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Contrast-enhanced Mammog-
raphy: Current Applications and
Future Directions
Kimeya F. Ghaderi, MD
Jordana Phillips, MD
Hannah Perry, MD
Parisa Lotfi, MD
Tejas S. Mehta, MD, MPH
Abbreviations: AD = architectural distortion,
BI-RADS = Breast Imaging Reporting and Data
System, CC = craniocaudal, CEM = contrast-
enhanced mammography, DCIS = ductal carci-
noma in situ, ILC = invasive lobular carcinoma,
MLO = mediolateral oblique, NPV = negative
predictive value, PPV = positive predictive value,
2D = two-dimensional
RadioGraphics 2019; 39:1907–1920
https://doi.org/10.1148/rg.2019190079
Content Codes:
From the Department of Radiology, Beth Israel
Deaconess Medical Center, 330 Brookline Ave,
Boston, MA 02215 (K.F.G., J.P., P.L., T.S.M.);
and Department of Radiology, University of
Vermont Medical Center, Burlington, Vt (H.P.).
Presented as an education exhibit at the 2018
RSNA Annual Meeting. Received March 24,
2019; revision requested July 29 and received
August 18; accepted August 26. For this journal-
based SA-CME activity, the authors J.P. and P.L.
have provided disclosures (see end of article); all
other authors, the editor, and the reviewers have
disclosed no relevant relationships. Address
correspondence to K.F.G. (e-mail: kghaderi@
bidmc.harvard.edu).
©
RSNA, 2019
SA-CME Learning Objectives
After completing this journal-based SA-CME
activity, participants will be able to:
■■Describe how to perform CEM.
■■Identify current and developing uses
of CEM.
■■Compare performance characteristics
of CEM with those of MRI in common
clinical scenarios.
See rsna.org/learning-center-rg.
1907
Breast Imaging
Contrast-enhanced mammography (CEM) is a developing mo-
dality used for the workup and management of breast cancer.
Although diagnostic imaging modalities such as mammography
and US have historically been the mainstays of initial breast cancer
workup, recent advances in breast MRI have allowed better disease
evaluation. However, MRI is not always readily available, can be
time consuming, and is contraindicated in certain patients. CEM is
an alternative to US and MRI, and it can be used to obtain contrast
material–enhanced information and standard mammograms simul-
taneously. A CEM examination is shorter than that of MRI, and the
modalities have similar rates of sensitivity to detect lesions. CEM
also costs less than MRI. The authors evaluate clinical uses of CEM
and discuss the literature supporting these indications.
©
RSNA, 2019 • radiographics.rsna.org
Introduction
Contrast-enhanced mammography (CEM) is an emerging modal-
ity that combines digital mammography with the administration of
intravenous contrast material. Breast cancers can be identified at
CEM by density and morphologic characteristics as well as by the
neovascularity associated with malignancy (1,2). The U.S. Food and
Drug Administration (FDA) approved the use of CEM in 2011 as an
“adjunct following mammography and/or ultrasound exams to local-
ize a known or suspected lesion” (3).
CEM is primarily used in the diagnostic setting to help identify
breast malignancy and to exclude a benign process with more confi-
dence. However, as radiology practices adopt CEM, questions arise
regarding the best use of this diagnostic tool. We review the common
clinical scenarios in which CEM has been applied, as well as the
literature supporting its use in those applications.
Image Acquisition and Interpretation
CEM is performed by using standard mammography equipment that
has been upgraded to include copper filtration and additional software
that make the unit capable of performing dual-energy imaging.
Before an imaging examination, nonionic low-osmolar iodinated
contrast material is administered to the patient intravenously at a
dose of 1.5 mL/kg at a rate of 3 mL/sec. Two minutes after contrast
material administration, standard bilateral craniocaudal (CC) and
mediolateral oblique (MLO) imaging is performed by using a dual-
energy technique that obtains low-energy and high-energy images.
Low-energy imaging is performed at a kilovoltage below the
k-edge of iodine (33.2 keV) (2). As a result, no iodinated contrast
material is depicted. Low-energy images appear similar to standard
digital two-dimensional (2D) mammograms and have been shown to
be noninferior to them (4,5).
1908 November-December 2019
Teaching Points
■■ CEM is primarily used in the diagnostic setting to help iden-
tify breast malignancy and to exclude a benign process with
more confidence.
■■ As CEM and MRI both delineate areas of contrast enhance-
ment, it is possible that CEM may similarly assist in differentiat-
ing benign causes of AD from malignant causes.
■■ As a result, calcifications with suspicious morphology must be
biopsied regardless of enhancement shown on images. It is
not clear whether CEM has a role in this setting.
■■ Subsequent studies by Lee-Felker et al and Fallenberg et al
demonstrated comparable sensitivity and performance of MRI
and CEM for evaluating disease extent in patients with newly
diagnosed breast cancer.
■■ Although limited, the available data suggest that CEM may
have a role in breast cancer screening.
High-energy imaging is performed above the
k-edge of iodine (33.2 keV) and reveals contrast
material uptake, but it is noninterpretable. The
entire examination is performed in approximately
5–6 minutes. The low- and high-energy images
are automatically postprocessed. The resulting
recombined image highlights areas of contrast
enhancement while the signal from background
breast tissue has been suppressed.
The low-energy and recombined images are
used for diagnostic evaluation. Additional di-
agnostic imaging, such as spot compression or
magnification views, can be performed after the
initial four views have been obtained. The ad-
ditional diagnostic imaging can be performed
with or without a dual-energy technique. How-
ever, if dual-energy imaging is desired, it must
be performed in a 10-minute window after con-
trast material administration to depict contrast
agent uptake in the breast before it washes out
(Fig 1) (6–9).
The low-energy and recombined images are
interpreted as part of a CEM examination. Any
abnormality identified on the low-energy image
should be correlated with the recombined image,
and vice versa. The value of low-energy imaging
findings seen at CEM is explored in this article.
If incidental areas of enhancement are iden-
tified on the recombined images and no low-
energy correlate is identified, it may be necessary
to perform US or MRI. An interpretation of the
low-energy and recombined images should be
included in the imaging report, and a manage-
ment decision should be made based on both sets
of images.
Currently there is no CEM-specific Breast
Imaging Reporting and Data System (BI-RADS)
lexicon for image interpretation. As a result, the
BI-RADS mammography lexicon is used for low-
energy images and the BI-RADS MRI lexicon is
radiographics.rsna.org
used for recombined image evaluation (10,11). A
CEM examination is billed as diagnostic mam-
mography with the addition of contrast agent.
CEM is associated with a level of radiation
exposure similar to that of digital mammography.
While some studies have shown that a CEM ex-
amination exposes the patient to a radiation dose
20%–80% higher than that of standard mam-
mography, a recent study demonstrated that the
dose of radiation from CEM is within the range
of radiation doses patients receive for other com-
mon mammographic examinations (7,12–14).
Abnormalities Seen at Screening
Abnormalities identified at screening mammogra-
phy include masses, focal asymmetry, asymmetry,
architectural distortion (AD), and microcalcifica-
tions. When abnormalities are identified, patients
are recalled for additional diagnostic imaging,
including mammography and US (15–18). The
additional diagnostic images are evaluated to
determine the probability of malignancy. CEM
is increasingly being used to help evaluate these
imaging findings (8,19,20).
CEM can be performed as an adjunct to
diagnostic imaging or in place of traditional diag-
nostic mammography. Current studies show that
low-energy images are similar to conventional 2D
mammograms (4,5). When CEM is used instead
of traditional diagnostic mammography, imag-
ing is performed in four views. Any additional
diagnostic imaging can be performed immedi-
ately after the standard four projections, with or
without the dual-energy technique.
Studies report that CEM has high sensitivity
for delineation of malignant findings, particu-
larly masses, AD, and microcalcifications, in
patients who have been recalled after screening.
Masses
Diagnostic workup of a breast mass, whether it
is depicted at imaging or is palpable, typically
involves diagnostic mammography followed by
targeted US (18). Although multiple retrospec-
tive studies by Lobbes et al (20,21) have de-
scribed the value of CEM for patients recalled
after screening, none have specifically addressed
breast masses (19,21,22).
However, a study by Lalji et al (22) included
a large percentage (76%) of recalled patients
who had masses and underwent CEM. They
performed a reader study comparing the low-
energy images obtained at CEM to the images
obtained at the complete CEM examination.
The low-energy images were used as a surro-
gate for conventional mammography. The study
found that compared with conventional mam-
mography, CEM had a sensitivity of 97% and a
RG • Volume 39 Number 7 Ghaderi et al 1909

