DOI:10.2214/AJR.07.4027
AJR 2009; 192:450-454
© American Roentgen Ray Society
Characterization of Adrenal Pheochromocytoma Using Respiratory-Triggered Proton MR Spectroscopy: Initial Experience
Sooah Kim1,
Nouha Salibi2,
Andrew D. Hardie1,3,
Jian Xu2,
Ruth P. Lim1,
Vivian S. Lee1 and
Bachir Taouli1
1 Department of Radiology, New York University Langone Medical Center, 530 First
Ave., MRI, New York, NY 10016.
2 Siemens Medical Solutions USA, Malvern, PA.
3 Present address: Department of Radiology, Medical University of South
Carolina, Charleston, SC.
Received March 25, 2008;
accepted after revision August 19, 2008.
N. Salibi and J. Xu are employees of Siemens Medical Solutions.
Address correspondence to B. Taouli
(bachir.taouli{at}nyumc.org).
Abstract
OBJECTIVE. The aim of our study was to evaluate the feasibility of
respiratory-triggered proton single-voxel MR spectroscopy for the diagnosis of
adrenal pheochromocytoma and to determine whether certain spectral resonances
detected on single-voxel MR spectroscopy are specific for adrenal
pheochromocytomas compared with adrenal adenomas.
CONCLUSION. Adrenal pheochromocytomas have a unique MR spectral
signature, showing 6.8 ppm resonance that is not seen in adenomas. This unique
spectral signature may be attributed to the presence of catecholamines and
catecholamine metabolites that are abundant in pheochromocytomas.
Keywords: adenoma • adrenal gland neoplasms • catecholamine • MR spectroscopy • pheochromocytoma
Introduction
Adrenal pheochromocytomas are rare catecholamine-secreting tumors derived
from chromaffin cells. These tumors carry a high risk of cardiac arrhythmia
and malignant hypertension. Therefore, a correct, noninvasive preoperative
diagnosis is important. Pheochromocytomas have a variable imaging appearance,
which is often nonspecific, and thus no one imaging method has been
universally advocated for diagnosis. Proton MR spectroscopy has been used
extensively to investigate tumor metabolism in other organ systems, such as
the brain and prostate. Published studies regarding the use of MR spectroscopy
for the characterization of adrenal gland masses are limited
[1,
2] and, to our knowledge, no
study has yet used a respiratory-triggered spectroscopy technique to reduce
motion-related artifacts.
The purpose of our study was to show the feasibility of
respiratory-triggered proton single-voxel MR spectroscopy for characterizing
adrenal pheochromocytomas on the basis of their metabolic content.
Materials and Methods
Patient Population
This HIPAA-compliant prospective study was performed with the approval of
our institutional review board. Written informed con sent was obtained from
each patient before the study. Six consecutive patients (two men and four
women; mean age, 48.8 years; age range, 31–68 years) with adrenal masses
> 2.0 cm in maximum diameter underwent MRI and respiratory-triggered
single-voxel MR spectroscopy at our institution. The final diagnosis was based
on the presence of fat on in-phase and out-of-phase imaging for adenoma and
histopathology for pheochromocytoma.
MRI
MRI of the adrenal glands was performed us ing two different 1.5-T clinical
scanners (Magnetom Sonata and Magnetom Symphony, Siemens Medical Solutions)
and body phased-array coils (6-element matrix coil). The routine adrenal MRI
protocol included the following breath-hold sequences: axial gradient-echo
T1-weighted in-phase and out-of-phase imaging, coronal T2 HASTE, axial
T2-weighted fast spin-echo imaging, and 3D fat-suppressed T1-weighted
interpolated spoiled gradient-echo imaging. At our institution, patients with
adrenal masses receive IV contrast material only in cases of
non-fat-containing lesions.
An MR spectroscopy sequence (1H MR spectroscopy) was added to
the routine MRI protocol and was performed before any contrast administration
to avoid possible spectral changes caused by contrast material
[3,
4]. Proton single-voxel MR
spectroscopy was performed using a respiratory-triggered double spin-echo
sequence combined with a navigator-echo 2D prospective acquisition correction
(PACE, Siemens Medical Solutions). The 2D PACE technique uses respiratory
triggering to the end-expiration phase of the respiratory cycle by tracking
the motion of the diaphragm. Spectral data were acquired with and without
water suppression. As determined by the respiratory cycle, the average TR was
approximately 4,500 milliseconds. The remaining measurement parameters were
TE, 30 milliseconds; 32 averages; 1,024 data points; bandwidth, 1,000 Hz;
acquisition time, 3–4 minutes. Automated 3D shimming was performed
followed by manual shimming as needed. The spectroscopic voxel (ranging from 8
to 27 cm3) was positioned by one of the authors within the adrenal
mass on the basis of a combination of the 3-plane unenhanced images (Fig.
