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Clinical Radiology xxx (2013) e1ee9
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Clinical Radiology
journal homepage: www.clinicalradiologyonline.net
Improved diagnostic accuracy in differentiating malignant
and benign lesions using single-voxel proton MRS of the
breast at 3 T MRI
S. Suppiah a, b, K. Rahmat a, *, M.N. Mohd-Shah a, C.A. Azlan a, L.K. Tan a, Y.F.A. Aziz a,
A. Vijayananthan a, A.L. Wui a, C.H. Yip c
a
Department of Biomedical Imaging, University Malaya Research Imaging Centre (UMRIC), Kuala Lumpur, Malaysia
Department of Imaging, Faculty of Medicine and Health Sciences, Universiti Putra, Malaysia
c
Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
b
art icl e i nformat ion
Article history:
Received 14 November 2012
Received in revised form
19 March 2013
Accepted 5 April 2013
AIM: To investigate the diagnostic accuracy of single-voxel proton magnetic resonance
spectroscopy (SV 1H MRS) by quantifying total choline-containing compounds (tCho) in
differentiating malignant from benign lesions, and subsequently, to analyse the relationship of
tCho levels in malignant breast lesions with their histopathological subtypes.
MATERIALS AND METHODS: A prospective study of SV 1H MRS was performed following
dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in 61 women using a 3 T
MR system. All lesions (n ¼ 57) were analysed for characteristics of morphology, contrastenhancement kinetics, and tCho peak heights at SV 1H MRS that were two-times above
baseline. Subsequently, the tCho in selected lesions (n ¼ 32) was quantified by calculating the
area under the curve, and a tCho concentration equal to or greater than the cut-off value was
considered to represent malignancy. The relationship between tCho in invasive ductal carcinomas (IDCs) and their Bloom & Richardson grading of malignancy was assessed.
RESULTS: Fifty-two patients (57 lesions; 42 malignant and 15 benign) were analysed. The
sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV), of
predicting malignancy were 100, 73.3, 91.3, and 100%, respectively, using DCE-MRI and 95.2,
93.3, 97.6, and 87.5%, respectively, using SV 1H MRS. The tCho cut-off for receiver operating
characteristic (ROC) curve was 0.33 mmol/l. The relationship between tCho levels in malignant
breast lesions with their histopathological subtypes was not statistically significant (p ¼ 0.3).
CONCLUSION: Good correlation between tCho peaks and malignancy, enables SV 1H MRS to
be used as a clinically applicable, simple, yet non-invasive tool for improved specificity and
diagnostic accuracy in detecting breast cancer.
Ó 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
Introduction
Single-voxel proton magnetic resonance spectroscopy (SV
H MRS) enables non-invasive assessment of the biochemical
1
* Guarantor and correspondent: K. Rahmat, Department of Biomedical
Imaging, University Malaya Research Imaging Centre (UMRIC), Faculty of
Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia. Tel.: þ603
79492091; fax: þ603 79494603.
E-mail address: [email protected] (K. Rahmat).
composition of breast lesions. Previous studies conducted
using 1.5 T MR systems1e6 reported the presence of the
resonance of total choline (tCho)-containing compounds at
3.2 parts per million (ppm), which includes contributions
from choline, phosphocholine, glycerophosphocholine, and
taurine as reliable biomarkers of breast cancer.7 This is
because choline-containing metabolites detected in breast
lesions are an indicator of the increased cellular metabolism
noted in malignant breast tumours.
