Navigating contrast-enhanced digital mammography

APPLIED RADIOLOGY © n 21 March 2017 Contrast-enhanced digital mammography (CEDM) takes sequential images at high and low energies that are used to construct a digitally subtracted image, highlighting areas of contrast medium enhancement. The low-energy image is of the same diagnostic quality as standard 2-dimensional mammography.1 However, the digitally subtracted image is unlike those that mammographers are accustomed to interpreting and its use initially may be overwhelming. With this paper, the authors aim to increase understanding of normal anatomic and non-anatomic structures encountered on subtracted images and increase awareness of commonly encountered artifacts. In addition, the authors outline a standardized reporting system to help further streamline interpretation and reporting of CEDM images.


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ontrast-enhanced digital mammography (CEDM) takes sequential images at high and low energies that are used to construct a digitally subtracted image, highlighting areas of contrast medium enhancement.The low-energy image is of the same diagnostic quality as standard 2-dimensional mammography. 1 However, the digitally subtracted image is unlike those that mammographers are accustomed to interpreting and its use initially may be overwhelming.
With this paper, the authors aim to increase understanding of normal anatomic and non-anatomic structures encountered on subtracted images and increase awareness of commonly encountered artifacts.In addition, the authors outline a standardized reporting system to help further streamline interpretation and reporting of CEDM images.

What is CEDM?
CEDM is a quick, well-tolerated, relatively low-cost breast imaging technique that combines standard full-field digital mammography (FFDM) with an intravenous, low-osmolar, iodinated contrast medium.After administration of contrast material in the antecubital vein, 2 sequential images are acquired at high and low energies.The low-energy image (26-32 kVp) yields soft tissue and calcification detail similar to standard FFDM; 2 the high-energy image (45-49 kVp) is specifically selected to be greater than the K-edge of iodine (33.2 keV). 3These 2 images are then digitally subtracted from each other to produce a single contrast medium-enhanced image that highlights areas of neovascularity, similar to magnetic resonance imaging (MRI).

CEDM Appearance of anatomic, non-anatomic structures
Two fellowship-trained breast imagers (B.K.P. and V.J.P.) performed a retrospective review of 110 CEDM cases conducted at our institution to evaluate the appearance of various anatomic and non-anatomic structures and artifacts in each subtracted image.

Anatomic structures
Skin-The appearance of the skin on a CEDM-subtracted image can be variable (Figure 1).Predominately, the skin

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is nonenhancing or shows a thin line of enhancement.Rarely, it shows artifactual thickening not seen on the standard 2-dimensional image.This artifact is thought to be related to current detector limitations in regard to high-energy X-ray doses.Given the variable appearance of the skin on subtraction images, any findings should be correlated with the low-energy image.Patient presentation of skin enhancement and thickening on the subtraction images can differ and should be evaluated on the standard low-energy mammography image.
Nipple-Peripheral superficial enhancement of the nipple is commonly seen on MRI, attributable to the rich blood supply of the nipple areolar complex. 11,12 onversely, the subtraction image on CEDM can yield various appearances of the nipple.The most common is that of no enhancement.Occasionally, a thin dark line is seen at the base of the nonenhancing nipple, which may give the illusion of a thin rim of peripheral enhancement.A less common appearance is minimal enhancement at the base of the nipple.In patients with flat nipples, a prominent thin rim of enhancement may be seen contiguous with the adjacent skin.The differences in nipple enhancement between MRI and CEDM are likely secondary to a combination of the differing contrast agents used and the compression applied with CEDM.
As with typical FFDM, every effort should be made to place the nipple in profile.When the nipple is not in profile (Figure 2A) the nipple may be mistaken for an enhancing mass within the anterior breast.By comparison, an image showing the nipple in profile allows for better detection of subareolar masses and helps prevent the nipple from being mistaken for a mass (Figure 2B).When limitations prevent the nipple from being placed into profile, a BB marker should be used to denote its location.
Pectoralis muscle-The majority of pectoralis muscles do not show enhancement on subtracted images.However,

FIGURE 5. Mole enhancement. (A) Left craniocaudal subtraction image shows a small oval area of enhancement (arrow) in the medial, posterior breast. On further examination of the low-energy image, a rim of air appears to surround an oval density in this area, suggestive of a skin lesion. (B) Repeat craniocaudal 2-dimensional image of the left breast taken after a mole marker was placed, confirming that the oval enhancing lesion corresponded to a cherry angioma.
A B