1A,
1B,
1C).
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Fig. 1A —64-year-old woman with right adrenal pheochromocytoma.
Single-voxel MR spectroscopy sequence using 3-plane reference images shows
placement of 8 cm3 voxel (lines) in center of adrenal
mass, avoiding contamination from retroperitoneal fat.
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Fig. 1B —64-year-old woman with right adrenal pheochromocytoma.
Single-voxel MR spectroscopy sequence using 3-plane reference images shows
placement of 8 cm3 voxel (lines) in center of adrenal
mass, avoiding contamination from retroperitoneal fat.
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Fig. 1C —64-year-old woman with right adrenal pheochromocytoma.
Single-voxel MR spectroscopy sequence using 3-plane reference images shows
placement of 8 cm3 voxel (lines) in center of adrenal
mass, avoiding contamination from retroperitoneal fat.
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Although data were collected with the patient breathing freely, the spectra
of 2D PACE single-voxel MR spectroscopy allowed detection of small metabolic
resonances by minimizing the effects of respiratory motion and by allowing the
collection of data with more averages than allowed within a breath-holding
measurement. As a result, small metabolite signals were better seen against
the reduced background noise. Breath-hold single-voxel MR spectroscopy of the
abdomen is usually adequate only for measuring large signals such as water and
fat.
Spectroscopic Data Analysis
Spectroscopic data were processed using commercially available software
(Syngo, Siemens Medical Solutions) by one of the authors. Processing included
zero filling, multiplication by a gaussian filter with < 1-Hz line
broadening, Fourier transformation, and phase and baseline corrections.
Automated curve fitting yielded peak height, line width, and integral value.
All spectral analysis was performed in the range of 0–9.0 ppm. This
includes the range downfield from water (> 4.7 ppm), which is not routinely
evaluated on in vivo MR spectroscopy. Assignment of spectral resonances from
2D PACE single-voxel 1H MR spectroscopy was based on the knowledge
that catecholamines and catecholamine metabolites are elevated in the blood
serum and urine of patients with pheochromocytoma because of a significant
contribution from catecholamine metabolism within the tumor itself
[5]. This led to the
investigation of a possible correlation between the spectral resonances
expected from the chemical structure of catecholamines (dopamine, epinephrine,
and norepinephrine), catecholamine metabolites (metanephrine and
normetanephrine) (Fig. 2), and
the resonances in the measured pheochromocytoma spectra. Further correlation
was made with catecholamine and metabolite spectra published in the Human
Metabolome Database [6]. In
addition, known lipid resonances were determined in the analysis window in the
range of 1.0–2.0 ppm
[7].
Results
Three pheochromocytomas and three fat-containing adenomas (mean lesion
diameter, 3.6 cm; range, 2.9–5.5 cm) were present in six patients. The
pheochromocytomas were all histopathologically proven after surgical
resection. The fat-containing adenomas were diagnosed on the basis of typical
MRI findings on T1 in-phase and out-of-phase gradient-echo imaging
[8,
9].
Clinical and Laboratory Findings
The details on the three patients with pheochromocytomas are as follows:
Patient number 1 was a 42-year-old man with a 5.5-cm left adrenal
pheochromocytoma. He had elevated serum dopamine (25 pg/mL; normal range,
0–20 pg/mL), epinephrine (1,188 pg/mL; normal range, 10–200
pg/mL), norepinephrine (1,497 pg/mL; normal range, 50–520 pg/mL), and
24-hour urine metanephrine (1,832 µg/24 hr; normal range, 35–460
µg/24 hr).
Patient number 2 was a 31-year-old woman with a 3.6-cm left adrenal
pheochromocytoma. She had elevated 24-hour urine metanephrine (486 µg/24
hr), normetanephrine (5,433 µg/24 hr; normal range, 50–650 µg/24
hr), and vanillyl-mandelic acid (31.8 mg/24 hr; normal range 0.0–7.0
mg/24 hr). This patient underwent 131I metaiodobenzylguanidine
scanning 1 week after MRI, which was positive for a left adrenal
pheochromocytoma.
