Download Approach to Incidentally Discovered Adrenal Masses

case-Based review
Approach to Incidentally Discovered Adrenal
Masses
Case Study and Commentary, Paul M. Copeland, MD
CME jointly sponsored by
Wayne State University School of Medicine
and JCOM
The following article, “Approach to Incidentally Discovered Adrenal Masses” is a con­tinuing med­­­­ical
education (CME) article. To earn credit, read the
article and complete the CME evaluation on pages
60 and 61.
Program Audience
Primary care physicians.
Educational Needs Addressed
Clinically inapparent adrenal masses discovered
inadvertently in the course of diagnostic testing for
non–adrenal-related causes are found on 1% to
5% of abdominal computed tomography scans.
Although most adrenal “incidentalomas” are benign
and hormonally inactive, it is vitally important to
perform a proper diagnostic assessment in order to
identify functional adrenal tumors and malignancies.
At the same time, it is important to avoid unnecessary testing, with its attendant costs and risks to the
patient. Improvements in the resolution of imaging
techniques and the increased use of abdominal
scans suggest that the prevalence the these tumors
will continue to escalate.
Educational Objectives
After participating in this CME activity, primary care
physicians should be able to
1. Know the causes and prevalence of clinically
inapparent adrenal masses
2. Describe the approach to hormonal and radiologic evaluation
3. Know the indications and procedures for surgical
management of these masses
4. Describe the appropriate follow-up for surgical
and nonsurgical management
I
ncidentally discovered adrenal masses (“adrenal incidentalomas”) are found on approximately 2% to 3%
of imaging studies performed for reasons other than
suspicion of adrenal disease. The appropriate evaluation
and management of adrenal incidentalomas is challenging.
Most adrenal incidentalomas are benign and do not produce
a hormonal syndrome. It is important to avoid unnecessary
testing with its attendant costs and risks to the patient. At the
same time, determining which masses represent functional
adrenal tumors or malignancies is critical. Careful diagnostic evaluation is necessary to identify the likely pathologic
entity so that appropriate treatment can be provided.
CASE STUDY
Initial Presentation
A 47-year-old woman presents to an endocrinologist with a 3-cm left adrenal mass that was discovered on abdominal computed tomography (CT) performed
when she was passing a kidney stone.
History
The patient has had a 35-lb weight gain over the past year,
worsening control of chronic hypertension, and increased
peripheral edema. She developed hypokalemia, with values
as low as 3.1 mEq/L, while using hydrochlorothiazide for
her hypertension, and is now on a potassium supplement.
Her other medications include olmesartan and sustainedrelease metoprolol. Her hypertension has been somewhat labile with occasional diastolic blood pressure readings above
100 mm Hg. She has had headaches and episodes of tachycardia with heart rates up to 180 bpm, but no unexplained
sweats. She reports fatigue, muscle aches, and weakness.
She denies easy bruising, menstrual irregularity, hirsutism,
fractures, or loss of height. In addition to nephrolithiasis, her
past history is significant for a melanoma, stage unknown,
removed 8 years ago.
From North Shore Medical Center, Salem, MA.
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Vol. 14, No. 1 January 2007 JCOM 49
adrenal incidentalomas
Physical Examination
The patient weighs 192 lb and has a body mass index of
32 kg/m2. Blood pressure is 150/95 mm Hg and heart rate is
regular at 64 bpm. There are no murmurs or gallops. She has
a round face but no plethora, no increased supraclavicular
or cervicodorsal fat pads, and no hirsutism. Her abdomen is
obese without masses or striae. She has normal muscle mass,
with possible mild proximal lower extremity muscle weakness. There is 1+ pedal edema and no tremor.
Imaging Studies
The CT scan from the outside hospital shows a round,
smooth, homogeneous adrenal mass measuring 6 Houns­
field units on an unenhanced study. There is no evidence
of residual nephrolithiasis. A CT scan of the abdomen done
15 years ago is not available, but an adrenal mass was not
mentioned in the report.
Laboratory Evaluation
Laboratory data obtained prior to the visit reveal sodium,
141 mEq/L; potassium, 4.4 mEq/L; chloride, 103 mEq/L;
bicarbonate, 27 mEq/L; blood urea nitrogen, 22 mg/dL;
creatinine, 0.9 mg/dL; and glucose, 94 mg/dL.
• What are the possible etiologies of a clinically inapparent adrenal mass?
The most common adrenal mass is a benign adrenal ade­
noma. In autopsy series, adrenal adenomas have a prevalence of 1.4% to 8.7%. The higher prevalence figures included
adenomas as small as 0.2 cm [1]. Small, as well as large,
adenomas may be hyperfunctioning.