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a small percentage (11%) of subtracted images demonstrate pectoral outlining, which mimics faint enhancement (Figure 3).Pectoral outlining is an artifact attributed to patient motion and does not indicate inflammation or pathologic change within the muscle itself.Therefore, misregistration artifact, similar to that seen in MRI with patient motion, may be present when pectoral outlining is seen.
Vessels-Vessels enhance more prominently and wash out on the first view than on subsequent views, similar to results of MRI (Figure 4).Also similar to MRI, when breast cancer is present, neoangiogenesis results in an increased number of enhancing vessels supplying the affected breast. 13mph nodes-Although lymph nodes are most commonly found in the axilla, intramammary lymph nodes can be seen in up to 47% of breasts. 14hese findings are typically seen in the upper outer quadrants.Normal axillary and intramammary lymph nodes have characteristically benign appearances, including circumscribed margins; oval, round, or reniform shape; a fatty hilum; and proximity to a vessel.
Lymph nodes show various degrees of enhancement on CEDM images whereby the enhancement is not necessarily indicative of pathologic characteristics.Similar to MRI, normal lymph nodes may enhance avidly, whereas abnormal lymph nodes may not enhance at all. 15Evaluation of lymph node size and morphologic characteristics, as well as assessment of stability over time, is essential.Abnormal lymph nodes may show a more rounded appearance because the typical nonenhancing hilum becomes replaced by tumor.The enhancement pattern usually becomes more heterogeneous with increased lymph node size and may be secondary to metastatic implants or areas of necrosis.and mimic cancers.However, in our experience, typical moles and seborrheic keratoses do not enhance.An example of the importance of placing mole markers on potentially enhancing skin lesions is shown in Figure 5.

Non-anatomic structures
Clips-Placing clips after breast biopsy is common.Highly attenuated objects, such as clips and calcifications, can show a variable appearance.This variation depends on a demetal function that is intrinsic to CEDM software (Hologic, Inc).When the demetal function is off, clips and calcifications appear dark; in the enabled position, these structures appear bright.Currently, because artifacts can be caused by the demetal function, the default within the Hologic system is the off position.Future Hologic software upgrades are expected to fix these artifacts and allow the demetal function to remain on, giving clips and calcifications the bright appearance of which most mammographers are accustomed.A third type, that of alternating bright and dark appearance, gives a zebra artifact and is secondary to motion-causing misregistration (Figure 6).Misregistration is commonly seen.
Calcifications-Because the demetal function is defaulted to the off position, most calcifications are dark on subtracted images.However, microcalcifications (<0.5 mm) seen on the low-energy image appear to be occult, without a dark (Figure 7) or bright appearance.In some instances where the demetaling function was inadvertently turned on between views, calcifications appeared dark on one view but bright on the other view.Larger calcifications may not appear uniformly dark when misregistration is present (Figure 6, right panel).For these reasons, it is important to use the low-energy images to evaluate breasts for microcalcifications.A B are acquired one immediately after another, the potential for motion exists and can cause misregistration artifact.Misregistration between the two images results in adjacent dark and bright areas, causing so-called zebra artifact.This artifact has been seen related to clips, vessels, and calcifications (Figure 6).

Air gap and other high-attenuation ar-
tifacts-In our experience with CEDM, the most common artifact results from an air gap.Partial contact between the skin and the detector or compression paddle creates a dark artifact that takes the configuration of an area of incomplete contact.Imperfect contact may result from improper compression, skin dimpling, or skin folds (Figure 8).Similar to clips and calcifications, a dark halo appearance can be seen around other high-attenuation items, such as mole markers, scar markers, BB markers, pacemakers,

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and chest ports secondary to an imageprocessing artifact.
Contrast contamination-Contrast material external to the patient, such as on the skin, the paddle, or the detector, can cause superimposed bright artifacts.In a CEDM examination, caution is critical to prevent contamination.Figure 9 shows a case that was initially presumed to have multiple, bilateral areas of abnormal enhancement.On further review of the images, the areas of supposed enhancement showed a mirror image configuration suggestive of contrast contamination of the paddle or detector, or both.

