methylation of catecholamines is catalyzed

by the catechol-O-methyltransferase (COMT)

enzyme which produces normetanephrine and

metanephrine.

Because this conversion of catecholamines to metanephrines is an uninterrupted process within pheochromocytomas, measurement of plasma concentration of metanephrines is a much more sensitive means of tumor detection than the measurement of rises in plasma catecholamines, which may be paroxysmal.

Today, measurement of metanephrine levels in plasma or urine represents the foundation for pheochromocytoma diagnosis and is extremely sensitive.

Controversy exists regarding whether measurement of plasma-free metanephrines versus urinary–fractionated metanephrines should be used as the initial test.

VMA TESTING.

Because vanillylmandelic acid (VMA) is the

primary end metabolite of catecholamines, its

measurement in urine has long been used for

diagnosis of pheochromocytoma.

The relative rise of VMA levels in the presence of

a pheochromocytoma is much less dramatic

than the rise seen in the levels of

metanephrines, and the sensitivity of urine

VMA levels is therefore low (below 65% in

some series). However, the specificity of the test

is high

CLONIDINE SUPPRESSION TESTING.

Clonidine, an α2agonist, suppresses

catecholamine (specifically norepinephrine)

production by the sympathetic nervous system

but not by pheochromocytoma.

Comparison of normetanephrine levels before

and after clonidine administration has been

shown to yield results with favorable test

characteristics.

This evaluation is suggested by some

experts for secondary testing in patients

with pheochromocytoma who exhibit mild

or borderline elevations in metanephrine

levels.

TREATMENT

Preoperative Management

Catecholamine release during intra-operative

tumor manipulation can result in hazardous

blood pressure elevation and cardiac

arrhythmias.

In 2005, the First International Symposium on

Pheochromocytoma recommended that all

patients with pheochromocytoma and an

abnormal metabolic evaluation undergo

preoperative catecholamine blockade,

including patients who do not exhibit

evidence of blood pressure elevation and

lack classic symptomatology.

INTRAVASCULAR VOLUME MANAGEMENT

Restoration of intravascular volume is

perhaps the most important component of

preoperative management of patients with

pheochromocytoma.

Moreover, most centers admit patients the day

before surgery and initiate aggressive

intravenous fluid resuscitation.

The last dose of phenoxybenzamine and/or

metyrosine is usually given on the night prior to

surgery, and the next morning’s dose is held. This

approach minimizes potentially prolonged

hypotension following tumor resection

POSTOPERATIVE MANAGEMENT

In the immediate postoperative period, the

patient must be actively monitored. If

phenoxybenzamine was employed for

preoperative α-blockade, hypotension is

common, given the lasting effects of the agent.

Moreover, in a high catecholamine state, α2-

adrenoreceptor stimulation inhibits insulin

release. The withdrawal of this adrenergic

stimulus following tumor resection, may result in

rebound hyperinsulinemia and subsequent

hypoglycemia.

FOLLOW-UP

Repeat metabolic testing should be performed approximately 2 weeks after adrenalectomy to document normalization of chromaffin cell function. In patients in whom metanephrine levels remain elevated, MIBG imaging may be helpful.

Long-term postoperative follow-up of patients with pheochromocytoma is essential

No consensus on follow-up protocols exists; however, biochemical testing at 6 months after surgery, followed by annual testing, has been suggested. Post-operative cross-sectional imaging is reasonable to document tumor resection and appropriate healing of the resection bed. Need for subsequent imaging should be guided by results of biochemical testing

ADRENAL

INCIDENTALOMA

OVERVIEW

Adrenal incidentalomas are unsuspected adrenal masses greater than 1 cm in diameter identified on cross sectional imaging performed for seemingly unrelated causes. Patients who are undergoing a staging evaluation for another malignancy or who are later found to have symptoms relating to the adrenal lesion are excluded from the term “adrenal incidentaloma”.

The frequency of adrenal incidentalomas is relatively high, with contemporary imaging series reporting an incidence of approximately 5%, similar to that found in historical autopsy data. The incidence of the incidental adrenal mass increases with age, with a risk of less than 0.5% in individuals in their 20s and up to 7% in those 70 years of age or older.

Nearly 20% of adrenal incidentalomas are found to be potential surgical lesions.

IMAGING

Ultrasonography:

Ultrasonography is a suboptimal imaging

modality for detecting and fully

characterizing adrenal lesions.

