Breast ImagingFree Access

Contrast-enhanced Mammography: Current Applications and Future Directions

Tejas S. Mehta

Kimeya F. Ghaderi

Published Online:Nov 7 2019https://doi.org/10.1148/rg.2019190079

Abstract

Contrast-enhanced mammography (CEM) is a developing modality 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 simultaneously. 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

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.

Introduction

Contrast-enhanced mammography (CEM) is an emerging modality 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 localize 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 confidence.

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).

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 diagnostic imaging, such as spot compression or magnification views, can be performed after the initial four views have been obtained. The additional diagnostic imaging can be performed with or without a dual-energy technique. However, if dual-energy imaging is desired, it must be performed in a 10-minute window after contrast material administration to depict contrast agent uptake in the breast before it washes out (Fig 1) (6–9).

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

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 identified 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 management 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 used for recombined image evaluation (10,11). A CEM examination is billed as diagnostic mammography 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 examination exposes the patient to a radiation dose 20%–80% higher than that of standard mammography, a recent study demonstrated that the dose of radiation from CEM is within the range of radiation doses patients receive for other common mammographic examinations (7,12–14).

Abnormalities Seen at Screening

Abnormalities identified at screening mammography include masses, focal asymmetry, asymmetry, architectural distortion (AD), and microcalcifications. 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 diagnostic 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, imaging is performed in four views. Any additional diagnostic imaging can be performed immediately after the standard four projections, with or without the dual-energy technique.

Studies report that CEM has high sensitivity for delineation of malignant findings, particularly 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 retrospective studies by Lobbes et al (20,21) have described 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 surrogate for conventional mammography. The study found that compared with conventional mammography, CEM had a sensitivity of 97% and a specificity of 70% (22). Additional performance characteristics are listed in Table 1.

**Table 1: Studies Evaluating CEM in Common Diagnostic Scenarios**

There have been two studies comparing CEM to mammography and US in the setting of known breast cancer. However, to our knowledge there are no current studies directly 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 evaluating breast masses is to help identify any additional abnormalities in the ipsilateral or contralateral breast when a suspicious imaging finding is present. This is discussed further in the section addressing disease extent (29,30) (Fig 2).

Figure 2a. Grade 1 invasive carcinoma in a 47-year-old woman recalled from screening for additional evaluation of a suspicious mass. **(a)** MLO low-energy mammogram shows a spiculated mass (circle). **(b)** MLO recombined mammogram demonstrates enhancement of the mass only (circle), confirming that the malignancy is limited to this area. **(c)** US image correlate shows a 1.0-cm hypoechoic irregular mass. US-guided biopsy revealed grade 1 invasive carcinoma with predominantly lobular features.

Figure 2b. Grade 1 invasive carcinoma in a 47-year-old woman recalled from screening for additional evaluation of a suspicious mass. **(a)** MLO low-energy mammogram shows a spiculated mass (circle). **(b)** MLO recombined mammogram demonstrates enhancement of the mass only (circle), confirming that the malignancy is limited to this area. **(c)** US image correlate shows a 1.0-cm hypoechoic irregular mass. US-guided biopsy revealed grade 1 invasive carcinoma with predominantly lobular features.

Figure 2c. Grade 1 invasive carcinoma in a 47-year-old woman recalled from screening for additional evaluation of a suspicious mass. **(a)** MLO low-energy mammogram shows a spiculated mass (circle). **(b)** MLO recombined mammogram demonstrates enhancement of the mass only (circle), confirming that the malignancy is limited to this area. **(c)** US image correlate shows a 1.0-cm hypoechoic irregular mass. US-guided biopsy revealed grade 1 invasive carcinoma with predominantly lobular features.

Architectural Distortion

AD can have benign and malignant causes, which can be difficult to distinguish at diagnostic mammography. 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 tomosynthesis 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 mammography 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 recommended.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 background enhancement. The study demonstrated that CEM has a high sensitivity and negative predictive value (NPV) in patients with AD (23). The data suggest that the absence of enhancement associated with AD in patients with minimal background enhancement is a strong indication of benignity (Fig 3).

Figure 3a. 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 3b. 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 3c. 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 3d. 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.

CEM is useful to help evaluate AD that appears subtle or indeterminate at screening or at diagnostic tomosynthesis. CEM may also be used when AD is seen on an image and the imaging features are not reproducible with certainty. In these scenarios, the absence of associated enhancement can help prevent unnecessary follow-up imaging examinations or biopsy.

If AD is confirmed at diagnostic 2D mammography, tomosynthesis, or low-energy CEM imaging, biopsy should be performed regardless of enhancement shown at imaging until additional research in this area is available to validate the earlier study.

Microcalcifications

Patients are commonly recalled after screening because microcalcifications were found on images. Diagnostic management relies on risk stratification on the basis of BI-RADS descriptors (37-39). Microcalcifications that are considered suspicious should be biopsied, and those that are thought to be probably benign may be monitored with surveillance imaging.