0009-9260/$ e see front matter Ó 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.crad.2013.04.002
Please cite this article in press as: Suppiah S, et al., Improved diagnostic accuracy in differentiating malignant and benign lesions using singlevoxel proton MRS of the breast at 3 T MRI, Clinical Radiology (2013), http://dx.doi.org/10.1016/j.crad.2013.04.002
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S. Suppiah et al. / Clinical Radiology xxx (2013) e1ee9
Current practices include dynamic contrast-enhanced
magnetic resonance imaging (DCE-MRI) as part of the
standard breast imaging protocol.8 Previously, MRS breast
studies at 1.5 T have shown that it is a useful adjunct to
standard breast MRI protocols. More recent studies have
shown MRS breast at 3 T has the added advantage of
providing better spatial resolution for lesion localization.9 It
also provides improved spectral resolution of metabolites of
the MR spectrum for better detection of tCho peaks.10, 11
Standard breast imaging protocols enable the analysis of
the morphological and kinetic patterns of benign and malignant breast lesions detected at MRI. The high sensitivity
of breast MRI but its limited specificity poses a diagnostic
challenge for radiologists, producing a high false-positive
rate of cancer detection leading to unnecessary biopsies
being performed.1,8 The ratio of mass to non-mass lesions
differed significantly between true-positive (7.0 : 1.0) and
false-positive findings (1.2: 1.0), giving a low positive predictive value (PPV) of 51.7% for non-mass lesions detected
on standard MRI.12 DCE-MRI sensitivity has been reported
to be as high as 94e100%, but with variable specificity in the
range of 37e97%.13 By adding MRS to standard breast imaging, the specificity for the detection of breast cancer can
be consistently improved from 70% up to 92%.4,6 High field
scanning has been proven to be of use in improving diagnostic specificity.10 Although MRS breast at 3 T is gaining
momentum as a useful diagnostic tool, there are numerous
methods recommended for performing and interpreting
it.5e7,14 This leads to uncertainty as to which protocol to be
utilized for maximum diagnostic accuracy. Therefore, it
poses a problem to radiologists as there is a necessity for
selecting a fast, accurate, and clinically applicable protocol.
Therefore, the aim of the present study was to investigate
the diagnostic accuracy of SV 1H MRS at 3 T by quantifying
tCho-containing compounds in differentiating malignant
from benign lesions. Subsequently, the relationship between tCho levels in malignant breast lesions were
compared with their histopathological subtypes.
Materials and methods
Hospital ethical committee approval and written
informed consent were obtained. Sixty-one women (mean
age 49.7 years old, range 20e83 years old) were prospectively recruited based on findings of breast lesion(s) on
clinical examination, mammography, and/or ultrasound.
Sixty-five lesions were detected over 22 months and, after
exclusion criteria were applied, 57 lesions in 52 patients
were obtained for the study cohort (42 malignant: mean
size 3.6 cm, size range 1.2e15.8 cm; 15 benign: mean size
1.9 cm, size range 0.7e3.8 cm). Nine patients were excluded
due to five having erratic MRS spectra, two did not have
conclusive histology results, one patient defaulted biopsy,
and one patient did not have a lesion detected at MRI.
Single-voxel tCho spectra of all breast lesions and normal
breast tissue were obtained and correlated with the final
histology results with the reference standard being surgery
or core-biopsy results. The lesions were analysed for
morphological and dynamic contrast enhancement kinetics
characteristics. Subsequently, selected spectra of malignant
and benign lesions, as well as of normal breast tissue,
(n ¼ 32) were assessed for their tCho content and whether
this corresponded to their histopathological findings. Inclusion criteria were women who had a breast lump
detected either by clinical palpation or by radiological
investigation, i.e., mammography/ultrasound, and that
lesion was going to be either biopsied or excised. Exclusion
criteria were women who had a contraindication to MRI,
women who had undergone previous surgery/radiotherapy
on the lesion-containing breast, and those who only had
microcalcifications on mammogram and no solid mass lesions seen at breast ultrasound. Thirty-two spectra were
analysed for tCho content after the mathematical software
for tCho area under the curve quantification was acquired in
the later phase of the study period.
Studies were performed on a clinical 3 T MR system
(SignaÒ HDx MR Systems; GE Healthcare, Milwaukee, WI,
USA) with a dedicated bilateral eight-channel double breast
coil using the manufacturer’s proton MRS acquisition software, breast spectroscopic examination (BREASE).
Study protocol/sequences
Standard breast MRI protocol
The imaging protocol comprised of unenhanced axial T1weighted, T2-weighted, and short tau inversion recovery
(STIR) sequences as well as a 3D high-resolution dynamic,
contrast-enhanced with T1-weighted fat-suppressed sequences. Axial T2-weighted and STIR images had 4 mm
slice thickness, and 40 cm field of view (FOV). Prior to
spectroscopy, six-phase contrast-enhanced MR mammography using 0.2 mmol/kg intravenous gadopentate dimeglumine (Magnevist; Schering, Berlin, Germany) was
performed [10 flip angle,1.4 mm slice thickness, 40 cm FOV,
256 256 matrix size, 4.2 ms time-to-repeat (TR), and
2.5 ms time-to-echo (TE)]. Six consecutive scans were performed for 1 min each with no intersection gap. The regionof-interest (ROI) was placed on the most enhancing region
of the target lesions that were detected. Subsequently, dynamic contrast enhancement kinetic curves were plotted
using functional tool (FuncTool) on the manufacturerprovided software [Volume Imaging for BReast AssessmeNT (VIBRANT)] to assess for the contrast medium uptake.
