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Contrast Enhanced Spectral Mammography: A Review
Author’s Accepted Manuscript Contrast Enhanced Spectral Mammography: A ReviewCESM Review Bhavika K. Patel, M.B.I. Lobbes, John Lewin
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S0887-2171(17)30085-9 http://dx.doi.org/10.1053/j.sult.2017.08.005 YSULT779
To appear in: Seminars in Ultrasound, CT, and MRI Cite this article as: Bhavika K. Patel, M.B.I. Lobbes and John Lewin, Contrast Enhanced Spectral Mammography: A ReviewCESM Review, Seminars in Ultrasound, CT, and MRI, http://dx.doi.org/10.1053/j.sult.2017.08.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 Contrast Enhanced Spectral Mammography: A Review Bhavika K Patel, Marc Lobbes, John Lewin
Running Title: CESM Review First and Corresponding Author: Bhavika K. Patel, MD Email: [email protected] Telephone #: 480-342-0876 Fax #: 480-301-9160 Department of Radiology, Mayo Clinic, Phoenix, AZ, USA Co-author: Dr. M.B.I. Lobbes, MD, PhD, EDBI; Maastricht University Medical Center, department of Radiology and Nuclear Medicine, PO Box 5800, 6202 AZ Maastricht, the Netherlands Co-author: John Lewin, MD Email: [email protected] Department of Radiology, The Women’s Imaging Center, Denver, CO USA Correspondece and reprints: Dr. Bhavika K Patel Mayo Clinic Arizona 5777 East Mayo Blvd Phoenix AZ 85054 USA 480-342-0876 480-342-4978 (fax) [email protected] Text pages: 21 Words: 4854 Figures: 6 No funding was received for this study. Authors whose names are listed certify that they have NO affiliations with or involvement in any organization or entity with any financial interest, or nonfinancial interest in the subject matter or materials discussed in this manuscript. All authors above had: 1) Substantial contributions to conception and design, or analysis and interpretation of data; 2) Drafting the article or revising it critically for important intellectual content; 3) Final approval of the version to be published; and 4) Agreement to be accountable for all aspects of the work. Key words: Breast, CEM, CESM, CEDM, breast imaging, MRI
2 Abstract: Contrast-enhanced spectral mammography (CESM) provides low-energy 2D mammographic images comparable to standard digital mammography and a post-contrast recombined image to assess tumor neovascularity similar to MRI. The utilization of CESM in the United States is currently low but could increase rapidly given many potential indications for clinical use. This article discusses historical background and literature review of indications and diagnostic accuracy of CESM to date. CESM is a growing technique for breast cancer detection and diagnosis that has levels of sensitivity and specificity on par with contrast-enhanced breast MRI. Because of its similar performance and ease of implementation, CESM is being adopted for multiple indications previously reserved for MRI, such as problem-solving, disease-extent in newly diagnosed patients and evaluating the treatment response of neoadjuvant chemotherapy.
1. Introduction:
Screening mammography was proven in randomized clinical trials in the 1960s and 1970s to reduce breast cancer mortality and is a relatively low cost and rapid test for breast cancer screening.1, 2 The technology used in the original trials, screen-film mammography, has since been nearly completely replaced by full field digital mammography (FFDM), which was approved in 2000 for clinical use in the United States. Although more expensive in terms of equipment cost, FFDM improved efficiency, throughput, and digital information management.
It was hoped that FFDM would also result in improved diagnostic
performance, due to its superior contrast resolution (and despite its inferior spatial resolution).
3 Unfortunately, FFDM did not prove to be significantly better than film mammography in sensitivity for cancer detection. Clinical studies in the US and Norway,3-5 including the 50,000 subject U.S. ACRIN DMIST trial,6 showed no overall sensitivity improvement, although the DMIST trial did demonstrate a modest benefit in younger women. Even as the results of these digital trials were being processed, research continued to progress on advanced applications of new digital technologies. Two applications that held the most promise included digital breast tomosynthesis and contrast-enhanced spectral mammography (CESM, or contrast-enhanced dual-energy mammography, CEDM). The motivation for contrast enhanced mammography was the observation that cancers had been shown to preferentially take up intravenous contrast on breast MRI as its initial breast MRI results demonstrated nearly 100% sensitivity for invasive cancers.7 The hope was that the increased contrast resolution of FFDM, as compared to film mammography, would enable contrast uptake to be demonstrated. However, because contrast resolution was still far inferior to that of CT or MRI, subtraction would have to be utilized. The commonly used method of temporal subtraction, where a pre-contrast image is subtracted from a post-contrast image, was first considered.8 Although temporal subtraction was utilized in the cross-sectional modalities of both CT and MRI with great success, the technique had specific limitations for a projection technique such as mammography. Because of the requirement for the pre-contrast (mask) image to be registered with the post-contrast image, only a single view of one breast could be obtained. Additional views or images of the other breast would require re-injection after the contrast had washed out, necessitating a second study on a different day. An added problem unique to mammography was that evidence from MRI biopsy suggested that breast compression, which is required to minimize movement between the mask image and the postcontrast images, limited contrast uptake to the breast.9 Overcoming this last obstacle by using only limited compression and reducing motion artifacts with image processing, Jong et al.