UNENHANCED CT

An unenhanced CT scan is the first, and perhaps single best, and most easily interpreted test for intracellular lipid and therefore can diagnose an adrenal adenoma in more than 70% of cases. Low attenuation (<10 HU) on unenhanced CT corresponds to high intracytoplasmic lipid content and is diagnostic for an adrenal adenoma.

Using a threshold of 0 or less HU, there is 100% specificity for an adrenal adenoma.

A threshold of 10 HU is currently used. This cutoff affords a sensitivity of 71% and a specificity of 98% for the diagnosis of adrenal adenomas . In other words, 98% of lesions that exhibit an attenuation of 10 HU or less on non-constrast CT are adrenal adenomas, while less than 30% of adrenal adenomas are lipid-poor (also known as “atypical adenomas”) and exhibit an attenuation of greater than 10 HU.

CT WASHOUT STUDY

Approximately 30% of adrenal adenomas exhibit an attenuation of greater than 10 HU on unenhanced CT due to their lower lipid content. These “atypical adenomas” are indistinguishable from non-adenomas using non-contrast CT density measurements alone. Fortunately lipid-poor adenomas possess identical properties to lipid-rich adenomas regarding their rapid loss (washout) of enhancement following CT contrast load.

An absolute percent washout (comparing non-contrast values to 15-minute post-contrast density values) of greater than 60%, or a relative percent washout (comparing arterial phase density measurements to 15-minute post-contrast density values) of greater than 40% on delayed (washout) imaging, are indicative of adenoma.

MR IMAGING

While CT uses unenhanced attenuation to identify lipid-rich adenomas, MRI harnesses the interference between signal collected from fat and water tissue to evaluate for intracellular lipid content. On such opposed phase chemical-shift imaging, signal intensity loss on out-of-phase sequences, when compared to in-phase imaging, signifies the presence of intracellular lipid and definitively identifies the lesions in question is an adenoma.

Nevertheless, CT washout studies are considered the gold standard and appear to surpass opposed phase chemical-shift MR imaging in their sensitivity for identifying adenomas. It is important to note that gadolinium enhanced MR washout studies do not exhibit the diagnostic strength of iodine-based CT washout studies, and are not currently employed in clinical practice.

SUMMARY OF EVALUATION OF ADRENAL MASS

USING

MODERN CROSS-SECTIONAL IMAGING.

SIZE AND GROWTH

A relationship does exist between the size of an adrenal lesion and its malignant potential with larger masses more likely to exhibit adverse clinical and pathologic features.

Masses less than 4 cm are considered to possess low malignant potential (2% are adrenal carcinomas) and, if nonfunctional, can be observed safely.

Masses that exceed 6 cm should be considered malignant until proven benign, which generally requires definitive resection.

Management of incidentalomas between 4 and 6 cm is more controversial. In this intermediate size range, the rate of malignancy is estimated to be only 6%.

Nonetheless, in otherwise healthy individuals with acceptable perioperative risk profile, most experts recommend 4 cm as the cutoff diameter that warrants resection

The urologic oncologist must remember

that the incidence of benign adrenal

adenomas increases with age; therefore

adrenal lesions in younger patients, even

those less than 4 cm, must be managed with

greater caution than similar lesions in an

older age group. Likewise, lesions greater

than 4 cm in older patients with significant

co-morbidities may be better served with

observation than resection.

Reimaging at 6, 12, and, as possible, at 24

months is currently recommended in order

to verify oncologic indolence. Suspicious and

unusual tumors may require imaging at earlier

or more frequent intervals, while small (<2 cm)

homogeneous, well-circumscribed, nonfunctional

lesions can be followed less closely.

A rather arbitrary criterion of 1-cm growth

has been proposed as an indication for

resection; however, the patient must be

counseled that the chance of malignancy is

low if growth kinetics are flat.

BIOPSY OF ADRENAL MASSES

The role for adrenal biopsy has been limited

for the following reasons: (1) modern

imaging in the context of clinical

characteristics affords superb diagnostic

capabilities, (2) histologically adenomas

cannot be reliably differentiated from

adrenal carcinomas, and (3) adrenal biopsy

is not without risk.

Always exclude possibility of

pheochromocytoma before biopsy.

ASSESSMENT OF FUNCTION OF ADRENAL MASSES

The NIH consensus statement recommends

metabolic testing for all adrenal

incidentalomas.

