Genitourinar y Imaging • Original Research

Friedrich-Rust et al.
Sonography of Adrenal Masses

Genitourinary Imaging
Original Research

Contrast-Enhanced
Sonography of Adrenal Masses:
Differentiation of Adenomas
and Nonadenomatous Lesions
Mireen Friedrich-Rust 1 OBJECTIVE. The aim of this proof-of-principle study was to evaluate contrast-enhanced
Guenther Schneider 2 sonography in the characterization of adrenal masses.
Rainer M. Bohle 3 Subjects AND METHODS. Thirty-five consecutively registered patients with new-
Eva Herrmann 4 ly detected adrenal masses underwent hormonal evaluation and duplex and Doppler sonogra-
Christoph Sarrazin1 phy followed by contrast-enhanced sonography and CT or MRI. The dynamics of contrast
enhancement were analyzed with time–intensity curves. CT and MRI were used as the refer-
Stefan Zeuzem1
ence methods for the diagnosis of adenoma and myelolipoma. Metastasis was diagnosed with
Joerg Bojunga1 fine-needle biopsy, and all other adrenal masses were diagnosed at adrenalectomy. Fisher’s
Friedrich-Rust M, Schneider G, Bohle RM, et al. exact test was used to evaluate the criteria for diagnosis of malignant adrenal masses.
RESULTS. Size greater than 4 cm and hypervascularization were found significantly
more often in malignant than in benign lesions (71% vs 21% for size; 57% vs 7% for hyper-
vascularization). At contrast-enhanced sonography, early arterial or arterial contrast en-
hancement and rapid washout were seen in all patients with primary or secondary malignant
lesions of the adrenal gland and in only 22% of patients with benign adrenal masses (p < 0.05).
All primary malignant lesions were confirmed at histologic examination. In 32 of 35 patients
(91%), findings at CT or MRI were congruent with those at contrast-enhanced sonography in
regard to characterization of adenoma versus nonadenomatous lesion (p < 0.001). In two of
the 35 cases, however, all imaging methods favored the diagnosis of nonadenomatous lesion,
but the histologic result after adrenalectomy was adrenal adenoma. The sensitivity and speci-
ficity of contrast-enhanced sonography in the diagnosis of malignant adrenal mass were
100% and 82%.
Keywords: adenoma, adrenal gland, contrast-enhanced CONCLUSION. Contrast-enhanced sonography can be used to differentiate adenomas
sonography, incidentaloma, nonadenomatous, sonography and nonadenomatous lesions with a sensitivity comparable with that of CT and MRI and may
be a cost-effective method for preselection of patients with adrenal masses.
DOI:10.2214/AJR.07.3565

Received December 18, 2007; accepted after revision
June 28, 2008.
1 the detection of adrenal masses
Medizinische Klinik I, Klinikum der Johann Wolfgang
Goethe Universität, Theodor-Stern-Kai 7, 60590
Frankfurt am Main, Germany. Address correspondence
to J. Bojunga (Joerg.Bojunga@kgu.de).
2
Department of Radiology, Saarland University
Hospital, Homburg, Germany.
3
Department of Pathology, Saarland University
Hospital, Homburg, Germany.
4 92% (92 of 100 cases). The size of the adrenal
Faculty of Medicine, Internal Medicine–
Biomathematics, Saarland University, Homburg,
Germany.
AJR 2008; 191:1852–1860
0361–803X/08/1916–1852
© American Roentgen Ray Society
S
onography can be performed with
high sensitivity and specificity for
[1–5]. One study [1] showed that
even in healthy subjects, the right and left ad-
renal glands can be visualized with transab-
dominal B-mode sonography in 99% (79 of
80) and 69% (55 of 80) of cases, respectively.
The overall sensitivity and specificity for the
sonographic detection of adrenal masses inde-
pendent of size were 96% (48 of 50 cases) and
mass did not have a significant effect on sensi-
tivity and specificity [5]. Similar results were
found in another study [4] with 119 patients.
Although a study [3] showed that benign adre-
nal masses are on average smaller than malig-
nant adrenal masses, no conclusion concern-
ing the benignity of an adrenal mass was
drawn solely from the size of the adrenal
mass. Therefore, differentiation of benign and
malignant adrenal masses with sonography
has not been possible.
In only one pilot study [6] to our knowledge
has contrast-enhanced Doppler sonography of
adrenal masses with the contrast agent SH U
508A (Levovist, Bayer Schering Pharma) been
evaluated. The investigators found improved
visualization of the vascularization of adrenal
masses during power Doppler sonography.
However, differentiation of benign and malig-
nant adrenal masses was not possible in that
study. To our knowledge, no study has been
conducted to examine adrenal glands and adre-
nal masses with a contrast agent consisting of
a suspension of phospholipid-stabilized micro­
bubbles filled with sulfur hexafluoride (Sono-
Vue, Bracco), which has the advantage that