4 published a series of single projection temporal subtraction contrast enhanced mammography cases in 2003.10 To overcome the limitations inherent in temporal subtraction, the technique of dual-energy subtraction was applied to contrast-enhanced mammography.11 In dual energy subtraction, a pair of low-energy and high-energy images are acquired after contrast administration and used to construct the final recombined image. Because the contrast has already been delivered to the breast, full compression can be used and, because a mask image is not needed, multiple images can be taken in a single examination, allowing both breasts to be studied and lesions to be localized using orthogonal projections. The two source images are combined to make an image that, by equalizing the density of fibroglandular tissue and fat, minimizes the appearance of breast tissue and increases the conspicuity of iodinated contrast agent. The low- and high-energy beams are created by adjusting the peak kilovoltage (kVp) of the x-ray tube and changing the filtration. kVp values between 28 and 32 are typically used for the low energy beam and those between 45 and 49 are typically used for the high-energy beam. In addition, copper filtration is added to the high-energy beam to further harden it and images are combined using a weighted logarithmic subtraction. Prior to its use in contrast mammography, dual energy imaging was utilized in chest radiography systems to increase the visibility of soft tissue by eliminating overlapping bones. More recently, body imagers have become familiar with dual-energy through its application to CT to improve the quantification of contrast uptake for perfusion studies.12 In comparison to temporal subtraction, dual-energy subtraction offers many advantages and has therefore become the standard for contrast enhanced mammography (CEM). Dual-energy CEM-capable devices are commercially available from multiple vendors and are approved for clinical use in most countries, including the U.S. Over 100,000 CEM examinations have been performed to date in both research and clinical settings (Table 1).
5
To perform a CESM examination, a low osmolar iodinated contrast agent, similar to what is used in CT, is administered using a power injector at a rate of 2-3 mL/s. Contrast agents with concentration between 300 mgI/ml and 370 mgI/ml are typically used and the volume of contrast is like that used for an abdominal CT scan, approximately 1.5 mL/kg of body weight. Approximately two minutes after the injection, the patient is positioned as they would for a standard mammogram and a dual-energy image pair is acquired. Acquisition of an image pair typically takes less than 6 seconds and additional projections may then be obtained. A typical 4-view exam takes about 10 minutes to perform, similar to the time needed for a standard 4view mammography exam, although the total ‘room-time’ is slightly more than standard FFDM given the time required to prepare and administer the intravenous contrast administration (Table 2). The order of image acquisition has not been shown to be relevant and can be performed as normally performed at the institution to stimulate a consistent protocol, whether it is FFDM or CESM.
2. Indications:
Inconclusive findings at mammography
The diagnostic accuracy of FFDM is highly dependent on the density of fibroglandular tissue.13 Consequently, a typical mammogram may be difficult to read and may contain
6 masses, asymmetries or focal distortions that are not always associated with underlying breast cancer. Lobbes et al. showed that CESM is an excellent problem solving tool to address inconclusive findings on screening mammography.14 In their study, women recalled from breast cancer screening for inconclusive findings were subjected to CESM. They showed that in 113 women, the overall diagnostic performance relative to FFDM increased when using CESM. CESM achieved the following diagnostic parameters (comparison to FFDM): sensitivity 100% (+3%), specificity 88% (+46%), positive predictive value (PPV) 76% (+37%) and negative predictive value (NPV) 100% (+3%). In short, the most pronounced improvements were observed in specificity and PPV, demonstrating that CESM is especially useful in downgrading mammographic lesions when they were based on false positive recalls. Another interesting observation was the high NPV, suggesting that a negative CESM in these women generally excludes any kind of breast cancer, suggesting follow-up after six or twelve months for inconclusive findings may no longer be necessary. However, their study included only two readers who had experience reading CESM exams. In a subsequent publication, Lalji et al. demonstrated that (with a panel of ten radiologists with varying levels of experience with CESM) in another 199 cases similar improvements in diagnostic performance were observed.15 Readers included those experienced in reading CESM exams, experienced breast radiologists without any prior experience in CESM, and radiology residents. CESM achieved the following diagnostic parameters (comparison to FFDM): sensitivity 97% (+4%), specificity 70% (+34%), and area under the receiver operator curve (ROC) 0.833 (+0.188). These results not only confirmed the initial observations by Lobbes et al., but also demonstrated that CESM requires a minimal learning curve to effectively interpret studies
7 Staging of breast cancer using CESM
Next to breast cancer detection, assessment of disease extent is the most important indication for performing any kind of breast imaging. Accurate disease assessment enables surgeons and patients to reach a decision on the most preferable surgical treatment plan. Both over- and underestimation of disease extent are unwanted. Overestimation may result in the excision of an unnecessarily larger breast volume or may even lead to mastectomy when breast conservative therapy is possible. In contrast, underestimation carries the risk of positive surgical margins, requiring additional surgery to remove residual breast cancer. To date, breast MRI is the most accurate imaging tool to assess disease extent.16 High-quality breast MRI protocols optimize evaluation of enhancing structures (cancer) within the breast. When tumors grow, they require nutrients which, at first, are supplied by simple diffusion.17 When a tumor becomes larger, the center of a cancer becomes hypoxic and secretes vascular growth factors, which triggers the formation of adjacent blood vessels in a process called angiogenesis. However, these vessels are rapidly formed and disorganized, which makes them ‘leaky’ to contrast. Contrast is then able to extravasate into the tumor interstitium, resulting in enhancement of the lesion on breast MRI protocols. CESM is also based on this phenomenon, but utilizes iodine-based contrast agents instead of gadolinium-based ones. Because of the similarities in approach, CESM has been frequently compared to breast MRI. Fallenberg et al. studied differences in tumor size measurement between mammography, CESM, and breast MRI.18 In their study of 80 women, they found that the correlation (as expressed by the PCC: Pearson’s correlation coefficient) between the different imaging modalities and the final histopathological results was highest for CESM (PCC of 0.733, 0.654 for breast MRI, and 0.603 for mammography).
