Can contrast-enhanced mammography replace dynamic contrast-enhanced MRI in the assessment of sonomammographic indeterminate breast lesions?

Dynamic contrast-enhanced MRI of the breast has been used for several years in the assessment of indeterminate mammographic findings. Contrast-enhanced mammography is a relatively novel imaging technique that has shown comparable sensitivity and specificity to MRI. Contrast-enhanced mammography is a relatively easy feasible study with high sensitivity and low cost. Our aim was to assess the feasibility of replacing dynamic contrast-enhanced (DCE)-MRI by contrast-enhanced mammography in the assessment of sonomammographic indeterminate lesions (BIRADS 3 and 4). The study included 82 patients with 171 breast lesions. They all performed contrast-enhanced mammography and dynamic contrast-enhanced MRI. DCE-MRI sensitivity and NPV were significantly higher than those of contrast-enhanced mammogram (CEM). The overall accuracy of MRI was better than that of CEM; however, no statistically significant difference could be detected. Contrast-enhanced mammography and dynamic contrast-enhanced MRI improved the characterization of breast lesions. CEM showed slightly lower sensitivity and accuracy compared to MRI; however, because of being relatively easy, available, cheap, and acceptable by women, CEM can replace DC-MRI as a problem-solving tool in the characterization of indeterminate breast lesions.


Background
Breast cancer is a major health problem and a leading cause of death among women in Egypt. Early detection of breast cancer aims to reduce morbidity and mortality rates. Mammography has been established as the imaging modality for screening and early detection of breast cancer; however, it is accused of having low sensitivity and specificity in women with dense breasts [1].
Accurate diagnosis and characterization of breast lesions have an essential role in the management and improved prognosis of breast cancer [2,3].
CE-MRI is used nowadays as a problem-solving tool and as an adjunct to sonomammography in women at high risk or those with extremely dense breasts [4].
Dynamic contrast-enhanced (DCE)-MRI allows better characterization of lesions through morphologic and kinematic assessment after administration of contrast material [5].
Lesion characterization by DCE-MRI depends on the difference in vascular supply between normal and neoplastic tissue. Neoplastic tissue demonstrates contrast uptake due to the development of neovascularization [6].
However, MRI is a relatively expensive study that necessitates at least 30 to 40 min to acquire images and is not equally accessible to all women [2]. DCE-MRI is accused of having low specificity and being not recommended in the assessment of microcalcifications [7].
Contrast-enhanced mammography (CEM) is one of the relatively novel imaging modalities. CEM is a relatively easy feasible study with high sensitivity and low cost [2]. It provides low-energy images comparable to mammographic images and post-contrast recombined images to evaluate tumor neovascularity [8,9].
CEM allows better evaluation of calcifications by their visualization on low-energy images combined with enhancement criteria on the contrast-enhanced recombined images [10]. Dual contrast-enhanced mammography is the commonly used technique; this technique lacks kinematic information [8].
Our aim was to assess the feasibility of replacing CE MRI by contrast-enhanced spectral mammography in the assessment of sonomammographic indeterminate breast lesions (BIRADS 3 and 4) in contrast to most of the previous studies which were concerned upon sonomammographic suspicious breast lesions (BIRADS 4 and 5)

Methods
This study included 171 lesions in 82 patients, 20 of them had bilateral breast lesions. Their ages ranged from 29 to 71 years (mean age 49.298 ± 10.75). The study was approved by the ethical committee and informed written consent was taken from all subjects.

Patients with at least a single indeterminate lesion (BIRADS 3 and 4)
Exclusion criteria 1. Patients with a negative mammogram (BIRADS 1) or those with definite benign criteria (BIRADS 2) 2. Contraindication to mammography, e.g., Pregnant women 3. Contraindication to IV contrast, e.g., patients with renal impairment, allergic patients, or those known to have a history of anaphylactic reaction from contrast media 4. Contraindication to MRI, e.g., cardiac pacemaker, aneurysmal clips, and bone growth stimulators

Contrast-enhanced mammography technique
CEM examination was performed using Senographe Essential, GE healthcare full-field digital mammography machine, with sonobright. A one-shot intravenous injection (of 1.5 mL/kg) of non-ionic contrast media was performed. Two minutes after contrast administration, a low-energy (23-32 KVp) and high-energy (45-49 KVp) pair of images were acquired within 20 s of one another in mediolateral oblique (MLO) view and then in craniocaudal (CC) position. Recombined iodine-enhanced images were obtained by the subtraction of low-and high-energy images.
Dynamic contrast-enhanced MRI technique MRI was performed using a Siemens 1.5-T MRI system.
The examination was performed using a bilateral breast surface coil with the patient in the prone position.
The time interval between the two techniques ranged from 1 week to month duration. The kidney function was assessed before each modality.