1852 AJR:191, December 2008

 Sonography of Adrenal Masses

contrast enhancement and washout can be fol-
lowed for up to 5 minutes.
With advances in diagnostic imaging, dif-
ferentiation of malignant and benign adrenal
masses has improved substantially. CT and
MRI can be used to characterize benign adre-
nal masses in most patients with adrenal
masses. Whereas in the era before highly spe-
cialized CT and MRI 40–57% of patients with
adrenal adenomas underwent biopsy for diag-
nosis, only 12% of these patients undergo bi-
opsy at present [7]. Studies [8–12] have shown
that benign and malignant adrenal masses can
be differentiated at CT with a sensitivity of
85–100% and a specificity of 100–95%. If an
adrenal mass remains indeterminate after CT,
MRI or adrenal biopsy is performed [13–15].
CT and MRI, however, are expensive ex-
aminations compared with sonography. CT
is associated with substantial radiation expo-
sure, and CT and MRI are commonly per-
formed in addition to screening sonography.
Furthermore, adenomas are much more com-
mon than nonadenomatous lesions, and many
CT and MRI examinations are performed
only to rule out malignancy. Therefore, pre-
selection of patients with suspicious adrenal
masses at screening sonography would be
favorable. If this screening can be performed
with high sensitivity, the number of patients
who need additional diagnostic imaging with
CT or MRI would be markedly reduced, and
malignant lesions would not be missed. We
conducted a proof-of-principle study to eval-
uate contrast-enhanced sonography in the
characterization of adrenal masses.

TABLE 1: Characteristics and Clinical Findings in 35 Patients with Adrenal Masses

Benign or Malignant
Diagnosis Correct
Length Pattern on
No. of of Contrast- Histologic Finding Contrast-
Adrenal Masses Enhanced Diagnosis at Congruence on Surgical Enhanced
Diagnosis Masses (mm) Sonography CT or MRI of Findingsa Specimen Sonography MRI or CT
Adenoma 8 16–43 4 Adenoma Congruent Yes Reference
method
Adenoma 11 18–104 3 Adenoma Congruent Yes Reference
method
Adrenal hyperplasia 1 27 3 Adrenal hyperplasia Congruent Yes Reference
method
Adenoma 1 35 2 Nonadenomatous Congruent Adenoma No No
(metastasis, neuroendocrine
carcinoma)
Adenoma 1 30 1 Nonadenomatous Congruent Adenoma No No
(pheochromocytoma)
Adenoma 1 22 3 Nonadenomatous Incongruent Adenoma Yes No
(metastasis)
Myelolipoma 1 55 3 Nonadenomatous Incongruent Myelolipoma Yes Yes
(myelolipoma)
Angiomyolipoma 1 80 2 Nonadenomatous Congruent No Reference
(angiomyolipoma) method
Hemangioma 1 114 1 Nonadenomatous Congruent Hemangioma No No
(adrenocortical carcinoma)
Pheochromocytoma 1 66 1 Nonadenomatous Congruent Pheochromocytoma No Yes
(pheochromocytoma)
Posttreatment 1 36 4 Nonadenomatous Incongruent Yes Reference
metastasis (posttreatment metastasis) method
Metastasis 2 19–78 1 Nonadenomatous Congruent Yes Reference
(metastasis) method
Metastasis 1 37 2 Nonadenomatous Congruent Yes Reference
(metastasis) method
Cortisol-producing 1 44 1 Nonadenomatous Congruent Cortisol-producing Yes Yes
adrenocortical pheochromocytoma) adrenocortical
carcinoma carcinoma
Adrenocortical 1 79 1 Nonadenomatous Congruent Adrenocortical Yes Yes
carcinoma (metastasis) carcinoma
Adrenocortical 1 190 1 Nonadenomatous (adrenal Congruent Adrenocortical Yes Yes
carcinoma carcinoma) carcinoma
T-cell lymphoma 1 93 1 Nonadenomatous Congruent T-cell lymphoma Yes Yes
aCongruence between contrast-enhanced sonographic and CT or MRI findings for adenoma and nonadenomatous lesions.