8 However, strong correlation does not simply imply good agreement.19 If a certain test has an inherent structural over- or underestimation, the correlation can be excellent although the measurement error is not calculable in these kinds of analyses. They are, however, visible in Bland-Altman plots, where the mean difference between the test of interest and the gold standard are presented in scatterplots for different tumor sizes, including their variation as expressed by the 95% limits of agreement (LOA). Lobbes et al. studied both correlation and agreement between CESM and breast MRI in 57 cases20 and found that the PCC was excellent for both modalities: 0.905 and 0.915, respectively. The mean difference between CESM and histopathological measurement were also smaller than what was observed on MRI exams: 0.03 mm versus 2.12 mm, respectively. As this difference does not seem to be clinically relevant, the authors also studied whether an additional breast MRI exam would be helpful if the oncologically safe surgical margin was set on 1 cm. They did not find any examples where performing breast MRI after CESM yielded information that was surgically relevant in terms of assessing disease extent. However, it should be emphasized that the number of cases was limited, restricting the authors from studying the difference between CESM and breast MRI in multifocality of breast cancer, which is also an important item in assessing true disease extent. Nevertheless, these initial findings demonstrated that CESM may be a viable modality for the evaluation of disease extent prior to treatment (Figure 1). Symptomatic Patients CESM has been studied in the symptomatic setting as well. A retrospective reader study was performed in 100 symptomatic patients with CESM.21 ROC analysis showed statistically significantly improved overall performance of CESM compared to low-energy image alone (AUC 0.93 versus 0.83 respectively). The sensitivity and specificity of CESM compared to low-energy images alone was also improved (95% versus 84%, p<0.025 and 81% versus 63%, p<0.025). Using a decision-making scale used to rate the usefulness of the recombined
9 CESM images, the final assessment of the diagnostic imaging, 75% of the cases were deemed a useful or significant aid to diagnosis (with 25% of the cases having no value added from the CESM recombined image). Another retrospective reader study of 116 patients22 compared performance of CESM, FFDM and US and sensitivity of CESM was 100%, which was significantly higher than that of MG (90%, p<0.004) or US (92%, p<0.01). CESM accuracy was 78%, which was also higher than MG (69%, p<0.004) and US (70%, p=0.03). There was no statistically significant difference between AUCs for CESM and US (both 0.83), however both were significantly larger than that of MG (p<0.0004 for each). One clinically used scenario is to offer CESM to those patients with high levels anxiety despite a negative diagnostic evaluation with standard mammography and ultrasound within the past 6 months. These patients include individuals with a personal history of breast cancer, a persistent or new palpable abnormality, chronic/recurrent breast pain, or high-risk family history. A negative CESM study is reassuring to the patient and clinician and can be a quick answer in lieu of a breast MRI (Figure 2). The literature is still pending on this indication, but clinically we have found it reassuring.
Potential Clinical Indications Neoadjuvant Response Monitoring Neoadjuvant systemic therapy (NST) has evolved as a treatment regimen for previously inoperable, locally-advanced breast cancers. Oncologists now utilize NST in women with certain T1cN0 cancers along with stage II and III breast cancers to facilitate breast conversation and/or improve cosmesis. NST also helps clinicians gauge the in vivo sensitivity of the tumor to systemic therapy and has prognostic significance in patients who achieve a pathologic complete response (pCR). Given the increasing prevalence of NST as an initial
10 treatment strategy, an accurate means for detecting residual malignancy to guide surgical planning or other non-operative management is essential. At present, the most accurate modality to monitor response to neoadjuvant chemotherapy in breast cancer is MRI.23, 24
A recent study that included 21 patients demonstrated 91% specificity of CESM in predicting tumor response with a 100% sensitivity in detection of complete tumor response.25 The discordance between radiological response and pathological response was most prevalent in chemoresistent tumors (defined as MD Anderson score III). The study had 6 cases of false negative CESM which lowered the sensitivity of CESM in predicting tumor response to neoadjuvant treatment to 40%. It was speculated that residual cancer cells may remain as small foci in the tumor bed and receive nutrients by diffusion and not from vascular perfusion and therefore result in a false negative enhancement pattern on CESM. Although results are promising, larger studies are necessary to better understand which cohort of patients will best be served through CESM monitoring. Ongoing work by one of the authors (BKP) demonstrates CESM could serve as an alternative to breast MRI to monitor responsiveness of neoadjuvant systemic therapy (Figure 3). In a study of 47 patients with locally-advanced breast cancer who received NST, the lesion size measurements determined through CESM and MRI were highly correlated; equivalence tests demonstrated that the mean tumor size measured by CESM (p=0.0132) or by MRI (p=0.0194) is equivalent to the mean tumor size measured by pathology within -1 and 1 cm range. In our clinical experience, CESM has been particularly useful for those patients who have contraindications to MRI including in those patients who have a pacemaker, severe claustrophobia, metallic foreign bodies, etc.