Figure 1. Protocol for performing CEM at Beth Israel Deaconess Medical Center. HE = high-energy imaging, LE = low-energy imag-
ing, s = second.

Table 1: Studies Evaluating CEM in Common Diagnostic Scenarios

Imaging Modalities Population No. of Sensitivity Specificity

Scenario Author Compared Studied Participants (%) (%) PPV (%) NPV (%)
Masses Lalji et al CEM vs Patients referred 199 97 (all 70 (all 58 (all 98 (all
(22) LE from breast lesions) lesions) lesions) lesions)
cancer screen-
ing program
AD Patel et al CEM Patients under- 45 97 58 78 92
(23) going biopsy
for AD
Microcalcifi- Tardi- CEM vs Patients who 195 94 (all 74 (all 91 (all 81 (all
cations vel et al LE underwent di- lesions) lesions) lesions) lesions)
(24) agnostic CEM
Cheung CEM Patients with 87 89 87 73 95
et al BI-RADS
(25) 4 nonmass
microcalcifica-
tions
Houben CEM vs Patients with 147 94 37 54 88
et al LE suspicious
(26) calcifications
Symptomatic Tennant CEM vs Patients evalu- 100 95 81 ... ...
breast et al LE vs ated for breast
(27) MRI symptoms
MRI contrain- Richter et CEM vs Patients with 118 99 54 94 86
dicated al (28) MG cancer or
indeterminate
findings and
MRI contrain-
dication
Note.—LE = low-energy imaging, MG = full-field 2D digital mammography, NPV = negative predictive value,
PPV = positive predictive value.

specificity of 70% (22). Additional performance
characteristics are listed in Table 1.
There have been two studies comparing
CEM to mammography and US in the set-
ting of known breast cancer. However, to our
knowledge there are no current studies di-
rectly comparing CEM with the combination
of mammography and US in patients recalled
after screening. Therefore, it is unclear whether
CEM provides added value for evaluating a
solitary mass in patients who also undergo
mammography and US.
In fact, the main role of CEM when evaluat-
ing breast masses is to help identify any addi-
tional abnormalities in the ipsilateral or contra-
lateral breast when a suspicious imaging finding
is present. This is discussed further in the sec-
tion addressing disease extent (29,30) (Fig 2).
1910 November-December 2019 radiographics.rsna.org