AJR:191, December 2008 1853


Subjects and Methods
Patients
Between April 2006 and June 2007, 35 con­
secutively registered patients (14 men, 21 women;
mean age, 59 years; range, 36–84 years) sent to
our endocrinology referral center for further diag­
nostic evaluation of incidentally detected adrenal
masses were enrolled in this study. The adrenal
masses were detected incidentally at sonography
or CT. Baseline characteristics of the patients are
shown in Table 1. For analysis of hormonal
activity, all patients underwent detailed laboratory
testing (see later).
All patients underwent sonography of the
adrenal mass that included duplex and Doppler
sonography followed by contrast-enhanced sonog­
raphy. In addition, all patients underwent CT,
MRI, or both. Patients without clear signs of a
benign adrenal mass on MRI or CT underwent
fine-needle aspiration biopsy or adrenalectomy
and histologic evaluation of the specimen. The
study was performed in accordance with the ethi­
cal guidelines of the Declaration of Helsinki.
Informed consent in compliance with legislation
was obtained from each patient.
Sonographic Examination
All patients were examined in the supine
position with B-mode Doppler sonography with a
3.5-MHz transducer (EUB-8500, Hitachi). The
sonographic examinations were performed by two
experienced examiners blinded to the results of
MRI and CT. All patients had fasted overnight.
The adrenal mass was examined for size,
echogenicity, echotexture, margins, and perfusion
pattern. After B-mode sonography, conventional
power Doppler imaging was performed. Vascu­
larization of the adrenal mass was classified as
hypovascular, isovascular, or hypervascular in
comparison with the vascularization of the liver or
spleen. The presence of specific vascular patterns,
such as afferent blood vessels and irregular tumor
vessels was recorded.
Contrast-enhanced dynamic sonography was
performed with contrast-specific continuous-mode
software with a 3.5-MHz transducer (EUB- 8500)
and a low mechanical index (0.11). Aqueous sus­
pension of phospholipid-stabilized micro­bubbles
filled with sulfur hexafluoride (SonoVue) was
used as the sonographic contrast agent. The
contrast agent was injected IV in a 4.8-mL bolus
through a 20-gauge cannula into an antecubital
vein and was followed by a 10-mL saline flush.
The adrenal mass was scanned for 5 minutes with
the liver (right adrenal mass) or spleen (left
adrenal mass) as an in vivo reference. The first
contrast enhancement was observed and
categorized in the early arterial phase (< 20
1854 AJR:191, December 2008
Friedrich-Rust et al.
seconds after injection), arterial phase (20–40
seconds after injection), and parenchymal (late)
phase (> 40 seconds–5 minutes after injection).
Specific vascularization patterns such as central,
peripheral, and chaotic contrast enhancement
were assessed.
The video clip was digitally recorded, and a
region of interest was placed in the adrenal mass
and in the reference organ (spleen or liver) and
analyzed over time with time–intensity curves.
Contrast enhancement was compared with pre­
injection values and expressed in percentage of
baseline value. The perfusion patterns were
compared with the CT and MRI diagnoses and
judged congruent or noncongruent with CT or
MRI findings for differentiation of adenoma and
nonadenomatous lesions.
CT and MRI
If the incidental diagnosis of adrenal mass was
made at CT performed for other purposes, such as
abdominal pain, staging of primary malignant
tumor, and hormonal dysfunction, the CT scans
were reviewed for quality criteria by a radiologist
with 20 years of experience. Only a triple-phase
helical CT examination with delayed contrast
enhancement (iomeprol 400 mg I/mL, Iomeron
400, Bracco) was accepted for analysis. Percentage
of washout was calculated with the following
formula: (1 – delayed enhanced attenuation value /
initial enhanced attenuation value) × 100 [16]. If
clear criteria for a benign adrenal mass were
present (unenhanced attenuation ≤ 10 HU and
CT contrast washout ≥ 50% 10 minutes after
contrast administration) [16, 17], no additional
MRI was performed.
If the primary diagnosis of adrenal mass was
found during a sonographic examination, low-
image-quality CT, or CT without clear benign
criteria, MRI was performed at our clinic. MRI
was performed on a 1.5-T unit (Vision, Siemens
Medical Solutions). The MRI examinations
included unenhanced T1-weighted and T2-
weighted sequences, chemical shift imaging (in-
and out-of-phase imaging), and dynamic T1-
weighted contrast-enhanced imaging (gadobenate
dimeglumine, MultiHance, Bracco).
MRI was performed with T2-weighted turbo
spin-echo sequences (TR/TE, 4,000/108; flip
angle, 150°; echo-train length, 29), a T2-weighted
RARE sequence (HASTE, Siemens Medical
Solutions) (infinite/74; flip angle, 180°), and T1-
weighted gradient-recalled echo in-phase (160/
4.7; flip angle, 70°) and out-of phase (160/2.6;
flip angle, 70°) images. For dynamic contrast-
enhanced imaging, a T1-weighted FLASH 2D
sequence (174.9/4.1; flip angle, 80°) was used
during the arterial (20–25 seconds after injection),
portal venous (50–60 seconds after injection), and
equilibrium (> 5 minutes after injection) phases
of contrast enhancement. The field of view for all
sequences was 350–450 mm 2, and the matrix size
was 107–186 × 256. All sequences were perform­
ed with a breath-hold. The contrast agent was
administered with a power injector at a constant
injection rate of 2.5 mL/s. The dose of gado­
pentetate dimeglumine (Magnevist, Schering)
was 0.1 mmol/kg body weight, corresponding to
0.2 mL/kg body weight of a 0.5 mol/L formulation
injected in a volume based on body weight and
followed by a 20-mL saline flush.
Criteria for the diagnosis of adenoma on MRI
were homogeneous signal intensity on un­
enhanced T2-weighted and T1-weighted images,
homo­geneous enhancement on dynamic images
after contrast injection (0.1 mmol/kg body weight
of gadopentetate dimeglumine), and loss of signal
intensity of the lesion on out-of phase images
(evaluated by visual assessment of signal intensity
loss on opposed-phase images compared with in-
phase images) [18]. As an internal standard, the
signal intensity of the adrenal mass was compared
with the signal intensity of the spleen.
Hormonal Evaluation
In addition to routine laboratory testing, a specific
evaluation to detect the hormonal activity of an
adrenal mass was performed on all patients after
overnight fasting. The hormonal evaluation included
base levels of corticotropin, cortisol, dehydro­
epiandrosterone sulfate, aldosterone, renin activity,
plasma-free normetanephrine, plasma-free meta­
nephrine, and chromogranin A. In addition, an over­
night dexamethasone suppression test with 2 mg of
dexamethasone was performed to rule out Cushing’s
syndrome. A plasma aldosterone concen­tration to
plasma renin activity ratio of less than 20 together
with an aldosterone concentration within the normal
range and a cortisol concentration of less than 3 µg/
dL after an overnight suppression test were con­
sidered normal. The laboratory results were judged
by an endo­crinologist with 14 years of experience.
Final Reference Diagnosis
The reference standard was determined by an
experienced radiologist and an experienced endo­
crinologist working together. The final reference
diagnosis was defined by combining all available
information from imaging (CT and MRI) and
additional information from the hormonal evalu­
ation and histologic examination. Postsurgical
histo­logic verification of adrenal masses after
adrenalectomy was available in 10 cases. Metastatic
lesions (n = 3) were diagnosed with fine-needle
biopsy. In the other 22 cases, the diagnosis was
confirmed with CT (n = 10) or MRI (n = 12).
 Sonography of Adrenal Masses