11 Dense Breasts Dense breasts have been demonstrated to be a strong independent risk factor for breast cancer.26-29 Given new breast density laws in the United States, supplemental screening has been recommended in some dense-breasted women but specific recommendations have not yet been made as to who would benefit from what modality. In addition to tomosynthesis, whole-breast screening ultrasound and molecular breast imaging are available tools for supplemental breast screening (Figure 4). To date, few30 have compared mammography to mammography plus CESM in the dense breasted population. Fallenberg et al. had a study of 118 women, 56% of which were dense breasted, defined as ACR category 3 or 4 based on reader assessed BIRADS categories. Authors found an increase in sensitivity in dense (71.6% versus 93.3%) versus non-dense (85.8% versus 96.5%) breasted women to be statistically significant (p<0.001). Another study31 with 90% (129/143) dense breasted women demonstrated a sensitivity (p < 0.001), specificity (p = 0.016) and accuracy (p < 0.001) significantly higher on CESM compared to standard mammography. Mammography missed malignancy in 27 breasts of which 25 were dense breasts. Of these 25, 20 (80.0 %) breasts were positive on CESM suggesting there may be value added of CESM as supplemental screening tool in dense breasted population however larger studies are needed. Like all screening tests, however, the potential risks (some which are discussed below) need to be weighed in relation to the benefit of the additional cancers detected.
High-Risk Screening The sensitivity of mammography in high-risk populations with dense breast tissue has been shown to be as low as 30-60%.32-34 MRI, on the other hand, demonstrates a sensitivity of 77100% in high-risk, dense-breasted women and is therefore a more compelling modality. If, as
12 studies have already demonstrated, CESM has equal sensitivity to MRI,18, 35, 36 CESM may play an important role in high-risk screening like MRI. There is limited literature on the use of CESM in the high-risk screening population.37 In our limited experience, were have occasionally used CESM for evaluating women who meet the 20% lifetime risk of breast cancer threshold where MRI is contraindicated or evaluating same day add-ons when MRI appointments are unavailable. Further research is needed.
3. Advantages of CESM
In terms of diagnostic accuracy, CESM is consistently superior to FFDM. In a recent metaanalysis of eight studies, Tagliafico et al. showed that the pooled sensitivity was 98% (95% CI 96-100%), with a more moderate pooled specificity of 58% (95% CI 38-77%).38 The pooled ROC curve showed an AUC value of 0.93. Some of the other potentially eligible publications needed to be excluded since they did not provide absolute numbers in terms of true negative/positive or false negative/positive findings. Jochelson and Lobbes addressed this limited specificity in a letter to the editor, observing that three of the eight included papers were from one single group.39 This group yielded a mammography specificity 15%, which lead Jochelson and Lobbes to question the validity of the resultant CESM specificity of merely 40%. Therefore, the pooled estimates were recalculated excluding these three studies and resulted in a pooled specificity estimate of 78% (95% CI 56-90%). Other studies have compared combinations of mammography, ultrasound, and CESM. Dromain et al. showed that the sensitivity for mammography with ultrasound was significantly lower than the combination mammography/ultrasound/CESM: 71% versus 78%, p=0.006, respectively).40) Luczynska et al. showed that the sensitivity for detecting breast cancer was highest for CESM (100%), followed by ultrasound (92%), and then FFDM
13 (90%).22%) Although this paper did not purely compare mammography/ultrasound with CESM, it is safe to assume that the combination of mammography/ultrasound would yield comparable results as CESM. This is already suggested by the results of Houben et al., who showed that in recalls from screening, CESM detected an additional 3-4% of cancer foci purely based on the information provided by the recombined CESM images. 41 As some of these CESM-detected tumor foci were very small, it is questionable whether they would have been detected by performing additional breast ultrasound. Future studies should therefore also investigate the diagnostic accuracy of CESM combined with targeted ultrasound.
Miscellaneous
There are several other benefits of performing CESM, especially compared to breast MRI. Access to MRI units is limited in many parts of the world and the acquisition of breast MR images is costly while CESM is more likely to be more accessible to a larger population.42 With multiple vendors now entering the CESM arena, more units could be cost-effectively upgraded with CESM options.