Architectural Distortion
AD can have benign and malignant causes, which
can be difficult to distinguish at diagnostic mam-
mography. This can make management of AD
difficult, especially when the imaging findings
are subtle. Given that AD may be associated with
malignancy in approximately one-half to two-
thirds of patients (31–33), biopsy is considered
the standard of care (16,32,34).
Studies have evaluated whether tomosyn-
thesis can obviate biopsy by delineating which
cases of AD are benign. The results have been
mixed, demonstrating a positive predictive value
(PPV) of AD for malignancy of up to 74.5%.
This number decreases if there is no correlate at
US, or if AD is depicted at screening mammog-
raphy only rather than diagnostic mammography
(16,32,34,35). One study evaluating AD at MRI
has shown that the absence of enhancement may
be a more reliable predictor of benignity (36).
As CEM and MRI both delineate areas of
contrast enhancement, it is possible that CEM
may similarly assist in differentiating benign
causes of AD from malignant causes (23). Patel
and colleagues (23) performed CEM in all
patients with AD for whom biopsy was recom-
mended.Twenty-nine of the 30 malignant lesions
(97%) demonstrated enhancement at CEM (23).
It is possible that the one malignant lesion which
was not depicted was obscured by marked back-
ground enhancement. The study demonstrated
that CEM has a high sensitivity and negative
predictive value (NPV) in patients with AD (23). Figure 2. Grade 1 invasive carcinoma in a 47-year-old
The data suggest that the absence of enhance- woman recalled from screening for additional evalua-
tion of a suspicious mass. (a) MLO low-energy mam-
ment associated with AD in patients with mini- mogram shows a spiculated mass (circle). (b) MLO re-
mal background enhancement is a strong indica- combined mammogram demonstrates enhancement of
tion of benignity (Fig 3). the mass only (circle), confirming that the malignancy
CEM is useful to help evaluate AD that ap- is limited to this area. (c) US image correlate shows a
1.0-cm hypoechoic irregular mass. US-guided biopsy re-
pears subtle or indeterminate at screening or at vealed grade 1 invasive carcinoma with predominantly
diagnostic tomosynthesis. CEM may also be used lobular features.
when AD is seen on an image and the imaging
features are not reproducible with certainty. In
these scenarios, the absence of associated en- suspicious should be biopsied, and those that are
hancement can help prevent unnecessary follow- thought to be probably benign may be monitored
up imaging examinations or biopsy. with surveillance imaging.
If AD is confirmed at diagnostic 2D mam- Microcalcifications are well depicted at CEM.
mography, tomosynthesis, or low-energy CEM CEM demonstrates the morphology of microcal-
imaging, biopsy should be performed regardless cifications on low-energy images and shows any
of enhancement shown at imaging until addi- associated enhancement on recombined images
tional research in this area is available to validate (Fig 4).
the earlier study. A few studies have evaluated the use of CEM
in the setting of microcalcifications (Table 1)
Microcalcifications (24–26). In 2016, Tardivel et al (24) published
Patients are commonly recalled after screen- a review of 195 women with suspicious imag-
ing because microcalcifications were found on ing findings at mammography or US. Twelve
images. Diagnostic management relies on risk (6%) suspicious microcalcifications were found.
stratification on the basis of BI-RADS descriptors Four of these had no enhancement, but biopsy
(37-39). Microcalcifications that are considered revealed the presence of ductal carcinoma in situ
RG • Volume 39 Number 7 Ghaderi et al 1911

Figure 3. Grade 1 invasive ductal carcinoma in the left breast of a 78-year-old woman recalled from screening for AD. (a, b) CC (a)
and MLO (b) screening mammograms demonstrate a questionable area of AD in the left upper central breast (circle). (c, d) CC (c)
and MLO (d) recombined mammograms demonstrate a 1.6-cm spiculated enhancing mass (arrow) in the area of AD. US-guided
biopsy revealed grade 1 invasive ductal carcinoma.

Figure 4. Grade 2 invasive carcinoma in a 47-year-old woman recalled from screening for additional evaluation of right breast
microcalcifications. (a) CC low-energy mammogram and magnified image (inset) demonstrate segmental calcifications in the lateral
right breast. (b, c) CC (b) and MLO (c) recombined mammograms reveal associated nonmass enhancement in the area of the mi-
crocalcifications as well as a 1-cm enhancing mass in the upper central right breast (circle). US-guided biopsy of the mass revealed
grade 2 invasive carcinoma with ductal and lobular features, and stereotactic biopsy of the calcifications revealed invasive carcinoma.
1912 November-December 2019 radiographics.rsna.org

Figure 5. Right breast microcalcifications in a 44-year-old woman recalled from screening for additional evalu-
ation. (a) Mediolateral magnified diagnostic mammogram shows suspicious grouped right breast microcalcifi-
cations in the upper breast at an anterior depth. (b) MLO low-energy mammogram demonstrates microcalcifi-
cations (circle). (c) MLO recombined mammogram demonstrates mild background enhancement with no as-
sociated increased enhancement in the area of the microcalcifications. Since the microcalcifications were highly
suspicious, stereotactic core biopsy was performed. The results showed atypical ductal hyperplasia and atypical
lobular hyperplasia. The results of surgical pathologic analysis revealed lobular carcinoma in situ.

(DCIS) and invasive lobular carcinoma (ILC). Symptomatic Breast Disease

Cheung et al (25) evaluated a larger number of
patients with microcalcifications and found that
100% of cases of invasive ductal carcinoma and
84.2% of cases of DCIS demonstrated contrast
enhancement at CEM (25).
More recently, Houben et al (26) found that
CEM only minimally improved sensitivity of
mammography from 91% to 94% and that some
invasive cancers and DCIS did not show enhance-
ment at imaging. They also demonstrated that
CEM did not impact surgical decision making.
Overall, these studies suggest that the pres-
ence of enhancement on images suggests malig-
nancy, but the absence of enhancement cannot
exclude it. As a result, calcifications with suspi-
cious morphology must be biopsied regardless
of enhancement shown on images. It is not clear
whether CEM has a role in this setting (Fig 5).
Additional evaluation of CEM in this application
is warranted.
Evaluation and management of symptomatic breast
disease depend on a multidisciplinary approach
involving clinical evaluation and multimodality
imaging (40,41). The definition of a symptomatic
breast is varied, and symptoms include a palpable
mass, localized breast pain, and nipple discharge.
CEM is a promising tool in this setting (Fig 6).
Tennant et al (27) performed a reader review
of 100 consecutive CEM examinations per-
formed in patients with breast symptoms. The
results of histologic analysis revealed malignancy
in 73% of these patients (27). The sensitivity and
accuracy of mammography dramatically im-
proved with CEM. The sensitivity of low-energy
imaging was 84.4%, and the sensitivity of the
entire CEM examination was 94.5% (27).
While encouraging, this review compares
CEM with mammography, rather than mam-
mography or tomosynthesis with US, which is the
more common practice for evaluating patients
RG • Volume 39 Number 7
Figure 6. Grade 2 ILC in a 50-year-old woman who presented with a palpable left breast lump. MLO low-energy (a) and recom-
bined (b) mammograms of the left breast demonstrate two focal areas of nonmass enhancement (circles in b) in the left lateral breast.
(c) US image correlation shows a 1.9-cm subtle heterogeneous area (arrows). Biopsy revealed grade 2 ILC.
with breast symptoms. It is unclear if CEM im-
proves diagnostic performance for lesion visual-
ization and characterization compared with that
of mammography and US. However, studies have
shown that CEM demonstrates improved perfor-
mance for evaluating disease extent compared to
mammography and US. This will be discussed in
a later section (29,30).
As a result, the role of CEM may be primarily in
patients with breast symptoms and highly suspi-
cious abnormalities at imaging. In one practice that
has implemented CEM, US is performed first for
palpable lumps. If the US findings are concerning
for malignancy, a CEM examination is then per-
formed. In this scenario, standard imaging is used
in the triage of patients before CEM is performed.
Additional studies of CEM for this indication
would help direct management in the future.
Disease Extent
When women are newly diagnosed with breast
cancer, additional imaging with breast MRI or
US may be recommended to help determine the
extent of disease in the ipsilateral breast or addi-
tional sites of disease in the contralateral breast.
Data on the value of supplemental imaging are
controversial, including that of MRI. Current
Ghaderi et al 1913
imaging practices vary based on philosophy, as
well as insurance coverage and access to ad-
vanced imaging (42–44).
Multiple studies have evaluated whether CEM
can be used for this indication by comparing it with
conventional mammography and US or MRI (Ta-
ble 2) (1,28,29,45–47,50). When compared with
conventional mammography with or without US,
CEM is superior at depicting malignant tumors
(29,30). When compared to tumor size reported
at histopathologic analysis, CEM leads to overesti-
mation of tumor size by 2.9 mm, and US leads to
underestimation of tumor size by 2.8 mm (29).
CEM has also been compared with MRI. In
2013, Jochelson et al (45) evaluated 52 women
with newly diagnosed cancer and compared
CEM to conventional 2D mammography and
MRI. CEM and MRI were found to demon-
strate 96% of the index tumors versus 81% with
mammography alone. In this study, CEM helped
identify fewer incidental contralateral breast
malignancies compared with MRI but had fewer
false-positive results than MRI.
Subsequent studies by Lee-Felker et al (47) and
Fallenberg et al (46) demonstrated comparable
sensitivity and performance of MRI and CEM for
evaluating disease extent in patients with newly
1914 November-December 2019 radiographics.rsna.org