Cortisol-producing adenomas are another category of
incidentalomas. Using stringent criteria, dexamethasone
suppression testing suggests that 2% to 12% of adrenal incidentalomas hypersecrete cortisol at presentation. Among
adenomas initially considered nonfunctioning, approximately 1% to 2% will come to manifest cortisol hypersecretion if followed for up to 3 years [2]. Almost all of the
adenomas that subsequently hypersecreted cortisol were
3 cm or larger in diameter at the initial evaluation. Adenomas that hypersecrete mineralocorticoid (eg, aldosterone)
comprise only about 1% to 3% of clinically unsuspected adrenal masses. Pheochromocytoma has generally been found
in 1.5% to 9% of incidentalomas but accounted for 23% in a
Japanese series of 210 incidentalomas [3].
Adrenocortical carcinoma is rare based on data from
tumor registries (annual incidence of 1 per 600,000 in the
United States), yet it has been reported to represent approxi-
50 JCOM January 2007 Vol. 14, No. 1
mately 5% of incidentalomas. Much of these data come from
surgical series where there may be an ascertainment bias.
Also, the higher prevalence of adrenocortical carcinoma
among incidentalomas may reflect the slow growth of many
of these cancers. While there is no absolute minimal size for
adrenocortical carcinoma, all of those reported have had a
diameter greater than 1 cm. Although the median 5-year
survival for symptomatic adrenocortical carcinoma is only
35% [3], it may take several years before symptoms become
manifest. Cancers that have been inadvertently followed
rather than removed have been observed to only double in
diameter during a 7-year interval [5].
Malignancies commonly metastasize to the adrenal
gland. The most common primary sites are lung, breast,
melanoma, stomach, kidney, pancreas, and colon. However,
even in patients with known malignancies, almost half of
adrenal incidentalomas are benign adenomas.
Pseudoadrenal masses also need to be considered. These
masses may appear to be within the adrenal gland on the CT
scan but actually arise in other organs such as kidney, pancreas, spleen, stomach, liver, lymph nodes, or blood vessels.
Systemic illnesses may manifest in the adrenal gland.
Granulomas occur in tuberculosis and histoplasmosis. Adrenal cysts are seen in cryptococcosis, echinococcosis, and
paragonimiasis. The cysts of paragonimiasis can be filled
with creamy material and appear solid on CT scan [6]. Ad­
renal hemorrhage can be associated with trauma, sepsis,
hypotension, or anticoagulation.
Several inherited disorders have an increased frequency
of adrenal masses. Adrenal pheochromocytoma is associated with multiple endocrine neoplasia types 2A and 2B,
paraganglioma/pheochromocytoma syndrome types 1 and
4, neurofibromatosis type 1, and von Hippel-Lindau disease
[7]. Congenital adrenal hyperplasia frequently spurs an adrenocortical adenoma and, less commonly, bilateral nodular
adrenals or adrenocortical carcinoma [8]. Other etiologies of
adrenal masses are listed in Table 1.
• What is the approach to the clinical evaluation?
There are 4 main questions that should be answered by the
clinical evaluation: (1) Is the mass hormonally active and
likely to produce significant problems? (2) Is it a nonadrenal
or metastatic malignancy requiring removal or confirmation
for treatment planning? (3) Is it a granulomatous or cystic
manifestation of an infectious disease? (4) Is it a primary
adrenal malignancy? An approach to the workup is shown
in the Figure.
The initial step is the history and physical examination.
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Historical data obtained should include symptoms and signs
of hypercortisolism (eg, weight gain, abnormal fat distribution, hypertension, glucose intolerance, striae, muscle wasting, osteopenia, depression), hyperaldosteronism (eg, hypertension, weakness), virilization (eg, hirsutism, clitoromegaly)
or feminization (eg, gynecomastia), and catecholamine excess (eg, hypertension, tachycardia, palpitations, headache,
sweats). Since benign adenomas are more common with
aging, masses in younger patients (eg, < 50 years) should be
viewed with greater suspicion. An adrenocortical carcinoma
may be associated with symptoms related to local extension
(eg, back pain) or invasion into the vena cava. Adrenocortical
carcinomas can cause symptoms by distant metastases, most
commonly to the lung, liver, lymph nodes, peritoneum, bone,
and pleura. Infectious etiologies, hemorrhage, and large
benign masses (eg, myelolipoma) can also cause local pain.
Bilateral destructive lesions can cause adrenal insufficiency.
Any patient with significant clinical findings should be investigated thoroughly, as if the clinical concerns rather than
the incidentaloma had prompted the evaluation [9].
• What features on imaging can help characterize the
mass?