Microcalcifications are well depicted at CEM. CEM demonstrates the morphology of microcalcifications on low-energy images and shows any associated enhancement on recombined images (Fig 4).

Figure 4a. 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 microcalcifications 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.

Figure 4b. 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 microcalcifications 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.

Figure 4c. 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 microcalcifications 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.

A few studies have evaluated the use of CEM in the setting of microcalcifications (Table 1) (24–26). In 2016, Tardivel et al (24) published a review of 195 women with suspicious imaging findings at mammography or US. Twelve (6%) suspicious microcalcifications were found. Four of these had no enhancement, but biopsy revealed the presence of ductal carcinoma in situ (DCIS) and invasive lobular carcinoma (ILC). 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 enhancement at imaging. They also demonstrated that CEM did not impact surgical decision making.

Overall, these studies suggest that the presence of enhancement on images suggests malignancy, but the absence of enhancement cannot exclude it.

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 (Fig 5).

Additional evaluation of CEM in this application is warranted.

Figure 5a. Right breast microcalcifications in a 44-year-old woman recalled from screening for additional evaluation. **(a)** Mediolateral magnified diagnostic mammogram shows suspicious grouped right breast microcalcifications in the upper breast at an anterior depth. **(b)** MLO low-energy mammogram demonstrates microcalcifications (circle). **(c)** MLO recombined mammogram demonstrates mild background enhancement with no associated 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.

Figure 5b. Right breast microcalcifications in a 44-year-old woman recalled from screening for additional evaluation. **(a)** Mediolateral magnified diagnostic mammogram shows suspicious grouped right breast microcalcifications in the upper breast at an anterior depth. **(b)** MLO low-energy mammogram demonstrates microcalcifications (circle). **(c)** MLO recombined mammogram demonstrates mild background enhancement with no associated 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.

Figure 5c. Right breast microcalcifications in a 44-year-old woman recalled from screening for additional evaluation. **(a)** Mediolateral magnified diagnostic mammogram shows suspicious grouped right breast microcalcifications in the upper breast at an anterior depth. **(b)** MLO low-energy mammogram demonstrates microcalcifications (circle). **(c)** MLO recombined mammogram demonstrates mild background enhancement with no associated 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.

Symptomatic Breast Disease

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).

Figure 6a. Grade 2 ILC in a 50-year-old woman who presented with a palpable left breast lump. MLO low-energy **(a)** and recombined **(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.

Figure 6b. Grade 2 ILC in a 50-year-old woman who presented with a palpable left breast lump. MLO low-energy **(a)** and recombined **(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.

Figure 6c. Grade 2 ILC in a 50-year-old woman who presented with a palpable left breast lump. MLO low-energy **(a)** and recombined **(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.

Tennant et al (27) performed a reader review of 100 consecutive CEM examinations performed 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 improved 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 mammography or tomosynthesis with US, which is the more common practice for evaluating patients with breast symptoms. It is unclear if CEM improves diagnostic performance for lesion visualization and characterization compared with that of mammography and US. However, studies have shown that CEM demonstrates improved performance 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 suspicious 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 performed. 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 additional sites of disease in the contralateral breast. Data on the value of supplemental imaging are controversial, including that of MRI. Current imaging practices vary based on philosophy, as well as insurance coverage and access to advanced 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 (Table 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 overestimation of tumor size by 2.9 mm, and US leads to underestimation of tumor size by 2.8 mm (29).

**Table 2: Studies Evaluating CEM in New or Treated Cancer**

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 demonstrate 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 diagnosed breast cancer.

CEM demonstrates satisfactory 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 mammography equipment. CEM can be a low-cost and more accessible alternative to MRI in the evaluation of disease extent (Fig 7) (51).

Figure 7a. Right breast microcalcifications in a 57-year-old woman recalled from screening for additional evaluation. **(a)** CC screening mammogram and magnified image (inset) 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 mammogram demonstrates an 8-cm area of nonmass enhancement involving the entire outer breast, encompassing the two small groups of microcalcifications (arrow). **(d)** Axial MR subtraction image shows similar nonmass enhancement involving the lateral right breast.

Figure 7b. Right breast microcalcifications in a 57-year-old woman recalled from screening for additional evaluation. **(a)** CC screening mammogram and magnified image (inset) 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 mammogram demonstrates an 8-cm area of nonmass enhancement involving the entire outer breast, encompassing the two small groups of microcalcifications (arrow). **(d)** Axial MR subtraction image shows similar nonmass enhancement involving the lateral right breast.