Table 2: Studies Evaluating CEM in New or Treated Cancer

Imaging Modalities Population No. of Par- Sensitivity Specificity PPV NPV

Scenario Author Compared Studied ticipants (%) (%) (%) (%)
Disease extent Dromain et CEM vs Patients with abnor- 120 93 56 73 85
al (1) MG or mal findings at MG
US and US
Jochelson et CEM vs Patients with newly 52 96 ... 97 ...
al (45) MG vs diagnosed breast
MRI cancer
Fallenberg CEM vs Patients with newly 80 97 ... ... ...
et al (46) MG vs diagnosed breast
MRI cancer
Lee-Felker CEM vs Patients with newly 52 94 17 93 20
et al (47) MRI diagnosed unilateral
breast cancer
Response to Iotti et al CEM vs Patients with breast 46 100 84 57 100
neoadjuvant (48) MRI cancer and neoadju-
therapy vant chemotherapy
Barra et al CEM vs Patients with breast 33 76 87.5 95 54
(49) MRI cancer at end of
neoadjuvant chemo-
therapy
Patel et al CEM vs Patients with invasive 65 95 67 56 97
(50) MRI breast cancer who
underwent neo-
adjuvant systemic
therapy
Note.—MG = full-field 2D digital mammography.

diagnosed breast cancer. CEM demonstrates satis-
factory size correlation at pathologic analysis when
compared with MRI, although CEM has led to
overestimation of size in some cases (45,46).
Therefore, CEM costs less than MRI, and it is
relatively easy to upgrade standard digital mam-
mography equipment. CEM can be a low-cost
and more accessible alternative to MRI in the
evaluation of disease extent (Fig 7) (51).
Response to Neoadjuvant
Chemotherapy
After neoadjuvant chemotherapy, the imaging
evaluation of treatment response and residual dis-
ease helps guide surgical management. Current
practice involves clinical examination and mul-
tiple imaging modalities, with MRI as the most
accurate modality (52–54).
Since CEM performs similarly to MRI to help
evaluate disease extent, it may also be useful in
evaluating treatment response. Multiple stud-
ies have investigated this use of CEM (Table 2)
(28,50,48,49).
In 2017, Iotti et al (48) prospectively evaluated
CEM and MRI before, during, and after neoad-
juvant therapy in 54 women with biopsy-proven
breast cancer. Although the use of CEM and MRI
led to underestimation of the extent of residual
tumor, CEM demonstrated pathologic complete
response to treatment better than MRI (48).
In 2018, Patel and colleagues (50) retrospec-
tively compared CEM and MRI in 65 patients
with invasive breast cancer proven by pathologic
analysis after neoadjuvant systemic therapy. CEM
and MRI had comparable PPVs and levels of sen-
sitivity for depicting residual disease (50). The data
suggest that CEM may be used to demonstrate
treatment response and depict disease extent (Fig
8). CEM may be an especially useful tool in loca-
tions where MRI is not be readily available.
CEM as an Alternative to MRI
During the diagnostic workup of breast imaging
findings, there are many instances when MRI is
not available or is contraindicated for the patient
because of claustrophobia, MRI-incompatible
implants, or weight limitations. For this group of
patients, CEM is a useful diagnostic alternative.
Richter et al (28) performed a recent retro-
spective study of 118 patients contraindicated for
MRI, who also had known cancer or discordant
US-guided biopsy results. The patients under-
went digital mammography and CEM, and histo-
logic analysis was performed in 94 of the lesions.
RG • Volume 39 Number 7 Ghaderi et al 1915

Figure 7. Right breast microcalcifications in a 57-year-old

woman recalled from screening for additional evaluation.
(a) CC screening mammogram and magnified image (in-
set) demonstrate two new groups of microcalcifications
(circles). (b) CC low-energy mammogram of the right
breast shows a clip (arrow) from stereotactic core biopsy
of the anterior group of calcifications. Pathologic analysis
revealed microinvasive cancer. (c) CC recombined mam-
mogram demonstrates an 8-cm area of nonmass enhance-
ment involving the entire outer breast, encompassing the
two small groups of microcalcifications (arrow). (d) Axial
MR subtraction image shows similar nonmass enhance-
ment involving the lateral right breast.