Computed Tomography
A CT scan is the most common initial study in which an adrenal mass in incidentally discovered. Review of this study
and any previous studies that might be available should be
done. Stability of the mass for at least 6 months, preferably for
18 months, generally reflects a benign process. Attenuation,
measured in Hounsfield units (HU), may be defined for a
designated region of interest within the mass. The region of
interest for the CT density measurements should cover approximately one half to two thirds the size of the mass. Too
large an area might include adjacent fat. Too small an area
might lead to pixel sampling errors and may not reflect the
true density of the whole lesion [10]. On an unenhanced CT
scan, low attenuation within the mass suggests lipid content. The cells of cortical adenomas generally contain much
intracytoplasmic lipid. The attenuation is even lower in fatcontaining masses such as lipomas or myelolipomas.
Most often, the study on which an incidentaloma is
found has been performed with intravenous contrast. Distinguishing benign adenomas from nonadenomas is not as
reliable on a contrast study as it is on an unenhanced study.
CT density considerations assume measurement within a
relatively homogeneous mass. The cause of any heterogeneity must be considered. For example, areas of hemorrhage
may produce increased density within an otherwise lipid-
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Table 1. Etiologies of Adrenal Masses
Adrenal cortex
Benign
Malignant
Adenoma
Carcinoma
Oncocytoma
Metastasis
Adrenocortical-pituitary hybrid
tumor
Nodular hyperplasia
Adrenal medulla
Benign
Malignant
Pheochromocytoma
Malignant pheochromocytoma
Ganglioneuroma
Malignant ganglioneuroma
Other neoplasms
Benign
Malignant
Neurofibroma
Malignant neurofibroma
Schwannoma
Malignant schwannoma
Hemangioma
Angiosarcoma
Leiomyoma
Leiomyosarcoma
Teratoma
Teratocarcinoma
Hamartoma
Fibrous histiocytoma
Adenomatoid tumor
Lymphoma
Myelolipoma
Melanoma
Lipoma
Infectious
Echinococcosis
Cryptococcosis
Paragonimiasis
Granuloma
Other
Cyst
Hematoma
Amyloidosis
Extramedullary hematopoiesis
Xanthoma
containing mass. Conversely, on rare occasions, malignancies can contain areas of fat or arise alongside a benign
lesion, thereby creating a “collision tumor.”
If an unenhanced CT scan is available, the distinction is
better. Homogeneous masses with CT attenuation less than
2 HU may be considered benign adenomas (or, occasionally,
simple cysts or lipomas). An unenhanced CT attenuation
greater than 43 HU generally represents a lesion other than
an adenoma [11]. While homogeneity is generally a favorable
sign, benign adenomas can undergo cystic degeneration and
show heterogeneity. Also, rare homogeneous low-density
adrenocortical carcinomas have been reported, but these
Vol. 14, No. 1 January 2007 JCOM 51
adrenal incidentalomas
Incidentally discovered adrenal mass
Endocrine screening (see Table 2)
Nonfunctioning mass
Hormonally active mass
Unenhanced CT
Confirm, then surgery
Heterogeneous
or ≥ 2 HU
Homogeneous
< 2 HU
≤ 6 cm
< 3 cm
3–6 cm
Annual
clinical
evaluation
× 4 yr
CT washout
> 6 cm
< 38% RPW or
< 52% APW
> 6 cm
≥ 38% RPW or
≥ 52% APW
Decisively
Annual
benign
hormonal
imaging?
evaluation
(consider PET,
× 4 yr
NP59)
No
Yes
Annual
hormonal
evaluation
× 4 yr plus
at 6–12 mo
Other
primary
malignancy?
(consider
FNA, csMRI,
PET, NP59)
Mass size?
(consider FNA)
< 3 cm
Surgery
Annual
hormonal
evaluation
× 4 yr plus
imaging
at 6–12 mo
3–6 cm
Yes
Probably
benign
imaging?
(consider
PET, NP59)
Probably
benign?
Indeterminate
Yes
Annual hormonal
evaluation × 4 yr
plus imaging at
3, 6, & 18 mo
Indeterminate
Surgery
Figure. Management of an incidentally discovered adrenal mass. APW = absolute percentage washout; csMRI = chemical shift
magnetic resonance imaging; CT = computed tomography; FNA = fine-needle aspiration biopsy; HU = Hounsfield units; NP59 =
iodocholesterol scintigraphy; PET = positron emission tomography; RPW = relative percentage washout.
presented with syndromes of hormonal hypersecretion [12].
Special caution should be exercised to distinguish a simple
cyst from a pseudocyst [13]. Pseudocysts may form within
adrenal masses, including pheochromocytomas, functional
adenomas, and adrenocortical carcinomas.
While the criterion of less than 2 HU provides nearly 100%
specificity for a benign mass [14], only 47% of adenomas fall
below this CT density. A widely accepted threshold is less
than 10 HU. This criterion provides 96% to 98% specificity
and encompasses 71% to 79% of benign masses [15,16]. Although the 10 HU criteria has been generally accepted, the
52 JCOM January 2007 Vol. 14, No. 1
lower specificity should be gauged with caution and masses
in the 2 to 10 HU range deserve special scrutiny for other
characteristics, such as homogeneity [17]. Irregular borders
should be viewed with particular suspicion in any mass [18].