Next, CESM’s acquisition time is shorter: the image
acquisition per CESM exposure is only slightly longer than FFDM (mean exposure times 5.6s versus 1.1s, respectively),43 although additional time is required when preparing the patient for intravenous access and contrast administration. Future studies should include robust costeffectiveness analyses to demonstrate the superiority of CESM over breast MRI in this area as well. From a patient’s perspective, Hobbs et al. study the differences in preference and toleration between CESM and MRI. Although patients graded breast compression/positioning and contrast administration less favorable for CESM, in general, they still expressed a preference for CESM over breast MRI.44
14
4. Disadvantages of CESM
CESM also has some relevant disadvantages when compared to other breast imaging modalities.
Radiation exposure in CESM Because CESM consists of two image acquisitions (i.e. a low- and a high-energy image), the radiation dose is higher in comparison to FFDM. Dromain et al. were the first to report on CESM radiation dose and observed a 20% higher dose in comparison to FFDM.40 In a subsequent publication by Fallenberg et al. an even lower dose for CESM was reported when compared to FFDM (1.72 mGy versus 1.75 mGy, respectively).30 In the Fallenberg study, however, FFDM units of multiple vendors and both computed radiography and digital radiography images were used as reference standard. These studies were of limited clinical value, however, as they were performed on prototype CESM units where exposure settings had to be set manually, depending on breast thickness and glandularity (with the aid of a table with predefined exposure variables). In commercial, non-prototype CESM units, these parameters are determined by the automated exposure control (AEC).
Badr et al. also
observed a 54% increase in radiation dose compared to FFDM (2.65 mGy versus 1.72 mGy, respectively).45 Nevertheless, these results were based on numbers produced by the unit itself. Jeukens et al. were the first to validate machine-generated numbers using well-validated phantom measurements and observed an 81% increase in radiation dose in their clinical data set using the commercially available unit from GE Healthcare (Senographe* Essential with the SenoBright* CESM upgrade, GE Healthcare, Chalfont, UK).43 For a single exposure, the AGD for a CESM exam was 2.80 mGy, versus 1.55 mGy for a single FFDM exposure. These
15 findings were in line with previous results by Badr et al. and also in line with subsequent results found by James et al.46 James et al. used a commercially available unit from Hologic (Selenia Dimensions, software version 1.8.3, Malborough, MA, USA) and found that the AGD for CESM was 3.0 mGy versus 2.1 mGy for FFDM. Although the radiation dose of a CESM exam is higher than the FFDM radiation dose, it should be emphasized that the overall CESM dose is still within internationally accepted radiation dose limits and that the chances of inducing breast cancer through these exams is neglible. The health detriment caused by radiation exposure can be estimated from the AGD and the lifetime attributable risk (LAR) factors for breast cancer incidence and mortality. As was demonstrated by Jeukens et al., LAR for a unilateral, single FFDM or CESM exposure had a small risk of only 0.002-0.0003% per 100,000 women for breast cancer incidence, respectively.43 However, one should note that the lifetime risk of breast cancer incidence is much higher and, according to the American Association of Physicists in Medicine, an effective radiation dose beneath 50 mGy will not have adverse consequences.
Application of iodine based contrast agents in CESM
Unwanted side-effects, including hypersensitivity reactions and the occurrence of CIN, can occur when using iodine-based contrast agents. Hypersensitivity reactions can vary from mild and self-limiting up to severe anaphylactic shock but the risk of developing severe hypersensitivity reactions is small nowadays. With the latest generation of non-ionic iodinated contrast media, the incidence of hypersensitivity reactions has decreased, with an estimated incidence of 0.7-3.1%. Severe hypersensitivity reactions occur in only 0.02-0.04% of contrast administrations.47
Death caused by the administration of iodinated contrast agents is
extremely rare and generally reported in patients with severe and extensive co-morbidity.
16 However, women undergoing breast imaging for whatever reason generally do not fit into this latter category. As a practical example, Houben et al. recently observed hypersensitivity reactions in women undergoing CESM in 0.6% of the cases, with most reactions being mild and self-limiting after a prolonged observation period.41 Hence, the use of iodine based contrast agents in CESM is generally safe with respect to the risk of introducing hypersensitivity reactions. Nevertheless, institutions using CESM should familiarize themselves with the identification of hypersensitivity reactions and should train their staff to adequately cope with these stressful situations, for example through frequent simulator trainings. A second disadvantage of using iodinated contrast agents in CESM is that it might cause CIN, which is reported to occur in 1% to 20% of cases, depending on the population studied in various publications.48 CIN is defined as “as condition in which an impairment of renal function (i.e., an increase of serum creatinine by more than 25% or 44 umol/L) occurs within three days after intravascular administration of an iodine based contrast agent and in the absence of an alternative aetiology”.49 To identify patients at risk for developing CIN, questionnaires are usually employed to determine which patients should have their renal function assessed through blood testing. Nevertheless, CIN and its clinical impact is a topic of ongoing debate.50,
51
Since CIN cannot be treated, many national guidelines suggest
prehydration protocols in patients with impaired renal function that require contrast administration. A recent study by Nijssen et al. demonstrated that refraining from prehydration is a non-inferior and cost-saving approach in the prevention of CIN compared with preventative prehydration in this category of patients.52 Hence, countries should reconsider their national guidelines but an extensive review of CIN and its role in clinical practice is beyond the scope of this review.