MRS
The contrast-enhanced images were scrutinized to identify solid, enhancing lesions suitable for spectroscopic examination. Spectroscopic VOI placement was then performed
and adjusted to maximize coverage of the enhancing lesion
whilst minimizing coverage of adjacent adipose tissue
(minimum VOI size was 10 10 10 mm). Saturation bands
were then positioned around the selected VOI to reduce
signal coming from the surrounding breast tissue (Fig 1a). An
automatic pre-scan was undertaken by selecting a homogeneous VOI in the enhancing lesion. Once full- width halfmaximum (FWHM) of <6 Hz was achieved, image acquisition was performed. A point-resolved spectroscopy (PRESS)
Please cite this article in press as: Suppiah S, et al., Improved diagnostic accuracy in differentiating malignant and benign lesions using singlevoxel proton MRS of the breast at 3 T MRI, Clinical Radiology (2013), http://dx.doi.org/10.1016/j.crad.2013.04.002
S. Suppiah et al. / Clinical Radiology xxx (2013) e1ee9
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Figure 1 MRI of a 28-year-old woman (patient 35) who presented with palpable left breast lump. (a) High-resolution contrast-enhanced image
in the axial plane showed a heterogeneously enhancing lesion (red arrow) in the left breast. A VOI was placed in the enhancing solid lesion to
optimize coverage of the most enhancing part and to minimize the inclusion of adjacent adipose tissue. Saturation bands were placed around the
lesion before MRS data were acquired. /MR spectrum for the lesion showed lipid peak at 1.3 ppm (white arrow), choline at 3.2 ppm (yellow
arrow) and water peak at 4.74 ppm (blue arrow). This lesion was revealed to be a grade 3 IDC. (b) Voxel selection and placement for MRS of
normal tissue. Saturation bands were placed around normal-appearing breast tissue before MRS data were acquired for purpose of control data.
/MR spectrum for normal breast tissue showing absent choline metabolite peak at 3.2 ppm (yellow arrow) and a well-suppressed water peak
at 4.74 ppm (blue arrow).
sequence [TR/TE: 2000 ms/155 ms and with number of
excitations (NEX) 56 times], single-shot unsuppressed spectrum was performed in the VOI. An automatic water- and fatsuppressed (AWS) sequence, which is a chemical shift
selective imaging sequence (CHESS), was included to detect
tCho resonance at 3.2 ppm (Fig 1a). The total time taken for all
spectroscopic preparation steps and acquisitions was
approximately 5e6 min. The control spectra were acquired
from VOI placed in healthy-appearing glandular tissue with
saturation bands placed around it. The spectra of normal
breast tissues were not expected to have a choline peak at
3.2 ppm (Fig 1b).
Data interpretation
For the MR spectra that were acquired, chemical shifts
were corrected using a water signal at 4.74 ppm. The spectra
were shifted accordingly using spectral offset manipulations.
The MRI images were interpreted by two radiologists
(K.R. and Y.F.) with 8e12 years of subspecialty experience in
breast imaging. Objective morphological assessment of the
lesions using the American College of Radiology (ACR) BIRADSÒ-MRI (Breast ImagingdReporting and Data System
for MRI) lexicon and final assessment categories from 1 to 6
for each lesion were made. The American College of Radiology’s BI-RADS-MRI lexicon,15 was specifically used as a
tool to standardize the image interpretation and appropriate MRI BI-RADS category was documented and scores
were given based on morphological features and kinetics
characteristics scoring system.16,17 The scores were then
correlated with the histopathological reference standard
based on core-biopsy histology results but upgraded to
surgical histopathology results where applicable. DCE-MRI
characteristics were interpreted as explained by Kuhl
et al.18 and correlated with BI-RADS MRI descriptors of
malignancy.19
Initially, the presence of tCho in a lesion was identified by
a peak height at 3.2 ppm that was two-times above baseline
noise.7 Subsequently, selected spectra were analysed to
calculate the area under the curve of tCho peak at 3.2 ppm
using Spectroscopic Analysis for General Electric (SAGE) and
MATLAB (Mathworks, Natick, MA, USA) softwares. The
extracted peaks in the region of 3.2 ppm, SD 0.2 were
fitted with a Voigt line-shape curve-fitting algorithm to
calculate the area under the curve. Curve fits giving R2
values of 0.695e1.000 were considered to be good curve
Please cite this article in press as: Suppiah S, et al., Improved diagnostic accuracy in differentiating malignant and benign lesions using singlevoxel proton MRS of the breast at 3 T MRI, Clinical Radiology (2013), http://dx.doi.org/10.1016/j.crad.2013.04.002
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S. Suppiah et al. / Clinical Radiology xxx (2013) e1ee9
fits, and R2 <0.695 were considered poor fits. For lesions
with poor curve fit, any measured value of the area under
the curve was considered background noise, therefore,
these were considered to have no detectable tCho. The tCho
levels detected on MRS peaks in these lesions were then
correlated with histopathological results. The radiologists
were blinded to the patient data and histopathological results at the time of analysis of the tCho peaks.