Even better distinctions can be made using delayed
con­trast-enhanced CT scans. This “washout” technique
taps the observation that contrast washes out more rapidly
from adenomas than from malignant lesions. With this approach, images are obtained at peak dynamic phase (“enhanced scan”) and again at 10 minutes (some centers use
15 minutes) after intravenous contrast (“delayed enhanced
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scan”). The percent washout of enhancement relative to the
initial enhancement is calculated as (dynamic HU – delayed
HU/dynamic HU) × 100. A relative percentage washout of
less than 38% has 100% sensitivity and 95% specificity for
identifying metastatic lesions [11]. If an unenhanced scan
is done, an absolute percent washout also can be calculated
(dynamic HU – delayed HU/dynamic HU – unenhanced
HU) × 100. The absolute percent washout is more accurate
for benign masses that do not enhance much [19], such
as an organized hematoma. The threshold for absolute
percent washout is 52% [11]. This washout approach similarly distinguished between adrenocortical carcinoma and
adenoma [20,21], although washout in the adenoma range
has been reported in a well-differentiated carcinoma [22].
Also, pheochromocytomas may show substantial washout
of contrast [23], but these masses should be distinguished
by the hormonal evaluation.
The intravenous contrast washout approach may be
used at the initial CT study in a well-informed radiology
department. The technician can view the CT scan before
the patient leaves the table. If an adrenal mass is detected, a
delayed enhanced scan can be performed.
• What endocrine screening should be done?
The 2002 National Institutes of Health (NIH) consensus
conference statement recommends screening all patients for
pheochromocytoma with plasma free metanephrines and
for hypercortisolism with a 1-mg overnight dexamethasone
suppression test [24]. They make an exception for patients
with imaging characteristics of a myelolipoma (here again,
a collision tumor needs to be considered [25]) or an “adrenal
cyst” (ie, a simple cyst, not a cystic tumor).
Pheochromocytoma
Pheochromocytomas represent approximately 3% of incidentally discovered adrenal masses. Approximately 90% of
these patients have a history of hypertension or paroxysmal
symptoms. Others may have pheochromocytomas that are
clinically silent but potentially lethal. Autopsy series show
approximately 50% of patients with pheochromocytoma do
not have a recorded history of hypertension [26].
Although detection of pheochromocytoma is of utmost
importance, should all patients with adrenal incidentalomas
be screened? Pheochromocytomas are not low-attenuation
tumors on CT scans. Except for cystic or fat-containing
regions, pheochromocytomas are at least 2 HU on unenhanced CT scans [23]. Therefore, patients with homogenous
adrenal incidentalomas less than 2 HU should not require
screening. Caution should be exercised in reviewing the
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CT scan because cystic fluid can represent the majority of a
pheochromocytoma with the tumor tissue appearing only
as an outer rim. Since the false-positive rate for plasma free
metanephrines is 11% to 18%, judicious use of screening can
prevent engendering unnecessary follow-up testing.
Tests for plasma free metanephrines are more sensitive
than 24-hour urine tests [27]; however, the specificity of
urinary metanephrines was greater than that of plasma free
metanephrines among patients with sporadic (nonhereditary) pheochromocytoma (89% versus 82%). Using fractionated urinary metanephrines improved sensitivity over total
urinary metanephrines [28]. If the patient has paroxysmal
symptoms, yield is improved if the 24-hour urine collection
is initiated at the time of symptoms. In summary, if high
sensitivity is desired, plasma free metanephrines are preferred; if higher specificity is desired, urinary fractionated
metanephrines are advantageous.
Cortisol Excess
With regard to evaluation of cortisol excess, patients with
even mild symptoms or signs of hypercortisolism that
might be expected to improve after resection of an adenoma
merit screening. Studies, albeit uncontrolled, have shown
a variety of improvements after resection of adenomas
that hypersecrete cortisol. These patients with “subclinical
Cushing’s syndrome” showed reductions in blood pressure,
weight, and glucose intolerance after surgical removal of the
adenoma [29,30]. The term “subclinical autonomous glucocorticoid hypersecretion” (instead of subclinical Cushing’s
syndrome) avoids the perspective that elevated cortisol
needs to cause the full spectrum of Cushing’s syndrome
[24]. Additionally, screening is valuable to identify cortisol
excess stemming from a possible adrenocortical carcinoma.