This recommendation is supported by the

observation that more than 10% of adrenal

incidentalomas are metabolically active.

Current practice is to test all new adrenal

masses for cortisol and catecholamine

hypersecretion. In patients with a history of

hypertension, aldosterone hypersecretion

should also assessed.

TESTING FOR CORTISOL HYPERSECRETION

Three first-line tests are available to screen

patients with incidentalomas for Cushing

syndrome:

(1) an overnight low-dose dexamethasone

suppression test (OST),

(2) a late-night salivary cortisol test, and

(3) a 24-hour urinary–free cortisol

evaluation (UFC).

Nonetheless, reports suggest that UFC is

not sufficiently sensitive to detect

subclinical Cushing syndrome

Overnight Low-Dose Dexamethasone Suppression

Test.

The patient is given a prescription for 1 mg of

dexamethasone and instructed to take it

between 11 PM and 12 AM. The next morning, a

serum cortisol is obtained between 8 AM and

9AM.

Unlike the 24-hour urinary–free cortisol testing, OST

is not affected by the patient’s glomerular flow rate

(GFR).

Most importantly, the urologist must be aware

that the test can yield as high as a 50% false-

positive rate in women using oral

contraceptives, because the contraceptives

increase total (but not bioavailable) cortisol

levels by raising the patient’s cortisol-binding

Late-Night Salivary Cortisol.

Unacceptably high false-positive rates may

occur in patients with depression, altered

sleep patterns, and chronic illness, because

normal circadian variation in cortisol levels

can be altered in these individuals. Tobacco

use can affect salivary cortisol levels and

should be avoided on the day of testing.

24-Hour Urinary–Free Cortisol Evaluation.

Practice guidelines issued by the Endocrine

Society in 2008 recommend that the

dexamethasone suppression test or the late-

night salivary cortisol test supplant the 24-hour

urinary–free cortisol evaluation in initial

metabolic screening of patients with

incidentalomas.

This test is an integrated measurement of cortisol

secretion over a 24-hour period and does not depend

on variables that influence corticosteroid-binding

globulin levels (e.g., oral contraceptives)

This test remains the test of choice in pregnant

patients.

TESTING FOR ALDOSTERONE

HYPERSECRETION

Today the screening test of choice for Conn syndrome is a morning plasma aldosterone (ng/dL) to renin (ng/mL/hr) ratio (ARR). An ARR of 20 (some suggest 30) along with a concomitant aldosterone concentration above 15 ng/mL are indicative of Conn syndrome. The concurrent elevated aldosterone level appears important for cases in which the ARR is elevated simply due to a low renin level.

Potassium sparing diuretics such as amiloride, and especially mineralocorticoid receptor blockers such as spironolactone, alter the renin-angiotensin-aldosterone system and will affect test results. These agents should be stopped approximately 6 weeks prior to testing.

Cessation of other antihypertensive drugs is unnecessary.

TESTING FOR ADRENAL SEX STEROID

HYPERSECRETION

Routine testing of incidentalomas for sex

hormones is currently not recommended

TESTING FOR CATECHOLAMINE HYPERSECRETION

Pheochromocytoma is found in approximately 5% of patients who present for adrenal incidentaloma.

Free-fractionated plasma metanephrines and the 24-hour urinary–fractionated metanephrine tests constitute the mainstay for pheochromocytoma testing, given their superb sensitivity and suitable specificity. Indeed, the 2005 International Symposium on pheochromocytoma concluded that one of these two tests should be used for initial diagnosis and screening for pheochromocytoma.

Acetaminophen can produce a false-positive result due to cross reactivity in the assay and should be stopped for at least 5 days prior to testing. Tricyclic antidepressants and phenoxybenzamine should also be stopped, because these have been shown to be responsible for false-positive results.

Given strong opinions on both sides of the argument, the 2005 International Symposium on Pheochromocytoma failed to reach a consensus regarding the superiority of either test.

FOLLOW-UP

A small percentage (approximately 2%), of

metabolically silent adrenal incidentalomas

are reported to show new metabolic activity

during follow-up evaluation.

The most recent consensus statement by a

panel of experts recommends annual

metabolic hormonal screening for the first 3

to 4 years following diagnosis, especially for

masses that are 3 cm in diameter.

Thanks For Your

Attention