Table 1
Summary of benign and malignant lesions subgroup pathology.
Benign lesions
Fibroadenomas
Fibrocystic disease
Sclerosing adenosis
Intraductal papilloma
No. of
lesions
6
5
2
2
Statistical analysis
Total
Data were entered and tabulated into a computer
spreadsheet (Excel; Microsoft, Redmond, WA, USA). Statistical analysis was performed using statistical software SPSS
version 17.0 (Chicago, IL, USA). Statistical tests involving the
comparison of two categorical variables, e.g., significant
tCho peak detection versus malignant histology were performed using Pearson’s chi-squared test. In cases where
counts in the cells of the contingency tables were low,
Fisher’s exact test was used instead. For comparison of
continuous variables, e.g., calculated tCho peak values, independent sample t-tests were employed, except when
there were more than two groups, in which case analysis of
variance (ANOVA) was used. A p-value of <0.05 was
considered to be statistically significant with a confidence
level set at 95%. Receiver-operator characteristic (ROC)
curves were used for continuous data with a binary
outcome to determine the sensitivity of data cut-off points.
Kappa values for inter- and intra-observer variability
were calculated and showed good agreement. For categorical variables, both intra- and interobserver agreement was
good to excellent (Kappa value range ¼ 0.78e0.85,
p < 0.05). For scale variables, Spearman’s correlation were
used to look for intra- and interobserver agreement, and
found good agreement for all variables measured (Spearman’s rho range ¼ 0.81e0.88, p < 0.05). It was also noted
that in most categorical and scale variables, the intraobserver agreement yielded a higher agreement value
than their interobserver counterpart.
Results
Sixty-one women were recruited for the study and postprocessing was performed on 65 detected lesions. There
were several lesions/spectra with suboptimal examinations
(n ¼ 5) or without definite histopathology results (n ¼ 3),
which were discarded from the final analysis. The five
suboptimal examinations showed erratic spectrum with
reduced signal to noise ratios (SNR) due to patient movement or breathing artefacts, and were discarded from the
final analysis.
As a result, 52 patients and 57 lesions (42 malignant and
15 benign; Table 1) were used in the final analysis. In the
histopathologically proven malignant group, 30 patients
underwent mastectomies, eight patients opted for breast
conservative surgery, and four patients refused surgery.
The MRS spectra for all lesions were initially analysed
qualitatively. Forty out of the forty-two histopathologically
proven malignant lesions demonstrated a tCho peak; and 14
15
Malignant lesions
No. of
lesions
DCIS
IDC Grade 1
IDC Grade 2
IDC Grade 3
Lobular carcinoma
Malignant phyllodes
Breast Osteosarcoma
6
4
15
12
2
2
1
42
out of the 15 benign lesions did not have a significant tCho
peak. Fig 2 shows an example of an invasive ductal
carcinoma (IDC) with suspicious morphology, demonstrated a washout pattern on kinetic curve and significant
tCho on MRS. Two malignant lesions that did not demonstrate a significant choline peak were a 2.1 cm low-grade
IDC with prominent ductal carcinoma in situ (DCIS)
component (patient 37) and a 1.8 cm low-grade DCIS (patient 39). One benign fibroadenoma gave a false-positive
finding. A significant choline peak was also detected in a
malignant phyllodes tumour.20 Fig 3 shows the typical
benign features and absent choline peak on the spectra of a
benign fibrocystic lesion. Significant tCho peak above
baseline detected by MRS produced a sensitivity, specificity,
PPV, and negative predictive value (NPV) of 95.2, 93.3, 97.6,
and 87.5%, respectively (Table 2).