The NIH-recommended test is a 1-mg overnight dexamethasone suppression test [24]. With this test, the traditional cutoff for an abnormal morning serum cortisol is greater
than 5 mg/dL. Patients with clinical Cushing’s syndrome,
however, have had values as low as 1.8 mg/dL [31,32]. Since
the clinical concern in the setting of an incidentaloma is for
corticotropin (ACTH)–independent Cushing’s syndrome,
rather than pituitary Cushing’s disease, some researchers
have advocated the use of 3 mg [33] or 8 mg dexamethasone [34]. Alternative tests, yet to be validated for adrenal
incidentalomas, include bedtime (or “midnight”) salivary
cortisol. Salivary cortisol has superior predictive value compared with the 1-mg overnight dexamethasone suppression
test for Cushing’s syndrome that has presented clinically
[35]. While there is no published study of bedtime salivary
cortisol in incidentaloma patients, elevated midnight serum
cortisol was associated with higher systolic blood pressure
and fasting glucose concentrations [36].
Although 24-hour urinary free cortisol generally has
Vol. 14, No. 1 January 2007 JCOM 53
adrenal incidentalomas
Table 2. Endocrine Screening
Disorder
Test
Pheochromocytoma (all patients,
possible exception if unenhanced CT scan is homogeneous and density < 2 HU)
Cortisol excess (all patients)
Fractionated plasma free
metanephrines or urinary
fractionated metanephrines
Mineralocorticoid excess (patients with hypertension)
Overnight 1-mg dexamethasone suppression test
Serum potassium and plasma aldosterone to plasma
renin activity ratio
CT = computed tomography; HU = Hounsfield units.
lower sensitivity than the overnight dexamethasone suppression test, it may have a special role to detect adrenal
adenomas with abnormal receptors, such as for gastric inhibitory polypeptide that causes “food-dependent Cushing’s
syndrome.” These tumors intermittently hypersecrete cortisol, and an integrated measure is more sensitive than one
based on diurnal variation [37]. Incidentalomas with these
aberrant receptors have been reported [38,39].
Suppressed morning ACTH levels have not been as uni­
formly observed as might be anticipated in the setting of
an autonomous cortisol-secreting adenoma. ACTH levels in
the normal range have been observed in 28% of clinically
evident ACTH-independent Cushing’s syndrome [40]. In
1 study of adrenal incidentalomas, among patients defined
as having subclinical Cushing’s syndrome by a postovernight 1-mg dexamethasone suppression test cortisol of
greater than 3 mg/dL, only 44% had suppressed ACTH levels, whereas 79% had loss of diurnal cortisol rhythm [41].
In summary, the current recommendations for screening
include fractionated plasma free metanephrines or 24-hour
urinary fractionated metanephrines, but this recommendation may be modified when the CT image is incompatible
with pheo­chromocytoma. The other recommended screening test is an overnight 1-mg dexamethasone suppression
test, but depending on the criterion used, this test lacks adequate sensitivity or specificity; other tests of cortisol hypersecretion (bedtime salivary cortisol and 24-hour urinary free
cortisol) may be used selectively. The suggested endocrine
screening is summarized in Table 2.
• What additional endocrine screening should be done
in patients with hypertension?
The clinical concern for patients with hypertension and an
adrenal adenoma is for mineralocorticoid excess. Hyperal-
54 JCOM January 2007 Vol. 14, No. 1
dosteronism is rarely a sole manifestation of adrenocortical
carcinoma [42]. Patients should be screened with a serum
potassium level and a plasma aldosterone concentration
(PAC)–plasma renin activity (PRA) ratio. The NIH consensus conference recommended criteria for further evaluation
of aldosterone excess were a PAC-PRA ratio greater than 30
(PAC in ng/dL and PRA in ng/mL/hr) coupled with a PAC
greater than 18 ng/dL [24]. A positive screening test should
be evaluated further with suppressive tests [43].
Spontaneous hypokalemia is found in about 75% to
80% of patients with aldosteronomas. The sensitivity of
a low serum potassium level may be increased to greater
than 90% if performed after 3 days of ingesting more than
200 mmol of sodium per day [44]. Hypokalemia may also
help to signal mineralocorticoid excess other than aldosterone (eg, deoxycorticosterone).
• What is the role for other imaging techniques?
Although CT scan is the most common study for initial
detection of an adrenal mass, other imaging modalities,
such as ultrasound or magnetic resonance imaging (MRI),
may find an adrenal incidentaloma. Nuclear scintigraphy
and positron emission tomography (PET) have roles in the
further evaluation of uncharacterized masses.
Ultrasound
Ultrasound may be the initial study in which an adrenal mass is detected. Ultrasound typically misses smaller
masses. In one study, ultrasound detected only 65% of tumors smaller than 3 cm seen on CT [45]. The adrenal gland
may be seen especially well in thin patients but not in very
obese patients. Ultrasound is useful in characterizing a cyst.