CEM was shown to have a greater diagnostic
performance compared with mammography (Table
1) (28). While this study was limited by superimpo-
sition, artifacts, and timing challenges, CEM was
demonstrated to be a feasible alternative in patients
with contraindications to MRI (Fig 9).
Given its comparable performance to breast
MRI, practices will often choose to first imple-
ment CEM as an alternative to MRI. For these
patients, the breast imaging team has already
decided that enhancement information would be
useful and is therefore more willing to accept the
risks of a contrast agent–related event.
Future Directions
The role of CEM in breast cancer screening is
being studied. It is widely accepted that mam-
mography reduces breast cancer mortality. How-
ever, its sensitivity for depicting breast cancer
decreases in women with dense breast tissue and
in those at high risk for cancer (51,55–60).
As a result, supplemental screenings with US
and MRI are increasingly being performed. Cur-
rent guidelines suggest that MRI be considered
in women at high risk and in certain women at
intermediate risk for breast cancer. For those
with dense breasts, US may be an option. How-
ever, the increased risk of a false-positive result
must be taken into consideration (61).
US and MRI present some challenges. US
has an increased number of false-positive results
and is time consuming. (62,63). MRI also has
a lengthy examination time and can have false-
positive results. It also has the added challenge
1916 November-December 2019 radiographics.rsna.org

Figure 8. Biopsy-proven invasive ductal carcinoma of the left breast in a 74-year-old woman. (a) CC diagnostic mammogram
demonstrates an area of pleomorphic calcifications (circle) that corresponds to biopsy-proven invasive ductal carcinoma. (b, c) CC
low-energy mammogram (b) and CC contrast-enhanced recombined mammogram (c) obtained after four cycles of neoadjuvant
chemotherapy show decreased density but subtle nonmass enhancement in the area of the biopsy clip (circle). The size corresponds
to the results of surgical pathologic analysis, which revealed residual cancer.