Consequently, selected spectra (n ¼ 32) were analysed
for good curve fit and the area under the curve was calculated for each spectra. All malignant lesions showed good
curve fit, with R2 values between 0.695 and 1.0 (Table 3)
compared to benign lesions, which mostly had R2 values
below 0.695 (Table 4). ROC curves showed that an R2 value
of 0.695 gave a sensitivity of 100% and specificity of 94%
(Fig 4). Normalized arbitrary units (nAU) for lesions with R2
values <0.695 were considered to be not applicable. Fig 5
shows the ROC curve for arbitrary units (AU) and nAU
correlated with malignancy. Independent sample t-test
showed that nAU values significantly correlated with malignancy (p ¼ 0.003). The mean nAU for malignant lesions
was higher than the mean for non-malignant lesions (Fig 6).
Lesions 20 and 29 had the highest nAU values, from patients
37 and 47, who had grade 1 IDC and grade 2 IDC, respectively. Lesion 22 (from patient 38) was a benign fibroadenoma measuring 3.8 cm, which showed a good curve fit
(R2 ¼ 0.92) and relatively higher nAU value compared with
the rest of the non-malignant lesions.
The optimal threshold for normalized tCho level was
0.33 AU/mldequivalent to 0.33 mmol/l, which gave a good
trade-off between sensitivity and specificity for the detection of malignancy. It was also noted that the mean
normalized tCho value for grade 1 IDCs was the highest
compared with grade 2 and grade 3 IDCs. The mean
normalized tCho values for grade 1 (n ¼ 1), grade 2 (n ¼ 5),
and grade 3 IDCs (n ¼ 6) were 3.9 4.07 AU/ml;
2.96 2.41 AU/ml; and 1.38 0.90 AU/ml, respectively.
However, the ANOVA test did not show that the normalized
Please cite this article in press as: Suppiah S, et al., Improved diagnostic accuracy in differentiating malignant and benign lesions using singlevoxel proton MRS of the breast at 3 T MRI, Clinical Radiology (2013), http://dx.doi.org/10.1016/j.crad.2013.04.002
S. Suppiah et al. / Clinical Radiology xxx (2013) e1ee9
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Figure 2 A 63-year-old woman (patient 47) with grade 2 invasive ductal carcinoma. Left mammogram in the caudo-cranial (a) and medio-lateral
oblique (b) views showed an irregular, lobulated, high-density mass in the left upper inner quadrant (white arrow). (c) Colour Doppler ultrasound showed a corresponding hypoechoic solid mass with several penetrating vessels at the 10 o’clock position of the left breast (white arrow).
(d) Sagittal contrast-enhanced maximum intensity projection (MIP) images, showed a 5.1 cm irregular mass in the left upper quadrant (red
square). (e) Kinetic curve analysis demonstrated rapid uptake with washout pattern (type 3 kinetic curve; true-positive DCE-MRI finding).
(f) MRS showed elevated choline peak at 3.2 ppm (yellow arrow) (true-positive MRS finding).
tCho for the three different histopathological grades of IDCs
to be statistically significant (p ¼ 0.3).
The lesions were also assessed for their morphology and
DCE-MRI kinetics characteristics. Lesions that had equivocal
DCE findings but suspicious morphology or demonstrated
washout kinetics pattern after 3 min post-contrast medium
administration were interpreted as malignant.18,19 For total
scoring, taking into account morphological features combined with DCE-MRI contrast wash-out, lesions with a score
of >5 over 8 criteria were interpreted as malignant16,17; the
sensitivity, specificity, PPV, and NPV were 100, 73.3, 91.3,
and 100%, respectively (Table 2).
Discussion
MRS breast at 3 T has been shown to demonstrate better
diagnostic efficacy and has the advantage of better spectral
resolution to detect tCho peaks; therefore, there is
improved specificity and PPV for better detection of breast
carcinoma.9,11 The present study achieved 93.3% specificity
by qualitative analysis of tCho peak height and 86.7%
specificity for tCho values above 0.33 mmol/l by quantification of the area under the curve of the tCho peak; which is
compatible with prior breast MRS study results of between
88.5e100% performed by Sardanelli et al.,6 Bolan et al.,5 Tse
et al.21 and Kim et al.3
SVS 1H MRS was chosen as it has a fast acquisition time of
less than 6 min compared to multivoxel MRS, which generally
takes longer, i.e., approximately 10 min.14 SVS 1H MRS is also
easier to interpret as there is only one spectrum to analyse.
The ROI is chosen carefully by selecting the most enhancing
part of the breast lesion for voxel placement; therefore, giving
an accurate representation of tCho level within the lesion.
