adrenal - mums.ac.ir...differentiation of pheochromocytoma from adenoma centers on an assessment of...
TRANSCRIPT
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