Figure 9. Grade 2 invasive ductal carcinoma in a 74-year-old woman with a history of treated left breast cancer who presented
for an annual diagnostic mammogram. (a, b) CC (a) and MLO (b) mammograms of the right breast demonstrate a new 0.8-cm
mass in the upper lateral quadrant (arrow). Circles = mole markers. US (not shown) revealed two masses, which were biopsied and
determined to be grade 2 invasive ductal carcinoma. The patient underwent CEM because of an allergy to gadolinium. (c, d) CC
low-energy (c) and recombined (d) mammograms of the right breast show two biopsy clips in the location of the newly diagnosed
cancer (arrows in c) and an additional site of abnormal contrast enhancement between the two biopsy clips, which corresponds to an
additional site of disease (arrow in d). CEM helped confirm there were no additional sites of abnormal enhancement.
RG • Volume 39 Number 7
Table 3: Studies Evaluating Future Directions of CEM
Modalities
Author Compared Population Studied
Jochelson CEM vs MRI Patients with increased
et al breast cancer risk
(64)
Sorin et al CEM vs LE Patients with family or
(66) personal history of
breast cancer
of being expensive and is not accessible to all
patients (63–65).
As a result, some view CEM as a possible
alternative to these modalities for breast can-
cer screening (Table 3) (64,66). Jochelson et al
(64) performed a prospective pilot study of 307
women with an intermediate or high lifetime risk
of breast cancer who underwent CEM and MRI.
The study evaluated data from the initial screen-
ing and 2-year follow-up.
Three cancers were found during the initial
screening, all of which were found at MRI. Two
lesions were found at CEM, and none were
found at low-energy mammography (64). The
specificity of CEM and MRI were comparable
at 94.7% and 94.1%, respectively (64). While
promising, these results are preliminary and
are not sufficient to replace supplemental MRI
with CEM.
More recently, Sorin et al (66) compared low-
energy images (obtained in the place of conven-
tional 2D mammograms) with images obtained
by performing the full CEM examination in
Ghaderi et al 1917
No. of Sensitivity Specificity NPV
Participants (%) (%) PPV (%) (%)
307 ... 95 15 (of ...
biopsy)
611 90.5 76 12 100
Figure 10. DCIS in a 58-year-old woman with a
strong family history of breast cancer. MR images
were obtained during a routine screening, and con-
trast-enhanced mammograms were obtained in a re-
search trial. (a) CC low-energy mammogram shows
no abnormality. (b) CC recombined mammogram
demonstrates a 4.5-cm area of nonmass enhance-
ment (dashed rectangle) in the right central upper
breast. (c) Axial MR subtraction image of the right
breast shows up to a 4-cm area of nonmass enhance-
ment (dashed rectangle), corresponding to the area
seen at CEM. Pathologic analysis of an MRI-guided
biopsy specimen revealed DCIS.
women with intermediate breast cancer risk.
Family or personal history of breast cancer was
reported by 48.3% of patients, and 93.1% had a
mammographic breast density of C or D.
CEM was found to have a sensitivity of 90.5%.
Mammography demonstrated a sensitivity of 52.4%
(66). The authors determined that CEM depicts
cancer at an incremental rate of 13.1 cancers per
1000 women screened (66). Unfortunately, CEM
was associated with more false-positive imaging
findings than was conventional mammography. It
resulted in multiple unnecessary biopsies in lesions
proven to be benign at pathologic analysis. CEM
findings were inconclusive in 28 patients, who later
underwent MRI (66).
Although limited, the available data sug-
gest that CEM may have a role in breast cancer
screening (Fig 10). More research is being per-
formed to evaluate it for this indication (67).
Challenges
As with any emerging modality, CEM is not
without its challenges and limitations (13,68,69).
1918 November-December 2019
The most significant challenge of CEM relates to
the administration of contrast material. Iodinated
contrast material is associated with risks of aller-
gic reactions and extravasation events. Additional
staff training is required for the administration of
contrast material and for management of contrast
agent–related complications.
Additionally, CEM-directed biopsy is not yet
available. When suspicious lesions are found on
recombined images, biopsy must be performed
by using an alternative modality, such as standard
digital mammography, US, or MRI.
Similar to other imaging modalities, false-
positive and false-negative results may occur at
CEM. Benign entities such as fibroadenoma,
pseudoangiomatous stromal hyperplasia (PASH),
abscesses, and papillomas can be associated with
contrast enhancement, resulting in unnecessary
imaging and biopsies (1,23,32).
CEM is not sensitive enough to depict all breast
cancers and may miss cancers that show little as-
sociated enhancement, such as ILC or low-grade
DCIS. In addition, cancers may be obscured by
background parenchymal enhancement or may not
be included in the field of view, such as cancers that
are close to the chest wall (23,24,70,71).
Radiology practices may consider perform-
ing 1-year follow-up examinations as a part of
quality control and assurance. This is valuable
when radiologists are learning to interpret CEM
images. Repeating CEM may also be necessary
when imaging shows moderate to marked back-
ground enhancement.
Conclusion
CEM is an emerging modality that may pro-
vide critical information in a number of clinical
scenarios. Today, CEM is most commonly used
to evaluate disease extent in patients with contra-
indications to MRI. It is also increasingly being
used in the diagnostic setting for patients recalled
from screening. However, as the interest in CEM
grows, additional studies are needed to further
understand the role of CEM in breast imaging.
Disclosures of Conflicts of Interest.—J. P. Activities related to
the present article: institution received grant funding from GE
Healthcare; reviewed mammograms for Hologic. Activities not
related to the present article: consultant to Hologic. Other activities:
disclosed no relevant relationships. P.L. Activities related to the
present article: disclosed no relevant relationships. Activities not re-
lated to the present article: provided second opinions for Advance
Medical. Other activities: disclosed no relevant relationships.
References
1. Dromain C, Thibault F, Muller S, et al. Dual-energy
contrast-enhanced digital mammography: initial clinical
results. Eur Radiol 2011;21(3):565–574.
2. Lewin JM, Isaacs PK, Vance V, Larke FJ. Dual-energy
contrast-enhanced digital subtraction mammography:
feasibility. Radiology 2003;229(1):261–268.
radiographics.rsna.org
3. Kachelmeyer S, Blonski D. FDA 510K Summary Hologic
CESM. Vol 510. 2013. https://www.accessdata.fda.gov/
cdrh_docs/pdf12/K123873.pdf. Accessed March 17, 2019.
