Tissue characterization is vital to planning subsequent therapy after diagnosis of an adrenal mass. This article discusses adrenal morphology, imaging techniques, and an imaging algorithm to facilitate the most accurate means of characterizing the incidentally detected adrenal mass without the need for percutaneous biopsy.
Most adrenal masses are detected by computed tomography (CT) and
occur in up to 2% of patients.
The majority of these masses will turn out to be benign,
particularly in patients with no history of malignancy (unless
there are biochemical features to suggest a hyperfunctioning
However, many silent adrenal masses are detected in patients who
are being investigated by abdominal CT for malignant disease. The
differential diagnosis of an incidentally detected mass in this
group of patients is markedly different from that of a patient with
no history of malignancy. Up to 35% of patients with a history of
malignancy will have adrenal metastases, whether microscopic or
Conversely, if an adrenal mass is detected by CT in a patient with
malignancy, there is approximately a 30 to 40% chance that this
harbors metastatic disease.
Therefore, detection of an adrenal mass in a patient with cancer
has major implications for staging and treatment of the primary
Tissue characterization is vital to planning
subsequent therapy after diagnosis of an adrenal mass. Over the
last decade, imaging algorithms have been developed that have
substantially reduced the need for tissue diagnosis by percutaneous
biopsy. Biopsy should be avoided, not so much because it is an
invasive technique with a small risk of pneumothorax,
but because it is time-consuming, expensive, and perhaps most
importantly, has a reported diagnostic accuracy of only 80 to 90%.
Several morphological features of the adrenal
gland may permit lesion characterization, including lesion size,
shape, and heterogeneity.
Lesions greater than 5 cm are almost always malignant (figure 1)
(except for the rare myelolipoma).
Such large lesions are usually adrenal carcinomas. Lesion
irregularity also may indicate a malignant lesion, but a smooth
lesion can represent either benign or malignant disease. Most
incidentally-detected adrenal masses are in fact small and smooth
in shape and, therefore, lesion shape often is not very
Occasionally, larger lesions may demonstrate
inhomogeneity, particularly if intravenous contrast has been
administered. Benign lesions do not demonstrate areas of necrosis.
However, as most incidentally-detected lesions are small and
homogeneous (whether benign or malignant), this is not a reliable
test (figure 2). The easiest and least costly test is using a prior
study for comparison. If an older CT or magnetic resonance scan
(MRI) is available and the lesion has not changed in size in 6
months, then this most likely represents a benign lesion. Any
increase in size over this time is highly suspicious for
malignancy. If there is a marked increase in size and no features
of hemorrhage, then the lesion is definitely malignant and biopsy
is not required.
As the above morphologic features are often
nonspecific, a more accurate test is required to accurately
differentiate benign from malignant disease. Fortunately, both CT
and MRI techniques have been developed that enable lesion
characterization without the need for percutaneous biopsy in the
majority of cases. This is because the adrenal cortex and many
benign adrenocortical tumors contain intracytoplasmic fat (mainly
of cholesterol, fatty acids, and neutral fat) while malignant
lesions do not.
Any technique that can detect intracytoplasmic fat will enable
differentiation of benign from malignant lesions. However, for this
test to be clinically useful, its specificity for the detection of
an adenoma needs to approach 100%. As the test specificity
decreases, more malignant lesions may be called benign. This
unfortunate situation might mean that the referring physician would
attempt unnecessary curative surgery for the primary lesion, in the
assumption that the detected adrenal mass is a benign lesion.
The converse is not as important, however. If
a potential adrenal adenoma is found to be indeterminate, most
institutions will require tissue diagnosis before palliative
surgery is initiated. Put another way, the referring physician will
require a tissue diagnosis before denying the patient potential
Lipid-sensitive imaging techniques are not
100% specific and sensitive because only 60 to 70% of benign
adenomas contain enough intracytoplasmic fat to permit separation
of benign from malignant disease. Therefore, some adrenal adenomas
might potentially be characterized as metastases. Rather than
characterizing all lipid-poor lesions as malignant, lipid-poor
adenomas and malignant lesions are deemed indeterminate. These
indeterminate lesions will, however, require further
characterization, either by an alternative imaging method or by
percutaneous biopsy. Therefore, lipid-sensitive tests that can
detect benign disease can be made close to 100% specific for the
detection of an adenoma, with some reduction in sensitivity.