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Fig. 3A —Water-suppressed spectra acquired with respiratory-triggered
proton single-voxel MR spectroscopy sequence (TR/TE, 4,500/30; 32 averages).
Images from three patients with pheochromocytoma (42-year-old man [A],
31-year-old woman [B], and 64-year-old woman [C]) and three
patients with adrenal adenoma (42-year-old man [D], 68-year-old woman
[E], and 46-year-old woman [F]) show lipid resonances between 0
and 2.0 ppm. Pheochromocytoma spectra include characteristic resonances at
2.7, 3.16, 3.8, and particularly at 6.8 ppm (arrows,
A–C) that may be explained by contributions from various
chemical groups of catecholamines and catecholamine metabolites. Residual
water peak at 4.7 ppm in spectra of A–C was used as
reference. In spectrum of F, patient motion has affected shim and water
suppression.
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Fig. 3B —Water-suppressed spectra acquired with respiratory-triggered
proton single-voxel MR spectroscopy sequence (TR/TE, 4,500/30; 32 averages).
Images from three patients with pheochromocytoma (42-year-old man [A],
31-year-old woman [B], and 64-year-old woman [C]) and three
patients with adrenal adenoma (42-year-old man [D], 68-year-old woman
[E], and 46-year-old woman [F]) show lipid resonances between 0
and 2.0 ppm. Pheochromocytoma spectra include characteristic resonances at
2.7, 3.16, 3.8, and particularly at 6.8 ppm (arrows,
A–C) that may be explained by contributions from various
chemical groups of catecholamines and catecholamine metabolites. Residual
water peak at 4.7 ppm in spectra of A–C was used as
reference. In spectrum of F, patient motion has affected shim and water
suppression.
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Fig. 3C —Water-suppressed spectra acquired with respiratory-triggered
proton single-voxel MR spectroscopy sequence (TR/TE, 4,500/30; 32 averages).
Images from three patients with pheochromocytoma (42-year-old man [A],
31-year-old woman [B], and 64-year-old woman [C]) and three
patients with adrenal adenoma (42-year-old man [D], 68-year-old woman
[E], and 46-year-old woman [F]) show lipid resonances between 0
and 2.0 ppm. Pheochromocytoma spectra include characteristic resonances at
2.7, 3.16, 3.8, and particularly at 6.8 ppm (arrows,
A–C) that may be explained by contributions from various
chemical groups of catecholamines and catecholamine metabolites. Residual
water peak at 4.7 ppm in spectra of A–C was used as
reference. In spectrum of F, patient motion has affected shim and water
suppression.
|
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Fig. 3D —Water-suppressed spectra acquired with respiratory-triggered
proton single-voxel MR spectroscopy sequence (TR/TE, 4,500/30; 32 averages).
Images from three patients with pheochromocytoma (42-year-old man [A],
31-year-old woman [B], and 64-year-old woman [C]) and three
patients with adrenal adenoma (42-year-old man [D], 68-year-old woman
[E], and 46-year-old woman [F]) show lipid resonances between 0
and 2.0 ppm. Pheochromocytoma spectra include characteristic resonances at
2.7, 3.16, 3.8, and particularly at 6.8 ppm (arrows,
A–C) that may be explained by contributions from various
chemical groups of catecholamines and catecholamine metabolites. Residual
water peak at 4.7 ppm in spectra of A–C was used as
reference. In spectrum of F, patient motion has affected shim and water
suppression.
|
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View larger version (48K):
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[in a new window]
[as a PowerPoint slide]
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Fig. 3E —Water-suppressed spectra acquired with respiratory-triggered
proton single-voxel MR spectroscopy sequence (TR/TE, 4,500/30; 32 averages).
Images from three patients with pheochromocytoma (42-year-old man [A],
31-year-old woman [B], and 64-year-old woman [C]) and three
patients with adrenal adenoma (42-year-old man [D], 68-year-old woman
[E], and 46-year-old woman [F]) show lipid resonances between 0
and 2.0 ppm. Pheochromocytoma spectra include characteristic resonances at
2.7, 3.16, 3.8, and particularly at 6.8 ppm (arrows,
A–C) that may be explained by contributions from various
chemical groups of catecholamines and catecholamine metabolites. Residual
water peak at 4.7 ppm in spectra of A–C was used as
reference. In spectrum of F, patient motion has affected shim and water
suppression.
|
|
View larger version (46K):
[in this window]
[in a new window]
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Fig. 3F —Water-suppressed spectra acquired with respiratory-triggered
proton single-voxel MR spectroscopy sequence (TR/TE, 4,500/30; 32 averages).