Statistical Analysis
Statistical analysis was performed with SPSS
software (version 12.0, SPSS). Clinical and labora­
tory characteristics of patients were expressed as
mean ± SD, median, and range. Fisher’s exact test
was used to evaluate the criteria for diagnosis of
malignant adrenal masses. A value of p < 0.05 was
judged to be statistically significant.
Results
B-Mode Sonography and Power
Doppler Sonography
Thirty-five patients with incidentally de-
tected adrenal masses were included in the
study. At B-mode sonography no specific
shape (round, oval, polycyclic) of adrenal
mass was found for malignant or benign le-
sions. Malignant lesions, however, signifi-
cantly more often had an inhomogeneous
echotexture (71% vs 18%, p < 0.05) and a
mixed hyperechoic and hypoechoic pattern
(43% vs 4%, p < 0.05). The mean size of be-
nign lesions was 30 × 39 mm (median, 25 ×
34 mm; range, 10–114 mm), and the mean
size of malignant lesions was 60 × 77 mm
(median, 37 × 78 mm; range, 18–190 mm). A
diameter greater than 4 cm was found signifi-
cantly more often for malignant than for be-
nign lesions (71% vs 21%, p < 0.05) and had
a sensitivity of 71% (95% CI, 0.35–0.92) and
a specificity of 79% (95% CI, 0.60–0.90) in
the detection of malignant adrenal masses.
Power Doppler sonography revealed hy-
pervascularization or an afferent blood ves-
sel in six cases. Hypervascularization of the
adrenal mass or an afferent blood vessel was
found significantly more often in malignant
than in benign lesions (57% vs 7%, p < 0.05).
Nevertheless, no sufficient differentiation
between benign and malignant adrenal
masses was possible at B-mode and power
Doppler sonography.
Contrast-Enhanced Sonography
Four patterns of sonographic contrast en-
hancement were found (Fig. 1). Nine adrenal
masses exhibited early arterial contrast en-
hancement (< 20 seconds) with an intensity