However, in order for a lipid-sensi-tive test
to be clinically useful, it should not be too stringent. The test
has relatively little use if in order to achieve close to 100%
specificity, sensitivity is reduced to levels below 50%. In this
scenario, too many lesions remain indeterminate and additional
imaging or biopsy is required. A trade-off is, therefore, required
between sensitivity and specificity. In order for sensitivity to be
relatively high (>70%) the specificity needs to be lowered
slightly. Certainly specificity needs to be close to 100%, and an
acceptable level is probably greater than 95%. Although this
results in a clinically practical test, there will inevitably be
the occasional malignant lesion that is "down-staged" to an
adenoma. However, this unfortunate situation can often be avoided,
as there may be other clues that permit a lesion to be
characterized (recent increase in size, irregularity, or
inhomogeneity). Clinical experience has demonstrated over the last
decade that some slight lowering of specificity is still clinically
Computed tomography: noncontrast CT
Most incidentally detected adrenal lesions
are identified on CT. Ideally, then, lesion characterization should
be performed by CT in order to avoid the need for further imaging
or biopsy. Lipid sensitive imaging is well suited to CT. Not only
can macroscopic fat be evaluated by CT (i.e. myelolipoma) but
sufficient concentrations of intracytoplasmic fat also can be
detected. As CT density values are related to tissue attenuation
coefficients, fat-containing structures will lower the Hounsfield
unit (HU) measurements more than would other soft-tissue
structures, including water-containing structures, if fat is
present in a sufficient concentration. By placing a region of
interest (ROI) on the adrenal lesion, density measurements can
determine if the adrenal lesion contains enough intracytoplasmic
fat to be diagnosed as an adenoma.
Korobkin et al were able to demonstrate an
inverse linear relationship between the intracytoplasmic fat
content of an adrenal adenoma and the CT density value.
Adenomatous lesions usually contain significant intracytoplasmic
fat and CT density values are low (usually -10 to +10 HU) (figure
3). Pure fat-containing lesions (i.e. myelolipomatous lesions) will
have density values of 80 to 100 HU (figure 4). Conversely,
non-adenomatous lesions typically have higher CT density values, as
their cytoplasm is relatively lipid-poor (figure 5).
Using this principle, chemical shift MR
techniques also have revealed similar accuracies to unenhanced CT
for differentiating benign from malignant adrenal masses.
However, CT continues to remain the investigational modality of
choice for evaluating adrenal masses due to its widespread
availabil-ity, its high speed, and its low cost.
Many studies have confirmed the ability of
unenhanced CT to consistently characterize the incidentally
detected adrenal mass.
Most of these have attempted to determine a threshold density value
which would permit separation of benign from malignant lesions.
However, a wide range of sensitivities has been reported, and no
study has yet reported that any threshold will result in both 100%
sensitivity and specificity. A recent study
pooled the density values from 10 previous reports using
noncontrast CT in order to optimize the correct density threshold
value by which benign from malignant adrenal lesions can be
characterized. On the basis of this analysis, it was suggested that
if the goal is to avoid false positive diagnoses at all costs, one
should use a threshold value of 2 HU, as this results in 100%
specificity for the test. Any lesions with CT attenuation
coefficients below this level can safely be considered benign.
However, if one is willing to accept a small false negative rate in
order to achieve improvements in sensitivity, then perhaps a
threshold of up to 10 HU could be used. The precise cut-off used
must ultimately depend on the prevalence of malignant disease in
the patient population, and the goals of the imaging procedure.