A thin-walled, round, homogeneous fluid density lesion is
consistent with a benign cyst.
Magnetic Resonance Imaging
With increased use, MRI is detecting more adrenal masses.
Pheochromocytomas and adrenocortical carcinomas generally have high signal intensity on T2-weighted images, but
values can overlap benign adenomas [46]. Chemical shift
MRI enables better distinction. Chemical shift MRI gauges
intracellular lipid, conceptually similar to the impact of lipid
on CT attenuation. Chemical shift MRI uses the difference
in resonance frequency between the protons of lipid and
water. Unlike conventional spin-echo MRI, which places
a refocusing pulse at the midpoint between the excitation
pulse and the measurement time, chemical shift MRI moves
the refocusing pulse so that lipid and water magnetization
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is 180 degrees out of phase. The resulting pixel brightness
is the net difference between lipid and water magnetization. The signal intensity loss is maximal when content is
equal. Comparison is best made with a nonlipid-containing
organ such as the spleen. The presence of lipid in the adrenal
mass can be defined quantitatively by an adrenal to spleen
ratio, defined as the percentage of signal remaining in the
opposed-phase image relative to the in-phase image. Ratios
less than 70 are associated with benign adenomas. Several
studies also show the reliability of qualitative visual inspection of the change in signal intensity within the mass. Lipidpoor adenomas pose a problem for the sensitivity of chemical
shift MRI. Additionally, some metastases and adrenocortical
carcinomas have ratios in the adenoma range [47]. The overall sensitivity for detection of adenomas is 78% to 82% with a
specificity of at least 87% [15,48].
Nuclear Scintigraphy
Adrenocortical scintigraphy provides images of uptake of
radioactive cholesterol analogs. Scanning utilizes NP59,
an I-131 labeled cholesterol analog that is available from
the University of Michigan as an investigational new drug
[49,50]. In Europe, an alternative agent is selenium-75, selenomethylcholesterol. False-negative scans are common for
masses smaller than 2 cm in diameter [51].
Unlike nuclear scanning for thyroid nodules, the vast
majority of apparently “nonfunctioning” adrenal adenomas
are “hot.” Uptake on the same side (“concordant with”) the
mass on CT was reported in 93% of clinically silent cortical
adenomas [49]. Discordant uptake is generally found for
metastatic lesions, nonfunctional adrenocortical carcinoma,
cysts, and other space-occupying lesions. Rarely, concordant
uptake has been reported in metastatic cancer (eg, renal cell
carcinoma) [52]. Scanning can be useful for masses that are
appear to be lipid-containing by MRI or have borderline CT
“washout” results but otherwise do not have imaging characteristics (eg, irregular borders) that compel removal. In this
setting, a concordant uptake on scintigraphy would suggest
the mass is an adrenocortical adenoma whereas a discordant
uptake would suggest it is an adrenocortical carcinoma.
Rare “collision” tumors may cause incorrect interpretations [53]. A collision tumor represents 2 adjacent tumors,
such as an adrenal adenoma and a metastatic lesion. In this
circumstance, the nuclear scan may reflect 1 tumor, but not
the adjacent tumor. Careful review of the CT scan should
permit proper assessment.
PET
PET using 18-fluorodeoxyglucose detects metastatic lesions in the adrenal. Standardized uptake values (SUV) are
calculated for the lesion. In 1 study, the SUV for metastases
ranged from 2.3 to 26.1, while benign lesions had SUV
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between 0.5 and 3.3 [54]. Reported SUV for benign lesions
has ranged up to 4.8 [55]. While there is overlap, sensitivity
for detection of malignancy has been greater than 93% with
specificity greater than 94% [56]. Incorporating CT information can sometimes permit identification of adenomas
where PET suggested a malignant lesion [54].
• What are the implications of mass size?
Mass size is associated with risk of adrenocortical carcinoma. Adrenal adenomas 6 cm or larger in diameter are
rare, with 3 found among 12,000 autopsies. In clinical series,
adrenocortical carcinomas represent approximately 25% of
masses greater than 6 cm; only approximately 18% of these
large masses are adenomas [57].
Masses smaller than 6 cm, however, should not be ignored. Incidentally discovered adrenocortical carcinomas
smaller than 2 cm have been reported [58]. In addition, the
CT scan can underestimate the diameter of an adrenal mass
by as much as 30%. Adrenal tumors are often elliptical, and
transverse slices underestimate the superior-inferior dimension. A tumor that is actually 6 cm may be estimated as
small as 4.2 cm on the CT scan. Some of these measurement
difficulties may be avoided if 3 orthogonal dimensions are
recorded from the volumetric data available with current
multidetector row CT scanners [11].
• What is the role of fine-needle aspiration?
Fine-needle aspiration (FNA) of the adrenal may be done
under CT or ultrasound guidance [59–63]. Minor complications (eg, pain) are reported in 10% to 15% of patients.