Using an optimized threshold of the absolute tCho peak
integral expressed as arbitrary units is a simple and effective method to quantify tCho in breast lesions. A 0.941
sensitivity and 0.867 specificity was achieved with a
normalized tCho equal to 0.33 AU/ml, which is comparable
to a previous study conducted by Sardanelli et al.,6 which
achieved 0.842 sensitivity and 0.885 specificity with a
normalized tCho equal to 0.85 AU/ml. A recent MRS study at
1.5 T by Mizukoshi et al.22 in 2013 reported an tCho value of
0.61 mmol/l as an optimal cut-off point, which achieved
68% sensitivity and 79.4% specificity 22. In the present study,
the optimal threshold for normalized tCho was 0.33 AU/ml,
corresponding to approximately 0.33 mmol/l, and provided
a good trade-off between sensitivity and specificity for the
detection of malignancy. At 3 T, metabolite peaks at MRS are
Please cite this article in press as: Suppiah S, et al., Improved diagnostic accuracy in differentiating malignant and benign lesions using singlevoxel proton MRS of the breast at 3 T MRI, Clinical Radiology (2013), http://dx.doi.org/10.1016/j.crad.2013.04.002
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S. Suppiah et al. / Clinical Radiology xxx (2013) e1ee9
Figure 3 A 50-year-old woman (patient 27) presented with a left breast lesion that was revealed to be fibrocystic disease. (a) T2-weighted axial
image showed the high signal lesion (red arrow) in the left upper outer quadrant. (b) Sagittal post-gadolinium multiplanar reformatted (MPR)
image demonstrated the 3 cm lesion (red arrow) in the left upper outer quadrant. (c) Axial image of T1 fat-saturation contrast-enhanced MRI
demonstrated a well-defined, fairly homogeneously enhancing oval lesion in the left upper outer quadrant (red arrow). (d) MRS showed no
significant elevation of choline peak at 3.2 ppm (yellow arrow; true-negative MRS finding).
better discernible, which enables even low values of tCho
peaks to be significant for malignancy. Thus, lesions with
normalized tCho levels of 0.33 mmol/l should be biopsied
to rule out malignancy.
The VOI was placed after administration of gadolinium,
which did not adversely affect the ability to detect choline
peaks in malignant lesions as tCho peaks were detected in
the majority of malignant lesions. By injecting contrast
medium prior to MRS, the voxel prescription was focused
on the most metabolically active part of the tumour and
adipose tissue was avoided. Kousi et al.9 also recommended
performing MRS after gadolinium administration because it
improved small lesion localization and enabled better voxel
prescription. They performed MRS before and after contrast
medium injection, and achieved a sensitivity/specificity of
42.8%/84.6% and 78.5%/92.0%, respectively, for detecting
Table 2
Diagnostic accuracy of using morphology and dynamic contrast-enhanced
magnetic resonance imaging (DCE-MRI) scoring versus magnetic resonance
spectroscopy (MRS).
Grouping variable
Figure 4 ROC curve using test variable of R2 for discriminating malignant from non-malignant tissue.
Scoring system
Scores of >5 versus
scores <5
MRS
Choline peak detection
versus no peak
PPV
(%)
NPV
(%)
Sensitivity
(%)
Specificity
(%)
91.3
100.0
100.0
73.3
97.6
87.5
95.2
93.3
PPV, positive predictive value; NPV, negative predictive value.
Please cite this article in press as: Suppiah S, et al., Improved diagnostic accuracy in differentiating malignant and benign lesions using singlevoxel proton MRS of the breast at 3 T MRI, Clinical Radiology (2013), http://dx.doi.org/10.1016/j.crad.2013.04.002
S. Suppiah et al. / Clinical Radiology xxx (2013) e1ee9
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Table 3
Quantitative analysis of malignant lesions.
Lesion no.
Patient no.