Image analysis and interpretation of contrast-enhanced mammography and contrast-enhanced MRI
The 2013 MRI BIRADS lexicon was used in the characterization of detected lesions in both CEM and DCE-MRI with BIRADS category given to each lesion. CEM and CE-MRI were assessed for the presence or absence of enhancing lesions. Enhancing lesions were then classified as mass or non-mass. When an enhancing mass lesion was detected, it was further assessed for its margins (circumscribed, not circumscribed irregular, or not circumscribed speculated), degree of enhancement (mild, moderate, and severe), and pattern of internal enhancement (homogenous, heterogeneous, septations, or ring enhancement). When enhancing non-mass lesion was detected, it was further assessed for distribution (focal, linear, segmental, regional, multiregional, or diffuse), pattern of internal enhancement (homogenous, heterogeneous, clustered, and clumped), and degree of enhancement (mild, moderate, and severe).
Low-energy images of CEM were assessed in reference to the mammography 2013 BIRADS lexicon. Nonenhancing lesions on DCE-MRI were assessed in T1, T2, and STIR images.

Statistical analysis
Data were coded and entered using the statistical package SPSS (Statistical Package for the Social Sciences) version 25. Data were summarized using mean, standard deviation, median, minimum, and maximum in quantitative data and using frequency (count) and relative frequency (percentage) for categorical data. For comparing categorical data, chi-square (χ 2 ) test was performed. Correlations between quantitative variables were done using Spearman correlation coefficient. Standard diagnostic indices including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), positive likelihood ratio, negative likelihood ratio, and diagnostic efficacy were calculated.

Results
Our study included 82 cases with 171 breast lesions. The ages ranged from 29 to 71 years with a mean age of 49.298 ± 10.75 (mean ± SD). Upon correlating with the final diagnosis either by histological analysis of postoperative pathology, biopsy samples, fine-needle aspiration cytology (151 lesions were pathologically proved), or close follow up (applied only on 20 lesions that were categorized as Breast Imaging-Reporting and Data System (BIRADS) 2 and showed stationary course for 1 year in a way to confirm their benign nature); 51/171 (29.8%) lesions were benign, while 120/171 (70.2%) were malignant. The different pathological entities within benign and malignant groups were seen in Table 1.
The tumor multiplicity was assessed by CEM and MRI in reference to histopathology. CEM detected 22 additional lesions (sensitivity 85%), while MRI detected 26 additional lesions (sensitivity 100%)

Discussion
Full-field digital mammography is accused of having low sensitivity and specificity especially in the dense breast due to overlapping glandular tissue.
Both CE-MRI and CEM have the advantage of providing morphological and functional information as they depend on neovascularity and angiogenesis of lesions [2].
Dynamic contrast-enhanced MRI breast has been used in the assessment of indeterminate mammographic lesions for a long time [11]. The disadvantages of CE-MRI are mainly its relatively high cost, long examination time, limited availability compared to the availability of mammography machine, and non-visualization of calcification [12]. Contrast-enhanced mammography uses a dual-energy technique performed after contrast administration to identify and characterize lesions based on angiogenesis, as well as morphologic features and density [9]. Also, low-energy images of CEM could detect microcalcifications, architectural distortion, and non-enhancing lesions [12].
The main disadvantage in CEM is that it lacks kinematic information about tumor enhancement [13].
Our study revealed that DCE-MRI sensitivity and NPV were slightly yet significantly higher than that of CEM (p value 0.014 and 0.013, respectively). The overall accuracy of DCE-MRI was better than that of CESM; however, no statistically significant difference could be detected.
Our results were comparable with Fallenberg et al. that showed that DCE-MRI sensitivity was slightly but significantly superior to CESM (p value < 0.001) [13].
Yousef et al. [16] concluded that CEM and MRI were equal in the sensitivity; however, their study was conducted on twenty cases only [16].
However, Łuczyńska et al. [18] found that diagnoses based on CESM are slightly more reliable than those based on breast MRI. The sensitivity of CESM examination was 100%, higher than the 93% sensitivity of breast MRI (p ≤ 0.04). The accuracy of the CESM exam (79%) was also higher than that of breast MRI (73%) in their study, but this difference was not statistically significant. NPV was 100% for CESM and only 65% for breast MRI (p < 0.001) [18].  The specificity of CE-MRI was slightly higher than that of CEM in our study but this was not a statistically significant difference. Fallenberg et al. [13] found that the specificity of CESM was better than that of MRI. This could be attributed to the difference in population between their study and our study as their study included only cases with pathologically proven index lesion, yet in our study we included sonomammography indeterminate lesions including both benign and malignant pathologies [13].
In another study done by Xing et al. [19], the sensitivity, PPV, and NPV of CEM were comparable to those of MRI. However, the specificity of CEM was higher than that of MRI [19].
Regarding the assessment of multiplicity in our study in reference to histopathology, CE-MRI was better than CEM in the detection of multiplicity.
Our results were comparable to Jochelson et al. that concluded that CESM had a lower sensitivity for depicting additional ipsilateral cancers than breast MRI [20].
However, Łuczyńska et al. found that CESM detected multifocal breast cancers in all cases studied [18] Limitation of the study The assessment in the study was limited by the absence of a standardized BIRADS lexicon for CEM examination; however, we applied the 2013 MRI BIRADS lexicon morphology descriptors. A standardized lexicon of morphology descriptors seen on CEM would provide the optimal analysis and reporting of enhancing lesions detected in the breast.

Conclusion
Contrast-enhanced mammography and dynamic contrast-enhanced MRI improved the characterization of breast lesions. CEM showed slightly lower sensitivity and accuracy compared to MRI however because of being relative ease, available, cheap, and acceptable by women; CEM can replace DC-MRI as a problem-solving tool in the characterization of indeterminate breast lesions.