Major complications, such as hemorrhage, pneumothorax, or
abscess occur in less than 13%. Needle track seeding by metastases has been reported [64]. Pheochromocytoma should
be excluded prior to FNA to avoid precipitating a crisis.
The major role of FNA is diagnosing malignancies metastatic to the adrenal gland. If CT or MRI studies are equivocal
and a distinction of adenoma from metastasis is required for
treatment planning, a FNA has excellent yield. In 4 large series, FNA was diagnostic in 221 of 254 biopsies [59–62].
FNA is not generally useful in distinguishing adrenocortical adenoma from adrenocortical carcinoma. Only an
exceptional carcinoma may be identified by extreme atypia,
such as cellular pleomorphism, variably shaped nuclei in a
multinucleated cell, and numerous atypical mitoses [65]. Future work may employ gene expression. Notably, insulin-like
growth factor II overexpression has been frequently observed
Vol. 14, No. 1 January 2007 JCOM 55
adrenal incidentalomas
in pathology specimens from adrenocortical carcinoma but
not from adenomas [66].
Workup and Assessment
The patient has several symptoms of Cushing’s
syndrome with abdominally localized weight gain,
round face, edema, muscle weakness, fatigue, and worsened
hypertension. An overnight 1-mg dexamethasone suppression test yields a serum cortisol of 3.8 mg/dL. A 24-hour
urinary free cortisol is slightly elevated at 47 mg/dL (normal,
4–45 mg/dL). One midnight salivary cortisol is elevated at
0.27 mg/mL (normal, up to 0.18 mg/mL for females aged 31–
50 years), although another is top-normal at 0.17 mg/mL. A
random serum cortisol is 10.2 mg/dL and an ACTH is 6 pg/mL.
Serum aldosterone, plasma renin activity, plasma metanephrine and normetanephrine, and 24-hour urinary fractionated
metanephrines and catecholamines are normal.
Since the patient has symptoms attributable to cortisol
excess and biochemical evidence of cortisol hypersecretion,
she is offered an adrenalectomy.
• What procedure should be used for resection of an
adrenal mass?
• What tests are indicated prior to surgery?
The options for surgical removal of an adrenal mass include open (transabdominal and posterior) and laparoscopic
(transperitoneal and retroperitoneal) procedures. Until recently, larger masses were exclusively removed by open
procedures. Laparoscopic adrenalectomy has been successful with large tumors provided there is no evidence of extraadrenal or vascular invasion [67,68]. Laparoscopy has also
been used for removal of an isolated metastatic mass in
patients with favorable prognostic features such as long
disease-free interval [69,70]. Selective removal of the tumor,
sparing the adjacent normal adrenal gland, has been used
for benign tumors [71,72]. CT-guided radiofrequency ablation has also been used for both metastases and benign
tumors [73]. For all procedures, patients with evidence for
hypercortisolism should be protected from adrenal insufficiency with perioperative corticosteroid supplementation.
Positive hormonal screening should be confirmed prior
to surgery. Generally, there should be at least 2 abnormal
tests of cortisol hypersecretion combined with clinical
features of cortisol excess prior to removal of a presumed
cortisol-secreting adenoma [74]. Aldosteronomas should
be confirmed by a suppression test. In patients older than
40 years, where nonfunctioning adenomas are more common, a selective adrenal vein catheterization study should
be done to confirm the incidentaloma as the source of the
56 JCOM January 2007 Vol. 14, No. 1
excess aldosterone [75,76]. If the diagnosis of pheochromocytoma is uncertain, a clonidine suppression test can be
performed [77]. If the CT scan is not suggestive of pheochromocytoma, a nonadrenal pheochromocytoma concurrent with a nonfunctioning adrenal adenoma should be
considered [78]. Additionally, several authors recommend a
metaiodobenzylguanidine (MIBG) scan prior to surgery to
exclude metastatic pheochromocytoma [79].
• What changes can be expected after removal of an adrenal adenoma in a patient with subclinical Cushing’s
syndrome?
Glucose tolerance, hypertension, and obesity have been
noted to improve following resection of adenomas associated with subclinical Cushing’s syndrome [30]. Bone density
improvement has yet to be convincingly demonstrated; it
remains controversial whether subclinical Cushing’s syndrome causes bone mineral loss [57,80].
Follow-up
The patient undergoes a transperitoneal laparoscopic left adrenalectomy. Pathology shows an
adrenocortical adenoma. She takes prednisone 5 mg daily
postoperatively and eventually is fully weaned off at
6 months after surgery. At 1 year after surgery, she no longer needs olmesartan or hydrochlorothiazide to control her
blood pressure and no longer requires potassium supplements. She continues sustained-release metoprolol for her
episodes of tachycardia. Her weight remains the same, but
her headaches clear, her peripheral edema resolves, and she
no longer feels tired.