17 False positive findings caused by CESM
During CESM, enhancing lesions may be observed on recombined images that were deemed unsuspicious or otherwise not visible on low-energy images. The PPV of enhancement of lesions in a CESM exam warrants tissue sampling of these lesions, regardless of their morphology. This creates a situation in where the usage of CESM results in additional tissue sampling of lesions that turn out to be benign (i.e. false-positive findings). The presence of false-positive findings has been described in several publications. Badr et al. showed that enhancement was observed in 33% of 27 benign lesions.45 Jochelson et al. observed two false-positive findings in 52 cases (of note, 13 were observed in the breast MRI group)36) and Lobbes et al. detected five false-positive findings in a population of 113 women recalled from screening.14 Most of these false-positive lesions are caused by fibroadenomas (Figure 5). although a vast variety of benign lesions have been reported as false-positive CESM findings. Although these might lead to unnecessary tissue biopsy, the current biopsy protocols are extremely safe, with the two most important complications being hematomas or infection at the biopsy site. The incidence of biopsy-related complications is estimated to be 0.2%.41
At present, there have been no studies with published results on CESM-guided stereotactic biopsy or localization.53Although rare, CESM may demonstrate enhancing lesions on recombined images that do not have a correlate on low-energy (mammographic) images. Hence, conventional stereotactic biopsy is not possible, creating the necessity to perform CESM-guided biopsy procedures. Although technical developments are in progress, it is currently not possible to perform these kinds of interventions. As a workaround, breast MRI is generally employed in these cases to determine if the enhancing abnormality is real and not an artifact. Subsequently, an MRI-guided biopsy procedure can be scheduled if the lesion is real
18 and accessible through MRI-guided biopsy. From our clinical experience, the occurrence of such cases is rare and the abovementioned workaround has always lead to a final diagnosis in these challenging cases.
5. Conclusions
CESM is a growing technique for breast cancer detection and diagnosis that has levels of sensitivity and specificity on par with contrast-enhanced breast MRI. Because of its similar performance and ease of implementation, CESM is being adopted for multiple indications previously reserved for MRI, such as problem-solving, disease-extent in newly diagnosed patients and evaluating the treatment response of neoadjuvant chemotherapy.
CESM is
currently being studied for screening both high-risk and medium-risk patients. CESM is also more efficient and less costly than MRI due to reduced equipment costs and shorter examination times. Future studies with larger patient numbers are necessary to validate the initial literature.
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Lobbes MB, Lalji UC, Nelemans PJ, et al. The quality of tumor size assessment by
contrast-enhanced spectral mammography and the benefit of additional breast MRI. J Cancer. 2015;6(2):144-150.
21 21.
Tennant SL, James JJ, Cornford EJ, et al. Contrast-enhanced spectral mammography
improves diagnostic accuracy in the symptomatic setting. Clin Radiol. 2016;71(11):11481155. 22.
Luczynska E, Heinze S, Adamczyk A, et al. Comparison of the Mammography,
Contrast-Enhanced Spectral Mammography and Ultrasonography in a Group of 116 patients. Anticancer Res. 2016;36(8):4359-4366. 23.
Rosen EL, Blackwell KL, Baker JA, et al. Accuracy of MRI in the detection of
residual breast cancer after neoadjuvant chemotherapy. AJR Am J Roentgenol. 2003;181(5):1275-1282. 24.
Marinovich ML, Macaskill P, Irwig L, et al. Agreement between MRI and pathologic
breast tumor size after neoadjuvant chemotherapy, and comparison with alternative tests: individual patient data meta-analysis. BMC Cancer. 2015;15:662. 25.
ElSaid NAE, Mahmoud HGM, Salama A, et al. Role of contrast enhanced spectral
mammography in predicting pathological response of locally advanced breast cancer post neo-adjuvant chemotherapy. Egyptian Journal of Radiology and Nuclear Medicine. 2017;48(2):519-527. 26.
Byrne C, Schairer C, Wolfe J, et al. Mammographic features and breast cancer risk:
effects with time, age, and menopause status. J Natl Cancer Inst. 1995;87(21):1622-1629. 27.
Warner E, Lockwood G, Tritchler D, et al. The risk of breast cancer associated with
mammographic parenchymal patterns: a meta-analysis of the published literature to examine the effect of method of classification. Cancer Detect Prev. 1992;16(1):67-72. 28.
Boyd NF, Byng JW, Jong RA, et al. Quantitative classification of mammographic
densities and breast cancer risk: results from the Canadian National Breast Screening Study. J Natl Cancer Inst. 1995;87(9):670-675.
22 29.
Brisson J, Merletti F, Sadowsky NL, et al. Mammographic features of the breast and
breast cancer risk. Am J Epidemiol. 1982;115(3):428-437. 30.