Conversely, lesions with attenuation values above 25 HU are rarely
benign, and these lesions should be assumed to be malignant. Of
course, further confirmation will be required, as the occasional
adenoma will demonstrate HU values above this.
Computed tomography: contrast-enhanced CT
Although noncontrast CT is a highly effective
method for differentiating benign from malignant adrenal disease,
most incidental adrenal lesions are initially detected by
contrast-enhanced CT, often in patients being investigated for an
extra-adrenal malignancy. Rather than performing an additional
noncontrast CT at a later stage, several authors have attempted to
characterize adrenal masses using contrast-enhanced CT, again by
using adrenal density values to detect intracytoplasmic lipids. As
expected, adrenal glands enhance, complicating the lipid sensitive
tests used to characterize their lesions. It has been shown that
the initial dynamic contrast-enhanced CT is not useful for lesion
characterization because both benign and malignant lesions enhance
to similar density values.
A threshold value cannot, therefore, be chosen by which benign
fat-containing lesions can be separated.
However, several authors have attempted to
characterize these lesions using a delayed contrast-enhanced CT.
These researchers suggest that by waiting a period of time after
dynamic contrast-enhanced CT, there may be enough "washout" of
contrast from the adrenal gland after which density values can
again be used to characterize the incidentally detected adrenal
mass. Followed to its extreme, a delay of more than 24 hours would
equate to a noncontrast CT. However, this is neither practical nor
desirable, and as a result, these authors have attempted much
shorter time delays.
It has been shown that characterization can
be performed as early as 10 to 15 minutes after the dynamic scan.
Researchers in the above studies have demonstrated that benign,
fat-containing lesions have significantly lower density values than
nonfat-containing lesions on these delayed scans (figure 6). The
precise cut-off threshold has yet to be fully established, though
it is probably approximately 30 HU.
Lesions below this value can be confidently assumed to be benign,
and lesions above this value remain indeterminate, requiring
further imaging with MRI, or biopsy.
More recent reports have attempted
to characterize adrenal lesions using a different paradigm than
simple density values at a single time point after
contrast-enhanced CT. As it has been demonstrated that benign
adrenal lesions "washout" significantly faster than malignant
adrenal lesions after injection of IV contrast,
more accurate characterization might be performed by comparing
density values on the delayed CT scan to the initial dynamic
contrast study. A ratio can be derived, from which a threshold can
be used in a similar fashion to the threshold values used to
separate benign from malignant lesions on noncontrast and simple
delayed contrast-enhanced CT.
In one study, Korobkin et al demonstrated
that the density value of adenomas at 10 minutes after contrast
administration was only 28% of its peak enhancement on the initial
The density values of malignant lesions, on the other hand, had
only decreased to 93% of their initial value on the dynamic scan.
Using this data, Korobkin et al,
and Szolar et al,
from a similar study, were able to derive relative percent washout
threshold ratios (relative because the unenhanced value is unknown)
to separate benign from malignant lesions. The formula for deriving
the relative threshold ratio is: delayed enhanced value/initial
enhanced value * 100%.
Although the values from the two studies varied slightly, it has
been determined that if the density value on the 10-minute delayed
study drops by more than 50% compared to the initial dynamic scan,
then the test is close to 100% specific and sensitive.
Interestingly, Korobkin and coworkers went a step further and
demonstrated that lesions found to be indeterminate by noncontrast
CT (adenomas with density values greater than 10 HU) could indeed
be characterized using the relative delayed washout percent value
without the need for further imaging or biopsy. If further studies
can corroborate this finding, then MRI and/or percutaneous biopsy
might be avoided altogether.