1
26
2
27
4
28
6
29
8
30
9
31
11
32
13
33
17
35
20
37
23
39
25
40
27
44
28
46
29
47
30
48
31
50
Mean
SD
Median
25th percentile
75th percentile
Age (years)
LLD (cm)
R2
VOI (ml)
Absolute tCho
Peak Integral (AU)
Normalized tCho
Peak Integral (AU/ml)
Histopathology findings
54
65
53
55
65
43
65
45
45
39
59
68
31
62
63
65
32
52.5
11.7
54.0
44.0
64.0
5.8
1.8
5.4
5.2
1.8
2.0
2.6
2.5
5.8
2.1
1.8
3.1
7.5
1.4
5.1
3.2
15.8
4.6
3.5
3.2
2.1
5.8
0.98
0.91
0.97
0.98
0.91
0.71
0.98
0.92
0.90
0.75
0.76
0.77
0.89
0.99
0.99
0.81
0.94
0.88
0.11
0.91
0.77
0.98
1.75
1.89
2.59
3.42
1.89
6.40
3.42
3.14
6.00
2.98
2.94
3.69
10.02
1.31
4.36
5.38
7.36
4.11
2.26
3.42
2.77
5.69
5.25
1.62
1.39
2.49
1.62
0.95
3.14
2.86
1.28
10.8
0.94
0.85
11.51
1.30
12.2
1.97
0.14
3.61
3.95
1.97
1.12
4.20
3.28
1.02
0.92
1.66
1.02
0.59
2.09
1.91
0.85
6.78
0.63
0.57
3.05
1.30
6.92
1.23
0.09
2.04
2.00
1.30
0.74
2.57
IDC grade 2
IDC grade 1
IDC grade 3
IDC grade 3
IDC grade 1
IDC grade 2
IDC grade 2
IDC grade 2
IDC grade 3
IDC grade 1
DCIS grade 1
IDC grade 3
IDC grade 3
DCIS grade 3
IDC grade 2
IDC grade 3
Malignant phyllodes
LLD, largest lesion diameter; VOI, volume of interest; R2, best spectral curve fit; tCho, total choline containing compounds; AU, arbitrary unit.
tCho presence. In addition, an intermediate TE value of
155 ms was chosen, which provided a good trade-off between satisfactory SNR and clearly resolvable choline peaks
at 3.2 ppm while minimizing possible relaxation losses and
motion-related artefacts associated with longer TEs.
Normalized tCho levels were detected in the range of
0.09e6.92 AU/ml within 17 malignant and one benign lesions. This finding is comparable to the study performed by
Sardanelli et al.,6 which detected tCho levels between
0.38e19.8 AU/ml. It also concurs with studies by Bolan
et al.5 and Roebuck et al.,1 which detected levels between
0.4e10 and 0.4e5.8 mmol/l, respectively, using phantoms of
known choline concentration to study and further quantify
the tCho to millimoles per litre units.
Although there was some overlap of values among
benign and malignant lesions (Fig 6), malignant lesions had
a higher mean normalized tCho value of 2.04 2 AU/ml,
compared with non-malignant lesions that had a mean
Table 4
Quantitative analysis of non-malignant lesions.
Lesion no.
Patient no.
Age (years)
LLD (cm)
R2
VOI (ml)
Absolute tCho
Peak Integral (AU)
Normalized tCho
Peak Integral (AU/ml)
Histopathology findings
3
5
7
10
12
14
16
18
19
24
26
15
21
22
32
Mean
SD
Median
25th percentile
75th percentile
27
28
29
31
32
33
34
35
37
39
40
34
37
38
57
65
53
55
48
65
45
20
45
39
59
68
20
39
20
46
31.3
13.3
29.5
20.0
44.3
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
NA
2.3
1.4
3.8
1.3
2.2
1.2
2.1
1.4
2.7
0.04
0.59
0.03
0.51
0.21
0.48
0.69
0.02
0.23
0.07
0.29
0.69
0.17
0.92
0.55
0.58
0.31
0.62
0.27
0.86
3.49
3.69
3.42
2.98
2.66
3.14
3.69
6.00
2.24
2.94
3.69
4.56
3.45
2.98
2.02
3.25
1.06
3.21
2.26
4.28
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
1.76
0.00
0.12
0.45
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
0.00
1.10
0.00
0.09
0.32
0.00
0.00
0.00
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
Normal
FA
FA
FA
FCD
tissue
tissue
tissue
tissue
tissue
tissue
tissue
tissue
tissue
tissue
tissue
LLD, largest lesion diameter; VOI, volume of interest; R2, best spectral curve fit; tCho, total choline containing compounds; AU, arbitrary unit; FA, fibroadenoma;
FCD, fibrocystic disease.