4. Lalji UC, Jeukens CRLPN, Houben I, et al. Evaluation
of low-energy contrast-enhanced spectral mammography
images by comparing them to full-field digital mammog-
raphy using EUREF image quality criteria. Eur Radiol
2015;25(10):2813–2820.
5. Francescone MA, Jochelson MS, Dershaw DD, et al.
Low energy mammogram obtained in contrast-enhanced
digital mammography (CEDM) is comparable to routine
full-field digital mammography (FFDM). Eur J Radiol
2014;83(8):1350–1355.
6. Dromain C, Balleyguier C, Adler G, Garbay JR, Delaloge
S. Contrast-enhanced digital mammography. Eur J Radiol
2009;69(1):34–42.
7. Jeukens CR, Lalji UC, Meijer E, et al. Radiation exposure
of contrast-enhanced spectral mammography compared
with full-field digital mammography. Invest Radiol
2014;49(10):659–665.
8. Bhimani C, Matta D, Roth RG, et al. Contrast-enhanced
Spectral Mammography: Technique, Indications, and
Clinical Applications. Acad Radiol 2017;24(1):84–88.
9. Jong RA, Yaffe MJ, Skarpathiotakis M, et al. Contrast-
enhanced digital mammography: initial clinical experience.
Radiology 2003;228(3):842–850.
10. Knogler T, Homolka P, Hoernig M, et al. Application of
BI-RADS descriptors in contrast-enhanced dual-energy
mammography: comparison with MRI. Breast Care (Basel)
2017;12(4):212–216.
11. Kamal RM, Helal MH, Mansour SM, et al. Can we apply
the MRI BI-RADS lexicon morphology descriptors on
contrast-enhanced spectral mammography? Br J Radiol
2016;89(1064):20160157.
12. James JR, Pavlicek W, Hanson JA, Boltz TF, Patel BK. Breast
radiation dose with CESM compared with 2D FFDM and
3D tomosynthesis mammography. AJR Am J Roentgenol
2017;208(2):362–372.
13. Patel BK, Lobbes MBI, Lewin J. Contrast Enhanced Spec-
tral Mammography: A Review. Semin Ultrasound CT MR
2018;39(1):70–79.
14. Phillips J, Mihai G, Hassonjee SE, et al. Comparative dose
of contrast-enhanced spectral mammography (CESM),
digital mammography, and digital breast tomosynthesis.
AJR Am J Roentgenol 2018;211(4):839–846.
15. Lebron-Zapata L, Jochelson MS. Overview of Breast
Cancer Screening and Diagnosis. PET Clin 2018;13(3):
301–323.
16. Durand MA, Wang S, Hooley RJ, Raghu M, Philpotts LE.
Tomosynthesis-detected architectural distortion: manage-
ment algorithm with radiologic-pathologic correlation.
RadioGraphics 2016;36(2):311–321.
17. Chesebro AL, Winkler NS, Birdwell RL, Giess CS. De-
veloping asymmetries at mammography: a multimodality
approach to assessment and management. RadioGraphics
2016;36(2):322–334.
18. Lehman CD, Lee AY, Lee CI. Imaging management
of palpable breast abnormalities. AJR Am J Roentgenol
2014;203(5):1142–1153.
19. Houben IPL, Van de Voorde P, Jeukens CRLPN, et al.
Contrast-enhanced spectral mammography as work-up
tool in patients recalled from breast cancer screening has
low risks and might hold clinical benefits. Eur J Radiol
2017;94:31–37.
20. Lobbes MBI, Smidt ML, Houwers J, Tjan-Heijnen VC,
Wildberger JE. Contrast enhanced mammography: tech-
niques, current results, and potential indications. Clin Radiol
2013;68(9):935–944.
21. Lobbes MBI, Lalji U, Houwers J, et al. Contrast-enhanced
spectral mammography in patients referred from the breast
cancer screening programme. Eur Radiol 2014;24(7):
1668–1676.
22. Lalji UC, Houben IPL, Prevos R, et al. Contrast-enhanced
spectral mammography in recalls from the Dutch breast
cancer screening program: validation of results in a large
multireader, multicase study. Eur Radiol 2016;26(12):
4371–4379.
RG • Volume 39 Number 7
23. Patel BK, Naylor ME, Kosiorek HE, et al. Clinical utility
of contrast-enhanced spectral mammography as an adjunct
for tomosynthesis-detected architectural distortion. Clin
Imaging 2017;46:44–52.
24. Tardivel AM, Balleyguier C, Dunant A, et al. Added
Value of Contrast-Enhanced Spectral Mammography in
Postscreening Assessment. Breast J 2016;22(5):520–528.
25. Cheung YC, Juan YH, Lin YC, et al. Dual-energy contrast-
enhanced spectral mammography: Enhancement analysis
on BI-RADS 4 non-mass microcalcifications in Screened
Women. PLoS One 2016;11(9):e0162740.
26. Houben IP, Vanwetswinkel S, Kalia V, et al. Contrast-
enhanced spectral mammography in the evaluation of
breast suspicious calcifications: diagnostic accuracy and
impact on surgical management. Acta Radiol 2019;60(9):
1110–1117.
27. Tennant SL, James JJ, Cornford EJ, et al. Contrast-enhanced
spectral mammography improves diagnostic accuracy in the
symptomatic setting. Clin Radiol 2016;71(11):1148–1155.
28. Richter V, Hatterman V, Preibsch H, et al. Contrast-
enhanced spectral mammography in patients with MRI
contraindications. Acta Radiol 2018;59(7):798–805.
29. Patel BK, Garza SA, Eversman S, Lopez-Alvarez Y, Kosiorek
H, Pockaj BA. Assessing tumor extent on contrast-enhanced
spectral mammography versus full-field digital mammog-
raphy and ultrasound. Clin Imaging 2017;46:78–84.
30. Luczyńska E, Heinze S, Adamczyk A, Ryś J, Mituś JW,
Hendrick E. Comparison of the Mammography, Contrast-
Enhanced Spectral Mammography and Ultrasonography
in a Group of 116 patients. Anticancer Res 2016;36(8):
4359–4366.
31. Knutzen AM, Gisvold JJ. Likelihood of malignant disease for
various categories of mammographically detected, nonpal-
pable breast lesions. Mayo Clin Proc 1993;68(5):454–460.
32. Shaheen R, Schimmelpenninck CA, Stoddart L, Raymond
H, Slanetz PJ. Spectrum of diseases presenting as architec-
tural distortion on mammography: multimodality radiologic
imaging with pathologic correlation. Semin Ultrasound CT
MR 2011;32(4):351–362.
33. Baker JA, Rosen EL, Lo JY, Gimenez EI, Walsh R, Soo
MS. Computer-aided detection (CAD) in screening mam-
mography: sensitivity of commercial CAD systems for
detecting architectural distortion. AJR Am J Roentgenol
2003;181(4):1083–1088.
34. Bahl M, Baker JA, Kinsey EN, Ghate SV. Architectural
distortion on mammography: correlation with pathologic
outcomes and predictors of malignancy. AJR Am J Roent-
genol 2015;205(6):1339–1345.
35. Rangayyan RM, Banik S, Desautels JEL. Computer-aided
detection of architectural distortion in prior mammograms
of interval cancer. J Digit Imaging 2010;23(5):611–631.
36. Si L, Zhai R, Liu X, Yang K, Wang L, Jiang T. MRI in
the differential diagnosis of primary architectural distor-
tion detected by mammography. Diagn Interv Radiol
2016;22(2):141–150.
37. Liberman L, Abramson AF, Squires FB, Glassman JR,
Morris EA, Dershaw DD. The breast imaging reporting
and data system: positive predictive value of mammographic
features and final assessment categories. AJR Am J Roent-
genol 1998;171(1):35–40.
38. Orel SG, Kay N, Reynolds C, Sullivan DC. BI-RADS
categorization as a predictor of malignancy. Radiology
1999;211(3):845–850.
39. Burnside ES, Ochsner JE, Fowler KJ, Fine JP, Rubin DL,
Sisney GA. Use of microcalcification descriptors in BI-
RADS 4th edition to stratify risk of malignancy. Radiology
2007;242(2):388–395.