Images from three patients with pheochromocytoma (42-year-old man [A],
31-year-old woman [B], and 64-year-old woman [C]) and three
patients with adrenal adenoma (42-year-old man [D], 68-year-old woman
[E], and 46-year-old woman [F]) show lipid resonances between 0
and 2.0 ppm. Pheochromocytoma spectra include characteristic resonances at
2.7, 3.16, 3.8, and particularly at 6.8 ppm (arrows,
A–C) that may be explained by contributions from various
chemical groups of catecholamines and catecholamine metabolites. Residual
water peak at 4.7 ppm in spectra of A–C was used as
reference. In spectrum of F, patient motion has affected shim and water
suppression.
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Patient number 3 was a 64-year-old-woman with a 4.7-cm right adrenal
pheochromocytoma. Her laboratory workup was performed at an outside
institution and was not available for review.
Single-Voxel MR Spectroscopy Findings
All three pheochromocytomas showed a unique spectral signature, with the
most distinct and prominent resonance identified at 6.8 ppm (Fig.
3A,
3B,
3C,
3D,
3E,
3F). Other common resonances
were identified at 2.7, 3.16, and 3.8 ppm.
A residual water resonance was displayed as a reference at 4.7 ppm and
lipid resonances in the 0–2.0 ppm range. The resonances at 2.7, 3.16,
3.8, and 6.8 ppm may be explained by the presence of elevated levels of
catecholamines and catecholamine metabolites within the tumor (see
Discussion); however, it was not possible to attribute any individual
resonance to one particular substance or to quantify individual
concentrations.
Spectra from the three adenomas with suppressed water had only lipid
resonances in the range of 0–2.0 ppm (Fig.
3A,
3B,
3C,
3D,
3E,
3F). A large residual water
peak was present in patient number 3. The adenomas did not have any of the
additional resonances detected in the pheochromocytoma spectra.
Discussion
In this small series, we report a unique spectral signature of
pheochromocytoma using a 2D PACE single-voxel MR spectroscopy sequence, which,
to our knowledge, has never before been reported in vivo. We hypothesize that
these resonances could be attributed to signals from aromatic (6.8 ppm) and
methyl and methylene protons (2.7, 3.16, and 3.8 ppm) as configured in the
chemical structure of catecholamines and catecholamine metabolites. These
signals are increased in the plasma and urine of patients with
pheochromocytomas and are present in the tumors. Previous studies have
reported that elevated catecholamine metabolites in urine and plasma result
mostly from catecholamine metabolism within the tumor, where these levels
would be expected to be orders of magnitude higher than the elevated plasma
levels [5].
All catecholamines and catecholamine metabolites have a structure that
consists of an aromatic ring with attached hydroxyl or O-methylated
(-O-CH3) groups and a side chain of ethylamine (as in dopamine) or
hydroxyethylamine (as in epinephrine, norepinephrine, metanephrine, and
normetanephrine). Various substitutions on the amine group
(Fig. 2) and on the aromatic
ring account for differences in their spectra and in the relative intensities
of the various resonances. For example, as a result of the methylated amine
group (-HN-CH3) in epinephrine and metanephrine, a methyl proton
resonance at 2.7 ppm is seen in the epinephrine and metanephrine spectra. This
resonance is missing from the spectra of norepinephrine and normetanephrine,
which have a primary amine group instead of a methylated amine group at the
same position.
Similarly, metanephrine and normetanephrine have an -O-CH3 group
attached directly to the aromatic ring at the same position as the hydroxyl
group in the catecholamine structures. This explains the resonance at 3.8 ppm
seen in the metabolite spectra but not in the catecholamine spectra.
Resonances at 6.8 ppm from the aromatic ring protons and at 3.16 ppm from the
CH2 protons in the side chain are common to all catecholamines and
catecholamine metabolites. Smaller resonances from the remaining hydroxyl and
amine protons may not always be detected in vivo but may be seen in ex vivo
high-field spectra [6]. In
addition, resonances that are multiplets in ex vivo high-field spectra are not
resolved in vivo with the 1.5-T clinical scanners and present as single
peaks.