Fallenberg EM, Dromain C, Diekmann F, et al. Contrast-enhanced spectral
mammography: Does mammography provide additional clinical benefits or can some radiation exposure be avoided? Breast Cancer Res Treat. 2014;146(2):371-381. 31.
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. 32.
Kuhl CK, Schmutzler RK, Leutner CC, et al. Breast MR imaging screening in 192
women proved or suspected to be carriers of a breast cancer susceptibility gene: preliminary results. Radiology. 2000;215(1):267-279. 33.
Leach MO, Boggis CR, Dixon AK, et al. Screening with magnetic resonance imaging
and mammography of a UK population at high familial risk of breast cancer: a prospective multicentre cohort study (MARIBS). Lancet. 2005;365(9473):1769-1778. 34.
Pisano ED, Hendrick RE, Yaffe MJ, et al. Diagnostic accuracy of digital versus film
mammography: exploratory analysis of selected population subgroups in DMIST. Radiology. 2008;246(2):376-383. 35.
Thibault F, Balleyguier C, Tardivon A, et al. Contrast enhanced spectral
mammography: better than MRI? Eur J Radiol. 2012;81 Suppl 1:S162-164. 36.
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. 37.
Phillips J, Miller MM, Mehta TS, et al. Contrast-enhanced spectral mammography
(CESM) versus MRI in the high-risk screening setting: patient preferences and attitudes. Clin Imaging. 2017;42:193-197.
23 38.
Tagliafico AS, Bignotti B, Rossi F, et al. Diagnostic performance of contrast-enhanced
spectral mammography: Systematic review and meta-analysis. Breast. 2016;28:13-19. 39.
Jochelson M, Lobbes MB, Bernard-Davila B. Reply to Tagliafico AS, Bignotti B,
Rossi F, et al. Breast. 2017;32:267. 40.
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. 41.
Houben IPL, Van de Voorde P, Jeukens CR, et al. Contrast-enhanced spectral
mammography as work-up tool in patients recalled from breast cancer screening: advantages versus disadvantages (in press). Eur J Radiol. 2017. 42.
Patel BK, Gray RJ, Pockaj BA. Potential Cost Savings of Contrast-Enhanced Digital
Mammography. AJR Am J Roentgenol. 2017:1-7. 43.
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. 44.
Hobbs MM, Taylor DB, Buzynski S, et al. Contrast-enhanced spectral mammography
(CESM) and contrast enhanced MRI (CEMRI): Patient preferences and tolerance. J Med Imaging Radiat Oncol. 2015;59(3):300-305. 45.
Badr S, Laurent N, Regis C, et al. Dual-energy contrast-enhanced digital
mammography in routine clinical practice in 2013. Diagn Interv Imaging. 2014;95(3):245258. 46.
James JR, Pavlicek W, Hanson JA, et al. Breast Radiation Dose With CESM
Compared With 2D FFDM and 3D Tomosynthesis Mammography. AJR Am J Roentgenol. 2017;208(2):362-372.
24 47.
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contrast media. A report from the Japanese Committee on the Safety of Contrast Media. Radiology. 1990;175(3):621-628. 48.
Mehran R, Nikolsky E. Contrast-induced nephropathy: definition, epidemiology, and
patients at risk. Kidney Int Suppl. 2006(100):S11-15. 49.
Stacul F, van der Molen AJ, Reimer P, et al. Contrast induced nephropathy: updated
ESUR Contrast Media Safety Committee guidelines. Eur Radiol. 2011;21(12):2527-2541. 50.
Davenport MS, Cohan RH, Ellis JH. Contrast media controversies in 2015: imaging
patients with renal impairment or risk of contrast reaction. AJR Am J Roentgenol. 2015;204(6):1174-1181. 51.
McDonald RJ, McDonald JS, Bida JP, et al. Intravenous contrast material-induced
nephropathy: causal or coincident phenomenon? Radiology. 2013;267(1):106-118. 52.
Nijssen EC, Rennenberg RJ, Nelemans PJ, et al. Prophylactic hydration to protect
renal function from intravascular iodinated contrast material in patients at high risk of contrast-induced nephropathy (AMACING): a prospective, randomised, phase 3, controlled, open-label, non-inferiority trial. Lancet. 2017;389(10076):1312-1322. 53.
Covington M, Pizzitola VJ, Giurescu M, et al. Contrast-enhanced digital
mammography (CEDM) guided localization of suspicious enhancing lesions. presented at the Society of Breast Imaging Annual Meeting, Los Angeles, CA. 2017.
Poster
25
Table 1 Acquisition of the CESM images
26
Table 2
27
A
B
Figure 1 80-year-old female with new palpable right breast abnormality.
Diagnostic ultrasound
imaging showed 3.5 cm irregular mass in the left 1:00 breast underlying palpable abnormality. Ultrasound biopsy demonstrated high grade DCIS. Low energy (A) CESM shows no mammographic abnormality. Recombined (B) CESM and MRI (C) demonstrate a large 10 cm area of non-mass enhancement. Surgical pathology at time of mastectomy confirmed 10 cm of DCIS.
28
Figure 2.