Please cite this article in press as: Suppiah S, et al., Improved diagnostic accuracy in differentiating malignant and benign lesions using singlevoxel proton MRS of the breast at 3 T MRI, Clinical Radiology (2013), http://dx.doi.org/10.1016/j.crad.2013.04.002
e8
S. Suppiah et al. / Clinical Radiology xxx (2013) e1ee9
Figure 5 ROC curve using test variable absolute tCho (AU) and normalized tCho (nAU) for discriminating malignant from non-malignant tissue.
normalized tCho value of 0.09 0.32 AU/ml. The IDCs in the
present study showed high tCho levels. Nevertheless, contrary to the authors’ expectations, it was found that lowgrade IDCs had the highest mean value of tCho followed
by grade 2 and grade 3 IDCs. One would expect a higher
grade malignant lesion to have a significantly higher level of
detectable tCho, which was not the case in the authors’
experience. This observation may be attributed to the small
number of low-grade IDCs in the present study.
In addition, this study was able to detect tCho in sarcomas.
A previous study by Yeung et al.13 did not detect any tCho in
phyllodes tumours, which corroborated with another study
by Tse et al. 21, indicating that breast stromal tumours
generally do not have detectable tCho. Nevertheless, the
presence of choline peaks were identified in two malignant
phyllodes tumours in the present study, which has been reported in a recent publication.20 Furthermore, the quantitative MRS study was able to detect the presence of low levels of
choline in one malignant phyllodes tumour, i.e., 0.09 AU/ml,
which was likely attributed to better spectral resolution at 3 T.
MRS at 3 T shows an increase in specificity of lesion
detection along with greater spectral resolution of the
metabolite peaks. This can improve detectability of tCho and
other metabolites, decrease measurement errors, and enable
the study of smaller lesions. The synergistic combination of
high-field MR and tCho quantifying methods has the potential to greatly improve the clinical utility and availability
of breast MRS. The considerations of MRI breast at higher
field scanners, includes the need to reduce the number and
duration of the radiofrequency pulses per unit time so as to
adhere to specific absorption rate (SAR) limitations. This was
compensated for by reducing the flip angle to 10 . Due to
prolonged T1 relaxation times at 3 Tesla, the study began
with a longer TR of approximately 4e5 ms. These adjustments were made based on the recommendations by Kuhl
et al. for optimized breast MRI results at 3 Tesla.18
The limitation of this study was the relatively small
population of benign lesions. The whole study patient
population was not included in the quantitative analysis
due to technical difficulties in acquiring the software for
tCho quantification in the earlier phase of this study.
Quantification of the tCho based on histopathological subtypes was not statistically significant due to the very small
sampling of low-grade IDCs. Some lesions that had erratic
spectra due to technical problems (i.e., patient breathing/
movement artefacts, susceptibility artefacts due to field
inhomogeneity, and inability to perform proper high-order
shimming for certain lesions) were also excluded. It would
have also been better to perform MRS for normal tissue on
the non-lesion containing breast, as the peritumoural
environment could influence the tCho measurements.
In conclusion, the present study provides an SV 1H MRS
protocol for the detection of breast cancer, which is clinically applicable, has a relatively fast scan time, is simple to
interpret, and is diagnostically accurate, i.e., improved
specificity. Breast MRS at 3 T can improve diagnostic accuracy in differentiating malignant and benign breast lesions
when using a tCho cut-off point of 0.33 mmol/l. SV 1H MRS
using tCho peak quantification can be used clinically as a
non-invasive technique to improve the specificity of breast
cancer detection. Nevertheless, MRS is not recommended as
a standalone criterion for the diagnosis of breast cancer but
should be interpreted in combination with morphological
and dynamic contrast-enhancement kinetics features.
Acknowledgements
Figure 6 Boxplot showing the correlation between normalized
arbitrary units/normalized tCho values with histopathological
findings.
This research study has been supported by the University of
Malaya Research Grant (RG032/09HTM). K. Rahmat was
supported by University of Malaya Research Grant (RG 390/
11HTM). The authors gratefully acknowledge Dr Sharon Tan
Ling Ling and the UMRIC scientific committee for their
essential contri-butions.
Please cite this article in press as: Suppiah S, et al., Improved diagnostic accuracy in differentiating malignant and benign lesions using singlevoxel proton MRS of the breast at 3 T MRI, Clinical Radiology (2013), http://dx.doi.org/10.1016/j.crad.2013.04.002
S. Suppiah et al. / Clinical Radiology xxx (2013) e1ee9
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Please cite this article in press as: Suppiah S, et al., Improved diagnostic accuracy in differentiating malignant and benign lesions using singlevoxel proton MRS of the breast at 3 T MRI, Clinical Radiology (2013), http://dx.doi.org/10.1016/j.crad.2013.04.002