40. Willett A, Michell M, Lee M. Best practice diagnostic
guidelines for patients presenting with breast symptoms.
London, England: Association of Breast Surgery, 2010;
1–60. https://associationofbreastsurgery.org.uk/media/1416/
best-practice-diagnostic-guidelines-for-patients-presenting-
with-breast-symptoms.pdf. Accessed March 17, 2019.
41. Association of Breast Surgery @ BASO, Royal College
of Surgeons of England. Guidelines for the Manage-
ment of Symptomatic Breast Disease. Eur J Surg Oncol
2005;31(Suppl 1):1–21.
Ghaderi et al 1919
42. Peters NHGM, van Esser S, van den Bosch MAAJ, et al.
Preoperative MRI and surgical management in patients
with nonpalpable breast cancer: the MONET - randomised
controlled trial. Eur J Cancer 2011;47(6):879–886.
43. Hwang ES, Hyslop T, Lynch T, et al. The COMET (Com-
parison of Operative versus Monitoring and Endocrine
Therapy) trial: a phase III randomised controlled clinical
trial for low-risk ductal carcinoma in situ (DCIS). BMJ
Open 2019;9(3):e026797.
44. Pilewskie M, King TA. Magnetic resonance imaging in
patients with newly diagnosed breast cancer: a review of
the literature. Cancer 2014;120(14):2080–2089.
45. Jochelson MS, Dershaw DD, Sung JS, et al. Bilateral contrast-
enhanced dual-energy digital mammography: feasibility
and comparison with conventional digital mammography
and MR imaging in women with known breast carcinoma.
Radiology 2013;266(3):743–751.
46. Fallenberg EM, Dromain C, Diekmann F, et al. Contrast-
enhanced spectral mammography versus MRI: Initial results
in the detection of breast cancer and assessment of tumour
size. Eur Radiol 2014;24(1):256–264.
47. Lee-Felker SA, Tekchandani L, Thomas M, et al. Newly
diagnosed breast cancer: Comparison of contrast-enhanced
spectral mammography and breast MR imaging in the evalu-
ation of extent of disease. Radiology 2017;285(2):389–400.
48. Iotti V, Ravaioli S, Vacondio R, et al. Contrast-enhanced
spectral mammography in neoadjuvant chemotherapy
monitoring: a comparison with breast magnetic resonance
imaging. Breast Cancer Res 2017;19(1):106.
49. Barra FR, Sobrinho AB, Barra RR, et al. Contrast-Enhanced
Mammography (CEM) for Detecting Residual Disease
after Neoadjuvant Chemotherapy: A Comparison with
Breast Magnetic Resonance Imaging (MRI). BioMed Res
Int 2018;2018:8531916.
50. Patel BK, Hilal T, Covington M, et al. Contrast-enhanced
spectral mammography is comparable to MRI in the as-
sessment of residual breast cancer following neoadjuvant
systemic therapy. Ann Surg Oncol 2018;25(5):1350–1356.
51. Patel BK, Davis J, Ferraro C, et al. Value Added of Preopera-
tive Contrast-Enhanced Digital Mammography in Patients
With Invasive Lobular Carcinoma of the Breast. Clin Breast
Cancer 2018;18(6):e1339–e1345.
52.Rosen EL, Blackwell KL, Baker JA, et al. Accuracy of MRI in
the detection of residual breast cancer after neoadjuvant che-
motherapy. AJR Am J Roentgenol 2003;181(5):1275–1282.
53. Marinovich ML, Macaskill P, Irwig L, et al. Agreement
between MRI and pathologic breast tumor size after neo-
adjuvant chemotherapy, and comparison with alternative
tests: individual patient data meta-analysis. BMC Cancer
2015;15(1):662.
54. Lobbes MBI, Prevos R, Smidt M, et al. The role of magnetic
resonance imaging in assessing residual disease and patho-
logic complete response in breast cancer patients receiving
neoadjuvant chemotherapy: a systematic review. Insights
Imaging 2013;4(2):163–175.
55. Elmore JG. Review: Mammography screening reduces breast
cancer mortality in women at average risk. Ann Intern Med
2016;164(6):JC26.
56. Berry DA, Cronin KA, Plevritis SK, et al. Effect of screen-
ing and adjuvant therapy on mortality from breast cancer.
N Engl J Med 2005;353(17):1784–1792.
57. Oeffinger KC, Fontham ET, Etzioni R, et al. Breast Can-
cer Screening for Women at Average Risk: 2015 Guide-
line Update From the American Cancer Society. JAMA
2015;314(15):1599–1614.
58. Carney PA, Miglioretti DL, Yankaskas BC, et al. Individual
and combined effects of age, breast density, and hormone
replacement therapy use on the accuracy of screening mam-
mography. Ann Intern Med 2003;138(3):168–175.
59. Ma L, Fishell E, Wright B, Hanna W, Allan S, Boyd NF.
Case-control study of factors associated with failure to
detect breast cancer by mammography. J Natl Cancer Inst
1992;84(10):781–785.
60. Mandelson MT, Oestreicher N, Porter PL, et al. Breast den-
sity as a predictor of mammographic detection: comparison
of interval- and screen-detected cancers. J Natl Cancer Inst
2000;92(13):1081–1087.
1920 November-December 2019
61. Mainiero MB, Moy L, Baron P, et al. ACR Appropriate-
ness Criteria Breast Cancer Screening. American College of
Radiology. https://acsearch.acr.org/docs/70910/Narrative/.
Accessed March 18, 2019.
62. Weigert J, Steenbergen S. The connecticut experiment: the
role of ultrasound in the screening of women with dense
breasts. Breast J 2012;18(6):517–522.
63. Melnikow J, Fenton JJ, Whitlock EP, et al. Supplemental
Screening for Breast Cancer in Women With Dense Breasts:
A Systematic Review for the U.S. Preventive Services Task
Force. Ann Intern Med 2016;164(4):268–278.
64. Jochelson MS, Pinker K, Dershaw DD, et al. Comparison
of screening CEDM and MRI for women at increased risk
for breast cancer: A pilot study. Eur J Radiol 2017;97:
37–43.
65. Saslow D, Boetes C, Burke W, et al. American Cancer Society
guidelines for breast screening with MRI as an adjunct to
mammography. CA Cancer J Clin 2007;57(2):75–89.
66. Sorin V, Yagil Y, Yosepovich A, et al. Contrast-Enhanced
Spectral Mammography in Women With Intermediate Breast
This journal-based SA-CME activity has been approved for AMA PRA Category 1 Credit . See rsna.org/learning-center-rg.
radiographics.rsna.org
Cancer Risk and Dense Breasts. AJR Am J Roentgenol
2018;211(5):W267–W274.
67. U.S. National Library of Medicine. ClinicalTrials.gov [data-
base online]. Bethesda, MD: National Library of Medicine.
https://clinicaltrials.gov/ct2/home. Accessed March 17, 2019.
68. Perry H, Phillips J, Dialani V, et al. Contrast-Enhanced
Mammography: A Systematic Guide to Interpretation and
Reporting. AJR Am J Roentgenol 2019;212(1):222–231.
69. Dromain C, Thibault F, Diekmann F, et al. Dual-energy
contrast-enhanced digital mammography: initial clinical
results of a multireader, multicase study. Breast Cancer
Res 2012;14(3):R94.
70. Bhimani C, Li L, Liao L, Roth RG, Tinney E, Germaine
P. Contrast-enhanced spectral mammography: modality-
specific artifacts and other factors which may interfere with
image quality. Acad Radiol 2017;24(1):89–94.
71. Mori M, Akashi-Tanaka S, Suzuki S, et al. Diagnostic
accuracy of contrast-enhanced spectral mammography in
comparison to conventional full-field digital mammography
in a population of women with dense breasts. Breast Cancer
2017;24(1):104–110.
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