T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 T1 T2 T3 T4 T5 T6 T7 T8 T9 T10
12 24 36 48 60 72 84 96 108 120 12 24 36 48 60 72 84 96 108 120
Seconds Seconds

2
1

2
1
3
A B

T1 T2 T3 T4 T5 T6 T7 T8 T9 T10 T1 T2 T3 T4 T5 T6 T7 T8 T9 T10
12 24 36 48 60 72 84 96 108 120 12 24 36 48 60 72 84 96 108 120
Seconds Seconds

2
1
2

1
C D
Fig. 1—Sonographic contrast enhancement patterns.
A, Graph of pattern 1 shows early arterial (< 20 seconds) contrast enhancement with intensity peak between 11 and 43 seconds followed by rapid washout. Regions of
interest (ROIs) for yellow (ROI 2) and red (ROI 1) lines were placed in adrenal mass.
B, Graph of pattern 2 shows arterial contrast enhancement beginning in arterial phase (21–40 seconds) with intensity peak after 43–86 seconds. ROI for yellow line was
placed in spleen, ROI of red line in adrenal mass.
C, Graph of pattern 3 shows late and little contrast enhancement in late phase (> 40 seconds) with intensity peak after 60–110 seconds. ROI for green line was placed in
liver, ROI of red line in adrenal mass.
D, Graph of pattern 4 shows no recordable contrast enhancement. ROI for yellow line was placed in liver, ROI of red line in adrenal mass.