• What is appropriate follow-up in patients who do not
undergo surgery?
Follow-up in patients who do not undergo surgery has
2 main concerns: possible evolution of hormonal excess
and identification of a malignancy missed on the original
evaluation. Progression to hormonal hypersecretion has
been said to occur in up to 20%, but a large careful study
found fewer than 2% progressed over 3 years [2]. The risk
for progression of cortisol hypersecretion is greater among
masses larger than 3 cm. In one series, 1 of 8 patients with
subclinical Cushing’s syndrome subsequently manifested
full Cushing’s syndrome [81]. Pheochromocytoma first detected at follow-up has been reported rarely [82].
It has been recommended that patients be re-evaluated
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case-Based review
annually for 4 years for cortisol excess (by a 1-mg overnight
dexamethasone suppression test) and for pheochromocytoma (by a 24-hour urine for catecholamines and metabolites) [24]. Since progression to hypercortisolism is rare with
tumors less than 3 cm, among patients with smaller tumors
it may be reasonable to reserve repeat dexamethasone suppression testing for those with manifestations of glucocorticoid excess (eg, weight gain, hypertension, glucose intolerance, low bone density). Follow-up evaluation with urinary
fractionated metanephrines is reasonable for patients whose
masses had imaging characteristics compatible with pheochromocytoma.
Repeat CT scan at 6 to 12 months has been recommended
[24]. There have been rare reports of adrenocortical carcinoma apparently arising from an adenoma, but malignant
transformation is decidedly exceptional [83]. Overwhelmingly, benign tumors tend to maintain their benign nature.
Therefore, if the tumor can be confidently classified as a
cortical adenoma, several authors recommend no further
imaging follow-up [84].
Additionally, however, masses originally misclassified as
benign that prove to be carcinoma may grow slowly. Therefore, masses of a more indeterminate nature that are not
immediately resected should be followed for enlargement at
intervals up to 18 months (eg, at 3, 6, and 18 months). It should
be borne in mind that mass enlargement of more than 1 cm
over 1 year, while disconcerting and likely to prompt resection of an indeterminate mass, occurs in approximately 5% of
benign adenomas [2,85]. In one series, all 4 tumors removed
because of this criterion were benign [86].
SUMMARY
The majority of incidentally discovered adrenal masses are
benign, nonfunctional adenomas. It is crucial to determine
which masses represent functional adrenal tumors or malignancies. Imaging characteristics and endocrine testing
provide guidance in these distinctions. Follow-up is necessary to exclude evolving endocrine function and to detect
malignancy among those masses that are not conclusively
benign at the initial evaluation.
Corresponding author: Paul M. Copeland, MD, 496 Lynnfield St.,
Lynn, MA 01904, [email protected].
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Copyright 2007 by Turner White Communications Inc., Wayne, PA. All rights reserved.
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Vol. 14, No. 1 January 2007 JCOM 59
JCOM
CME
CME EVALUATION: Approach to Incidentally Discovered Adrenal Masses
DIRECTIONS: Each of the questions below is followed by several possible answers. Select the ONE lettered answer
that is BEST in each case and circle the corresponding letter on the answer sheet.
1. Most incidentally discovered adrenal masses are
(A) Adrenal cysts
(B) Nonfunctioning adrenal adenomas
(C) Cortisol-producing adenomas
(D) Metastases
2. Which of following statements about pheochromocytoma is FALSE?
(A) It accounts for approximately 10% of adrenal incidentalomas
(B) A homogenous mass < 2 Hounsfield units on
unenhanced computed tomography (CT) scan is
incompatible with the diagnosis
(C) It is common in patients with a history of hypertension or paroxysmal symptoms
(D) The condition must be excluded prior to fineneedle aspiration of the adrenal gland
4. Which of the following statements about adrenocortical
carcinoma (ACC) is TRUE?
(A) ACC commonly arises from an adenoma
(B) ACC accounts for approximately 5% of incidentalomas
(C) Fine-needle aspiration can help distinguish ACC
from adenoma
(D) None of the above
5. A patient is found to have a nonfunctioning hetero­
genous mass on unenhanced CT that is 7 cm in diameter.
What is the appropriate next step?
(A) Surgical removal
(B) Evaluate for cortisol excess
(C) CT washout
(D) Positron emission tomography
(E) None of the above
3. Which of the following tests is used to screen for cortisol
hypersecretion?
(A) 1-mg overnight dexamethasone suppression test
(B) 24-hour urinary catecholamines
(C) Fractionated metanephrines
(D) None of the above
60 JCOM January 2007 Vol. 14, No. 1
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CME
EVALUATION FORM: Approach to Incidentally Discovered Adrenal Masses
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