Chemical shift MRI
MRI techniques are also able to detect
intracytoplasmic fat within adrenal adenomas and are useful for
differentiating benign from malignant lesions. However, there is a
decreasing requirement for MRI, as CT can characterize an
increasing number of adrenal lesions. The technique by which MRI
can differentiate between lipid and non-lipid containing
structures, chemical shift MRI, still has an important role to
play, as some institutions prefer MRI to delayed contrast-enhanced
Normally, fat protons precess faster (and
therefore dephase faster) than water protons. Due to these
differing precessional frequencies, the two will be out-of-phase
after a variable time period (2.3 msec at 1.5T). Using normal
spin-echo T1-weighted imaging, the emitted signals from dephasing
fat and water protons are summated by using a refocusing pulse, and
are therefore imaged as structures with intermediate signal.
Gradient-echo (GRE) pulse sequences can now be performed such that
fat and water protons can be separated within an imaged voxel. In
GRE imaging, proton and fat refocusing pulses do not occur, so
water and fat protons will continue to cycle in- and out-of-phase
with respect to one another. Therefore, at 1.5T, fat and water
protons are out-of-phase after 2.3 msec and in-phase again at 4.6
msec, out-of-phase at 6.9 msec, and so on. By choosing echo times
at 2.3 and 4.6 msec, in-phase and out-of-phase images can be
obtained. On the in-phase images, fat and water signals will
summate and produce adrenals of intermediate signal, but on
out-of-phase images, the signals from fat and water will cancel
each other out and appear dark (figure 7).
Various modifications of the chemical shift
have been suggested and have been shown to be highly effective for
the characterization of adrenal masses (figure 8).
Some authors have suggested measuring the signal intensities on
in-phase and out-of-phase images and calculating adrenal/liver of
adrenal/spleen ratios in order to differentiate adrenal lesions.
However, it has been demonstrated that qualitative evaluation of
the adrenal mass signal in-phase and out-of-phase is just as
accurate as quantitative measurements.
Therefore, any visualized signal loss on out-of-phase images
indicates a benign lesion. Using these techniques, some
indeterminate adrenal lesions on noncontrast CT can be
characterized, although some adrenal adenomas contain insufficient
concentrations of fat to be characterized in this manner.
Percutaneous biopsy is, therefore, still required in some
Imaging algorithm for lesion characterization
Several researchers have now suggested an
imaging algorithm by which adrenal masses can be characterized.
Because CT detects most lesions, any algorithm should, ideally, be
CT-based. The algorithm depends on whether or not the patient has a
known extra-adrenal malignancy. If no extra-adrenal malignancy is
present, lesions with HU values below 10 are benign. However, even
lesions with HU values above this usually can safely be assumed to
be benign, unless demonstrating unusual morphologic features (such
as large size, irregularity, inhomogeneity). If some uncertainty
persists, a follow-up CT in 6 months is recommended to evaluate for
any change in the size of the lesion.
If the patient has a known primary
malignancy, the lesion must be characterized. Initially the study
must be compared to any prior CT images. Any increase in lesion
size strongly suggests a metastasis. If a noncontrast CT has been
performed, then an adenoma can be diagnosed for lesions with HU
values of 10 HU or less. For values above 10 HU, a chemical shift
MRI should be performed to evaluate for signal drop-off on the
out-of-phase images. If the lesion is still indeterminate, a
percutaneous biopsy should be performed (although recent studies
have suggested that these lesions can be characterized by washout
characteristics when using 10-minute delayed contrast-enhanced
If a contrast-enhanced CT has been performed
in a patient without a history of malignancy, delayed CT
measurements should be made. If on the 10- to 15-minute scan the HU
value is less than 30 HU, then the lesion is benign. However, even
if above 30 HU, the lesion can similarly be assumed to be benign,
as discussed above. For patients with a known malignancy,
demonstration of a lesion with density values of 30 HU or less
confirms a benign lesion on 10- to 15-minute delayed scans. If the
lesion is still indeterminate (having a HU of greater than 30),
then a relative percent washout value should be performed. If the
lesion has "washed out" by more than 50%, then this lesion is
benign. Remaining indeterminate lesions should be imaged by MRI and
if still indeterminate, a biopsy should be performed. By using such
an imaging algorithm, very few lesions will require percutaneous