Although further studies are needed, the presence of catecholamine in
amounts detectable by single-voxel MR spectroscopy within an adrenal mass is
likely to be a unique property of pheochromocytoma.
Adrenal masses are often detected incidentally using cross-sectional
imaging. The incidence of pheochromocytoma presenting as an adrenal
incidentaloma is low, estimated to be 3.2% in a prior study (36 of 1,111)
[10]. However, although MRI
has been shown to be accurate in differentiating adrenal adenomas from
metastases, MRI is less accurate in differentiating pheochromocytoma from
other adrenal lesions, with reported sensitivity of 64.7% and specificity of
88.0% in a prior study [11].
Currently, screening tests for pheochromocytoma in the presence of an adrenal
incidentaloma include assessment of the plasma-free metanephrine and urinary
fractionated metanephrine, although other tests are often used
[12]. In patients with an
adrenal mass, sometimes this method is unable to exclude a nonfunctioning
pheochromocytoma. Therefore, a highly specific, noninvasive imaging diagnosis
would be of great utility. It is particularly important to be able to diagnose
pheochromocytoma before intervention (biopsy or surgery) because the patients
are at significant cardiovascular risk during interventions due to the release
of catecholamine metabolites into the blood. Because MRI already is often used
as part of the diagnostic workup of adrenal incidentalomas, the addition of
single-voxel MR spectroscopy to conventional MRI sequences is quick and may
provide improved diagnostic accuracy. Although our study was performed only
for adrenal lesions, this technique may potentially be applicable for the
diagnosis of extraadrenal catecholamine-secreting paragangliomas and
pheochromocytomas. A definitive characterization of catecholamine-producing
tumors, whether hypersecreting or subclinical, could prove valuable in
preoperative evaluation.
To date, MR spectroscopy studies on adrenal masses are extremely limited.
Leroy-Willig et al. [1] applied
single-voxel MR spectroscopy using a modified Dixon method
[13] for the differentiation
of adrenal masses (n = 22) by measuring lipid content to distinguish
adrenal adenoma from adrenocortical carcinoma. The authors reported a mean
percentage of lipids in adenomas of 13.4%, significantly higher compared with
carcinomas (3.5%). A recent study
[2] assessed the spectra and
metabolic ratios of a large number of adrenal masses (n = 60,
including 10 pheochromocytomas) using point-resolved multi-voxel proton MR
spectroscopy performed during free breathing. The authors described cutoff
values of choline/creatine and choline/lipid ratios to distinguish adenomas
and pheochromocytomas from carcinomas and metastases. Although their study
showed that 4.0–4.3 ppm/creatine ratios greater than 1.50 proved to be
useful for differentiating pheochromocytomas from adenomas (with 80%
sensitivity and 100% specificity), the authors were not able to distinguish
pheochromocytomas from carcinomas using this criterion. In contrast to these
results, we did not identify resonances either at 4.0–4.3 ppm or
creatine resonance at 3.08 ppm in our pheochromocytoma and adenoma patients.
Three adenomas in our study showed only lipid resonances in the 0–2.0
ppm range. Hence, we were not able to apply the resonance ratios suggested by
this prior study to our population. In addition, this prior study did not
specifically correlate the metabolic resonances obtained with spectroscopy
with nuclear MR data of each catecholamine and its metabolites in
pheochromocytomas and, most important, did not evaluate the spectra beyond 5.0
ppm.
Our study has several limitations. First, we report only a small number of
cases. Second, other adrenal masses, such as metastases and carcinomas, were
not assessed. Third, in this preliminary clinical study, no correlation was
made between the levels of catecholamines in tumors based on single-voxel MR
spectroscopy and catecholamine levels in blood and urine.
In conclusion, our study shows the potential usefulness of 2D
respiratory-triggered single-voxel MR spectroscopy in characterizing
pheochromocytomas that show several resonances, with a highly distinct
prominent resonance at 6.8 ppm that may be attributed to catecholamines and
catecholamine metabolites. On the basis of our results, it is important to
analyze spectral data beyond the water resonance. Further evaluation could be
performed in a larger series to determine the sensitivity and specificity of
single-voxel MR spectroscopy for characterizing pheochromocytomas.
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Abstract
Introduction