AJR:191, December 2008 1855


peak between 11 and 43 seconds followed by
rapid washout (pattern 1). Three adrenal
masses exhibited arterial contrast enhance-
ment beginning in the arterial phase (21–40
seconds) with an intensity peak after 43–86
seconds (pattern 2). Fourteen adrenal masses
exhibited late and little contrast enhance-
ment in the late phase (> 40 seconds) with an
intensity peak after 60–110 seconds (pattern
3). Nine adrenal masses exhibited no record-
able contrast enhancement (pattern 4).
Contrast-Enhanced Sonographic Findings in
Comparison with CT, MRI, and Histologic
Findings
All nine adrenal masses with early arterial
peak enhancement with rapid washout on
sonograms (pattern 1) exhibited the criteria
for nonadenomatous lesions on CT or MRI.
Six of these nine adrenal masses exhibited
criteria of malignancy on CT and MRI, and
three were suspected of being pheochromocy-
toma according to MRI findings. Fine-needle
biopsy revealed metastasis of lung cancer in
two of the nine lesions, and the patients with
the other seven adrenal masses were trans-
ferred to surgery. Examination of the histo-
logic specimens confirmed the presence of
malignancy in four cases (two nonfunctional
adrenocortical carcinomas, one cortisol-pro-
ducing adrenocortical carcinoma, and one T-
cell lymphoma). The other three lesions were
benign (one pheochromocytoma, one adre-
nal adenoma, and one partially thrombosed
cavernous hemangioma). Among the three
lesions suspected of being pheochromocyto-
ma at MRI, the histologic finding was pheo-
chromocytoma in only one case; the other
two lesions were carcinoma and adenoma.
The adenoma exhibited central hemorrhage
and calcification. All patients tolerated sur-
gery without complications.
In addition to the nine lesions with sono-
graphic pattern 1, three other adrenal masses
were resected. Two of these lesions (22 × 15
mm and 30 × 26 mm) had a suspicious ap-
pearance on CT or MRI, and one lesion was
large (55 × 50 mm) and caused local symp-
toms. The former two adrenal masses exhib-
ited sonographic contrast enhancement pat-
terns 3 and 2, respectively, and the latter,
pattern 3. The former two masses were his-
tologically adrenal adenoma, and the latter
had MRI evidence of myelolipoma.
Among the 10 cases managed surgically,
the correct diagnosis concerning the histo-
pathologic entity was made with CT and
MRI in three cases. No differentiation be-
1856 AJR:191, December 2008
Friedrich-Rust et al.
tween primary and secondary malignant tu- metastatic at MRI but found to be adenoma at
mors of the adrenal gland was possible at histologic examination). With patterns 3 and 4
contrast-enhanced sonography. Eight of the as the criteria for benign adrenal mass and
10 resected lesions were found to be nonade- patterns 1 and 2 as the criteria for malignant
nomatous at sonography with the use of con- lesion, the diagnosis of malignant lesion was
trast enhancement patterns 1 and 2 for the made with contrast-enhanced sonography
diagnosis of nonadenomatous lesions. with a sensitivity of 100% (95% CI, 60–100%),
Among the nine adrenal masses with no specificity of 82% (64–93%), positive predic-
contrast enhancement on sonography (pat- tive value of 58% (32–81%), and negative
tern 4), all but one had CT or MRI evidence predictive value of 100% (83–100%).
of adrenal adenoma, and one was a metastat- In 91.4% (32 of 35) of examined patients,
ic lesion after successful chemotherapy and the findings at CT or MRI and contrast-en-
in accordance with the sonographic findings hanced sonography were congruent concern-
did not exhibit perfusion at MRI. This lesion ing the characterization of adenoma versus
was therefore judged to be nonadenomatous nonadenomatous lesion. In two of these cas-
and nonmalignant. es, however, findings with all imaging meth-
Among the 14 adrenal masses with slow ods suggested a nonadenomatous lesion, but
and late contrast enhancement at sonography histologic examination after adrenalectomy
(pattern 3), 11 were diagnosed as adrenal ade- revealed adrenal adenoma. One of the cases
nomas on the basis of CT or MRI findings. of divergent findings at CT or MRI and con-
One mass was misdiagnosed as metastasis at trast-enhanced sonography was metastasis
CT, but the histologic finding was adenoma after chemotherapy without remaining vas-
(Table 1). One mass was diagnosed as adrenal cularization. Perfusion was seen neither on
hyperplasia at MRI, and one as myelolipoma MRI nor on contrast-enhanced sonography,
at MRI and histologic examination. All three but the lesion could not be differentiated from
adrenal masses with arterial contrast enhance- adenoma at sonography. In the two other cas-
ment on sonography (pattern 2) beginning in es of divergent findings, the correct diagnosis
the arterial phase had the CT or MRI criteria was made at CT or MRI in one case (angio-
of a nonadenomatous lesion (one myelolipoma, myelolipoma) and with contrast-enhanced
one metastatic lesion, and one lesion deemed sonography in the other case (adenoma).
A B
C D
Fig. 2—Comparison of sonographic findings in adenoma and nonadenomatous lesions.
A and B, 57-year-old woman with histologically proven adrenocortical carcinoma. Images show B-mode (A)
and power Doppler (B) sonographic findings.
C and D, 43-year-old man with adrenal adenoma. Images show B-mode (C) and power Doppler (D) sonographic
findings.
 Sonography of Adrenal Masses