Figure 7c. Right breast microcalcifications in a 57-year-old woman recalled from screening for additional evaluation. **(a)** CC screening mammogram and magnified image (inset) 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 mammogram demonstrates an 8-cm area of nonmass enhancement involving the entire outer breast, encompassing the two small groups of microcalcifications (arrow). **(d)** Axial MR subtraction image shows similar nonmass enhancement involving the lateral right breast.

Figure 7d. Right breast microcalcifications in a 57-year-old woman recalled from screening for additional evaluation. **(a)** CC screening mammogram and magnified image (inset) 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 mammogram demonstrates an 8-cm area of nonmass enhancement involving the entire outer breast, encompassing the two small groups of microcalcifications (arrow). **(d)** Axial MR subtraction image shows similar nonmass enhancement involving the lateral right breast.

Response to Neoadjuvant Chemotherapy

After neoadjuvant chemotherapy, the imaging evaluation of treatment response and residual disease helps guide surgical management. Current practice involves clinical examination and multiple 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 studies 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 neoadjuvant 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) retrospectively 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 sensitivity 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 locations where MRI is not be readily available.

Figure 8a. 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 8b. 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 8c. 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.

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 retrospective study of 118 patients contraindicated for MRI, who also had known cancer or discordant US-guided biopsy results. The patients underwent digital mammography and CEM, and histologic analysis was performed in 94 of the lesions.

CEM was shown to have a greater diagnostic performance compared with mammography (Table 1) (28). While this study was limited by superimposition, artifacts, and timing challenges, CEM was demonstrated to be a feasible alternative in patients with contraindications to MRI (Fig 9).

Figure 9a. 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.

Figure 9b. 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.

Figure 9c. 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.

Figure 9d. 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.

Given its comparable performance to breast MRI, practices will often choose to first implement 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 mammography reduces breast cancer mortality. However, 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. Current 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. However, 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 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 cancer 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 screening and 2-year follow-up.

**Table 3: Studies Evaluating Future Directions of CEM**

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 conventional 2D mammograms) with images obtained by performing the full CEM examination in 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 suggest that CEM may have a role in breast cancer screening (Fig 10).

More research is being performed to evaluate it for this indication (67).

Figure 10a. DCIS in a 58-year-old woman with a strong family history of breast cancer. MR images were obtained during a routine screening, and contrast-enhanced mammograms were obtained in a research trial. **(a)** CC low-energy mammogram shows no abnormality. **(b)** CC recombined mammogram demonstrates a 4.5-cm area of nonmass enhancement (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 enhancement (dashed rectangle), corresponding to the area seen at CEM. Pathologic analysis of an MRI-guided biopsy specimen revealed DCIS.

Figure 10b. DCIS in a 58-year-old woman with a strong family history of breast cancer. MR images were obtained during a routine screening, and contrast-enhanced mammograms were obtained in a research trial. **(a)** CC low-energy mammogram shows no abnormality. **(b)** CC recombined mammogram demonstrates a 4.5-cm area of nonmass enhancement (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 enhancement (dashed rectangle), corresponding to the area seen at CEM. Pathologic analysis of an MRI-guided biopsy specimen revealed DCIS.

Figure 10c. DCIS in a 58-year-old woman with a strong family history of breast cancer. MR images were obtained during a routine screening, and contrast-enhanced mammograms were obtained in a research trial. **(a)** CC low-energy mammogram shows no abnormality. **(b)** CC recombined mammogram demonstrates a 4.5-cm area of nonmass enhancement (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 enhancement (dashed rectangle), corresponding to the area seen at CEM. Pathologic analysis of an MRI-guided biopsy specimen revealed DCIS.

Challenges

As with any emerging modality, CEM is not without its challenges and limitations (13,68,69). The most significant challenge of CEM relates to the administration of contrast material. Iodinated contrast material is associated with risks of allergic 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 associated 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 performing 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 background enhancement.

Conclusion

CEM is an emerging modality that may provide critical information in a number of clinical scenarios. Today, CEM is most commonly used to evaluate disease extent in patients with contraindications 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 related to the present article: provided second opinions for Advance Medical. Other activities: disclosed no relevant relationships.

Presented as an education exhibit at the 2018 RSNA Annual Meeting.

For this journal-based SA-CME activity, the authors J.P. and P.L. have provided disclosures; all other authors, the editor, and the reviewers have disclosed no relevant relationships.

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Article History

Received: Mar 24 2019
Revision requested: July 29 2019
Revision received: Aug 18 2019
Accepted: Aug 26 2019
Published online: Nov 07 2019
Published in print: Nov 2019

Vol. 39, No. 7

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Abbreviations

Abbreviations:
AD	architectural distortion
BI-RADS	Breast Imaging Reporting and Data System
CC	craniocaudal
CEM	contrast-enhanced mammography
DCIS	ductal carcinoma in situ
ILC	invasive lobular carcinoma
MLO	mediolateral oblique
NPV	negative predictive value
PPV	positive predictive value
2D	two-dimensional

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