CEDM Evaluation and reporting
No reporting method for high-energy subtracted CEDM images has been established.Our institution has adopted a standardized reporting system through the Breast Imaging-Reporting and Data System (BI-RADS) lexicon, similar to those already published for mammography, ultrasonography and MRI. 16he low-energy image is interpreted as a standard mammography scan.Breast density (ie, almost entirely fat, scattered areas of fibroglandular densities, heterogeneously dense or extremely dense) 16 is included in the report, in addition to pertinent imaging findings.
The next section in the CEDM report describes the findings on the subtracted image.The background parenchymal enhancement (BPE) is described (similar to BI-RADS MRI BPE) in 1 of 4 categories: minimal, mild, moderate, and marked (Table and Figure 10).Minimal BPE is defined as enhancement of 0% to 24%; mild as enhancement of 25% to 49%; moderate as enhancement of 50% to 74%; and marked as diffuse generalized enhancement of 75% to 100%.
Similar to MRI, increased BPE may result in increased call-back rates.BPE is graded as symmetrical or asymmetrical between the breasts and, similar to MRI, asymmetrical enhancement can be seen because of benign and malignant causes, including those in patients with a history of radiation treatment or extensive pathologic manifestation in one breast (Figure 11). 17indings described on low-energy mammography, such as calcifications, asymmetries, and masses, are further evaluated for any corresponding areas of abnormal enhancement on the subtracted images.Areas of abnormal enhancement are described further as mass or non-mass enhancement.
The term mass enhancement is used to describe a space-occupying lesion with mass-like borders; the term non-mass enhancement describes an asymmetry without clear borders. 16etermination of mass or non-mass enhancement is best made through interrogation of the low-energy image in conjunction with the subtracted image, because the shape and margins are often better delineated on the low-energy image.Both mass and non-mass enhancements are described by their quadrant location and given a 3-dimensional measurement.
In addition, areas of mass enhancement are described by their enhancement pattern, including homogeneous, heterogeneous, or rim enhancing.The degree of mass or non-mass enhancement is documented using 1 of 4 categories: none, mild, moderate, or marked.Finally, pertinent findings regarding structures outside the breast parenchyma (eg, axilla, skin, nipple) are reported (Figure 12).

Conclusion
CEDM is a novel modality that continues to show improved sensitivity A B

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in breast cancer detection compared with standard mammography.Studies reported in the literature continue to measure the performance of CEDM compared with standard mammography, MRI, and other breast-imaging modalities.We provide the first guide, to our knowledge, for radiologists and clinicians in interpreting the contrast-enhanced subtracted images.In providing case examples of the encountered anatomic and non-anatomic artifacts in our practice, we hope to ease the transition and help troubleshoot questions that may arise during the initial interpretation.A BI-RADS-based reporting structure is offered to enable consistent, quality-driven reports for clinicians.
Lewis, DO; Bhavika K. Patel, MD; and Victor J. Pizzitola, MD Dr. Lewis, Dr. Patel and Dr. Pizzitola are with the Department of Radiology, Mayo Clinic, Scottsdale, AZ.

FIGURE 1 .
FIGURE 1. Skin appearance.(A) Mediolateral oblique subtraction image illustrates a thin line of skin enhancement, which is a common benign finding.The low-energy (B) and subtraction craniocaudal (C) views show pathologic skin thickening and enhancement of a biopsy-proven breast carcinoma.

FIGURE 2 .
FIGURE 2. Nipple out of profile.(A) The subtraction view shows a mass with corresponding enhancement in the anterior right breast.This was thought to possibly represent an out-ofprofile nipple, mimicking an enhancing mass.(B) Craniocaudal view with the nipple in profile, confirming no retroareolar mass.

FIGURE 4 .
FIGURE 4. Vessels.Similar to magnetic resonance imaging, subtracted images show enhanced vessels.Subtraction mediolateral oblique images show typical enhancing vessels on the right.The left image shows a breast with an enhancing biopsy-proven carcinoma with associated angiogenesis.Of note, a prominent enhancing axillary lymph node is also seen.

FIGURE 6 .
FIGURE 6. Misregistration artifact.Subtraction images from two patients show misregistration artifact.Surgical clips seen on the subtraction image of the left panel show side-by-side bright and dark lines, causing so-called zebra artifact from the misregistration.Zebra artifact is present in the right panel as well, on the subtraction image of a dystrophic calcification.

FIGURE 7 .
FIGURE 7. Calcifications.A round calcification (arrow) shows the expected dark appearance on subtraction image.

FIGURE 10 .FIGURE 11 .
FIGURE 10. Background enhancement.Contrast-medium enhanced digital mammography reports should include the degree and symmetry of background enhancement.Subtraction images from three patients show minimal (A), mild (B), moderate (C), and marked (D) background parenchymal enhancement.

FIGURE 12 .
FIGURE 12. Lesion enhancement.Contrast-enhanced digital mammography reports should include the degree of lesion enhancement.Subtraction images from two different patients show various degrees of enhancement.(A) The anterior lesion (yellow arrow) shows mild enhancement and corresponds to a biopsy-proven hamartoma.The posterior lesion (red arrow) shows moderate enhancement and was a biopsy-proven invasive ductal carcinoma.(B) Marked enhancement can be seen in the large biopsy-proven invasive ductal carcinoma of the right upper breast.