The timing of contrast enhancement for with sensitivity comparable with that of CT malignant adrenal masses is essential for re-
contrast-enhanced sonography and that for and MRI in differentiating adenoma and ducing the number of expensive and invasive
CT or MRI were not directly comparable nonadenomatous lesions. Contrast-enhanced imaging studies performed. A high sensitiv-
owing to the different pharmacokinetics of sonography, however, is not reliable for dif- ity for the diagnosis of malignancy is needed
the contrast agents. The interpretations there- ferentiating the various histopathologic non- to ensure that a primary or secondary malig-
fore were made for each method separately adenomatous lesions from one another. nant lesion of the adrenal gland is not missed.
(Figs. 2–4). The incidence of incidentaloma found in Conversely, specificity for the diagnosis of
autopsy and CT studies is 4–6% [19–21]. malignancy is less critical, because the worst
Hormonal Evaluation Noninvasive differentiation of benign and consequence of a false-positive diagnosis is
All but two adrenal masses were nonfunc-
tional. One patient had clinical and laboratory
signs of Cushing’s syndrome. The dexametha-
sone overnight suppression test showed a
pathologic cortisol concentration of 24 µg/dL
(normal range < 3 µg/dL) at 8:00 am after a
dose of 2 mg of dexamethasone at 12 mid-
night. MRI showed a suspicious adrenal mass
with the differential diagnosis of pheochro-
mocytoma. Contrast-enhanced sonog­raphy
showed pattern 1 vascularization. Histologic
examination revealed cortisol-producing ad-
renocortical carcinoma.
Another patient had clinical and laborato-
ry signs of pheochromocytoma with a plasma
metanephrine concentration of 2,531 pg/mL
(normal range < 90 pg/mL) and plasma A B
normetanephrine concentration of 466 pg/
mL (normal range < 200 pg/mL). The MRI
findings were congruent with the diagnosis
of pheochromocytoma. Contrast-enhanced
sonography showed pattern 1 vasculariza-
tion. Histologic examination revealed benign
pheochromocytoma.

Discussion
This proof-of-principle study showed for
the first time, to our knowledge, that con-
trast-enhanced sonography can be performed

Fig. 3—Contrast-enhanced sonographic images

of patients in Figure 2. Adrenocortical carcinoma
(A, C, E, G) in 57-year-old woman exhibits rapid C D
early arterial enhancement with rapid washout.
No adjacent liver tissue is present. Center of
adrenocortical carcinoma is necrotic, and therefore
no perfusion is present in center. No contrast
enhancement is evident in adrenal adenoma (B, D, F,
H) in 43-year-old man, but arterial and portal venous
enhancement is present in adjacent liver.
A and B, Contrast-enhanced sonographic images
obtained in early arterial phase (16 seconds after
contrast injection).
C and D, Contrast-enhanced sonographic images
obtained in arterial phase, 22 seconds after contrast
injection.
E and F, Contrast-enhanced sonographic images
obtained in parenchymal phase, 48 seconds after
contrast injection.
G and H, Contrast-enhanced sonographic images
obtained in late phase, 70 seconds after contrast
injection.
(Fig. 3 continues on next page)
E F

AJR:191, December 2008 1857

 Friedrich-Rust et al.

Fig. 3 (continued)—Contrast-enhanced sonographic

images of patients in Figure 2. Adrenocortical
carcinoma (A, C, E, G) exhibits rapid early arterial
enhancement with rapid washout. No adjacent liver
tissue is present. Center of adrenocortical carcinoma
is necrotic, and therefore no perfusion is present
in center. No contrast enhancement is evident in
adrenal adenoma (B, D, F, H), but arterial and portal
venous enhancement is present in adjacent liver.
G and H, Contrast-enhanced sonographic images
obtained in late phase, 70 seconds after contrast
injection.

G H

T1 T2 T3 T4 T5 T6 T7 T8 T9 T10
12 24 36 48 60 72 84 96 108 120
Seconds

2
1
3

A B

T1 T2 T3 T4 T5 T6 T7 T8 T9 T10
12 24 36 48 60 72 84 96 108 120
Seconds

1
3
2

C D
Fig. 4—Region of interest (ROI) location and time–intensity curves for patients in Figures 2 and 3. ROIs are placed before contrast enhancement begins; therefore
background is very dark. Insets (A and C) show contrast enhancement for orientation of ROI placement.
A and B, 57-year-old woman with histologically proven adrenocortical carcinoma. All three ROIs are in different regions of adrenal mass. ROI 3 (green) in necrotic area
exhibits no contrast enhancement. Other two ROIs (yellow and red) show early arterial contrast enhancement and rapid washout (pattern 1).
C and D, 43-year-old man with adrenal adenoma. ROI 1 (red) is in liver; ROIs 2 (yellow) and 3 (green) are in adrenal mass. No contrast enhancement is present in adrenal
mass compared with liver (pattern 4).

1858 AJR:191, December 2008


that an additional or invasive examination is
necessary to establish the correct diagnosis.
In our proof-of-principle study, contrast-en-
hanced sonography fulfilled these criteria
with a sensitivity of 100% and a specificity
of 82% in the diagnosis of malignant lesions
of the adrenal gland.
As reported in previous studies [3] and
found in our study, the average size of benign
adrenal masses is smaller than that of malig-
nant adrenal masses (30 × 39 mm vs 60 × 77
mm). In a study involving 887 patients with
adrenal incidentaloma, a diameter greater
than 4 cm was found to have 90% sensitivity
and 24% specificity in the detection of adre-
nocortical carcinoma [22]. In our study, 11
adrenal masses were larger than 4 cm in di-
ameter, and three of these lesions were adre-
nocortical carcinoma, for a sensitivity of
100% (95% CI, 38–100%) and specificity of
75% (58–87%). The prevalence of adreno-
cortical carcinoma was 8.6%, higher than
the 4.7% reported in the literature [21]. A
size greater than 4 cm was found to have a
sensitivity of 71% and a specificity of 79% in
the detection of malignant adrenal masses.
Therefore, in accordance with previously
published data [22, 23], no sufficient conclu-
sion concerning the benignity of the adrenal
mass could be drawn solely from the size of
the mass.
According to present recommendations
[17], all patients received a hormonal evalua-
tion (after the history interview and physical
examination) as the first diagnostic proce-
dure. In this study, two adrenal masses (6%)
were functional (Cushing’s syndrome and
pheochromocytoma). Both patients were re-
ferred for surgery, and the diagnosis was
confirmed. According to the literature [23],
approximately 85% of adrenal incidentalo-
mas are nonfunctional, and 15% are func-
tional. The slightly lower number of func-
tional adenomas in our study might have
been due to the small number of patients ex-
amined in this pilot study. Another explana-
tion may be that an increasing number of in-
cidentalomas are detected as the result of
improvements in sonographic systems and
the inclusion of adrenal gland examinations
during screening sonography.
According to current recommendations
[17], all patients with negative results at hor-
monal testing underwent high-quality CT or
underwent MRI at our clinic to differentiate
benign and suspicious lesions that necessi-
tated further evaluation. Contrast-enhanced
CT and gadolinium-enhanced MRI have ex-
AJR:191, December 2008 1859
Sonography of Adrenal Masses
cellent sensitivity, specificity, and positive
predictive value in the diagnosis of benign
adrenal mass and are currently accepted as
reference methods in the evaluation of non-
functional adrenal masses smaller than 4 cm
in diameter [16, 17, 24–29]. Therefore, CT or
MRI was used as the reference standard when
signs of adenoma were overt, as they were in
the 22 patients with nonfunctional adrenal
masses. These patients were not referred for
surgery. Imaging (after 6, 12, and 24 months)
and laboratory (annually for 4 years) follow-
up was suggested [17, 24]. Three patients
with metastasis of primary lung cancer did
not undergo surgery because of the palliative
treatment concept. The diagnosis was con-
firmed with fine-needle biopsy.
In accordance with present recommenda-
tions [17], all nine patients with suspicious
findings at imaging were referred for sur-
gery. Malignancy was found in four patients,
and pheochromocytoma and myelolipoma
were confirmed in two patients. The misdi-
agnosis of adenoma for a nonadenomatous
lesion at CT or MRI can be explained by the
presence of hemorrhage and calcification in
the large adenomas.
An algorithm for the evaluation of adrenal
incidentaloma starts with a history interview,
physical examination, and hormonal testing
[17]. The next step, if the findings are nor-
mal, is imaging for phenotype. At this point,
in light of the results of our study, contrast-
enhanced sonography can be used as the first
and most cost-effective imaging method for
differentiating benign and suspicious ap-
pearances. Because the sensitivity for the
diagnosis of a malignant lesion in this study
was 100%, no malignant lesions were missed.
Because adenomas are common and malig-
nancy of incidentally diagnosed adrenal
masses is rare, contrast-enhanced sonogra-
phy may be a useful tool for excluding most
adenomas and selecting patients who need
additional diagnostic evaluation.
Because the specificity of MRI and CT is
higher than that of contrast-enhanced sonog-
raphy, the next step for all suspicious lesions
should be a second imaging study (CT or
MRI). However, the number of CT and MRI
examinations needed can be markedly re-
duced if preselection is performed with con-
trast-enhanced sonography. Therefore, con-
siderable cost reduction can be attained with
the expanded algorithm. On the basis of the
results of this proof-of-principle study, more
extensive studies of contrast-enhanced sono­
graphy for the characterization of adrenal
masses are needed for confirmation of our
preliminary data.
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