62-year-old woman with negative outside imaging (MG and US) for palpable
abnormality in left subareolar breast. Low energy (A) and recombined (B) CESM images confirm negative study. Clinical management was recommended with negative follow up on imaging and clinically 24 months later.
29
Figure 3.
38-year-old female with ultrasound guided biopsy demonstrating ER negative,
PR negative HER2 positive IDC of a palpable right breast mass. Low energy (A) and recombined (B) pretreatment CESM images demonstrate multicentric disease with mass (arrows) and intervening nonmass enhancement spanning the central and medial breast. Post treatment low energy (C) and recombined (D) images demonstrate no residual enhancement. Surgical pathology from mastectomy specimen confirmed no residual carcinoma.
30
Figure 4. 64-year-old female with dense breast on standard low energy mammogram. Recombined image clearly shows an irregular moderately enhancing mass (arrow) in the central breast, mid depth. This was biopsy proven IDC, NOS at the time of ultrasound guided biopsy.
31
4
Figure 5
46-year-old woman with mass on screening mammography. A) Oval mass with
indistinct margins on FFDM(arrow). B) CESM prior to biopsy demonstrates heterogenous enhancement in the lobulated mass in the upper outer quadrant on recombined image (arrow). C) US guided percutaneous biopsy demonstrated a benign fibroadenoma (arrow).
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PII: DOI: Reference:
S0887-2171(17)30085-9 http://dx.doi.org/10.1053/j.sult.2017.08.005 YSULT779
To appear in: Seminars in Ultrasound, CT, and MRI Cite this article as: Bhavika K. Patel, M.B.I. Lobbes and John Lewin, Contrast Enhanced Spectral Mammography: A ReviewCESM Review, Seminars in Ultrasound, CT, and MRI, http://dx.doi.org/10.1053/j.sult.2017.08.005 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 Contrast Enhanced Spectral Mammography: A Review Bhavika K Patel, Marc Lobbes, John Lewin
Running Title: CESM Review First and Corresponding Author: Bhavika K. Patel, MD Email: [email protected] Telephone #: 480-342-0876 Fax #: 480-301-9160 Department of Radiology, Mayo Clinic, Phoenix, AZ, USA Co-author: Dr. M.B.I. Lobbes, MD, PhD, EDBI; Maastricht University Medical Center, department of Radiology and Nuclear Medicine, PO Box 5800, 6202 AZ Maastricht, the Netherlands Co-author: John Lewin, MD Email: [email protected] Department of Radiology, The Women’s Imaging Center, Denver, CO USA Correspondece and reprints: Dr. Bhavika K Patel Mayo Clinic Arizona 5777 East Mayo Blvd Phoenix AZ 85054 USA 480-342-0876 480-342-4978 (fax) [email protected] Text pages: 21 Words: 4854 Figures: 6 No funding was received for this study. Authors whose names are listed certify that they have NO affiliations with or involvement in any organization or entity with any financial interest, or nonfinancial interest in the subject matter or materials discussed in this manuscript. All authors above had: 1) Substantial contributions to conception and design, or analysis and interpretation of data; 2) Drafting the article or revising it critically for important intellectual content; 3) Final approval of the version to be published; and 4) Agreement to be accountable for all aspects of the work. Key words: Breast, CEM, CESM, CEDM, breast imaging, MRI
2 Abstract: Contrast-enhanced spectral mammography (CESM) provides low-energy 2D mammographic images comparable to standard digital mammography and a post-contrast recombined image to assess tumor neovascularity similar to MRI. The utilization of CESM in the United States is currently low but could increase rapidly given many potential indications for clinical use. This article discusses historical background and literature review of indications and diagnostic accuracy of CESM to date. CESM is a growing technique for breast cancer detection and diagnosis that has levels of sensitivity and specificity on par with contrast-enhanced breast MRI. Because of its similar performance and ease of implementation, CESM is being adopted for multiple indications previously reserved for MRI, such as problem-solving, disease-extent in newly diagnosed patients and evaluating the treatment response of neoadjuvant chemotherapy.
1. Introduction:
Screening mammography was proven in randomized clinical trials in the 1960s and 1970s to reduce breast cancer mortality and is a relatively low cost and rapid test for breast cancer screening.1, 2 The technology used in the original trials, screen-film mammography, has since been nearly completely replaced by full field digital mammography (FFDM), which was approved in 2000 for clinical use in the United States. Although more expensive in terms of equipment cost, FFDM improved efficiency, throughput, and digital information management.
It was hoped that FFDM would also result in improved diagnostic
performance, due to its superior contrast resolution (and despite its inferior spatial resolution).
3 Unfortunately, FFDM did not prove to be significantly better than film mammography in sensitivity for cancer detection. Clinical studies in the US and Norway,3-5 including the 50,000 subject U.S. ACRIN DMIST trial,6 showed no overall sensitivity improvement, although the DMIST trial did demonstrate a modest benefit in younger women. Even as the results of these digital trials were being processed, research continued to progress on advanced applications of new digital technologies. Two applications that held the most promise included digital breast tomosynthesis and contrast-enhanced spectral mammography (CESM, or contrast-enhanced dual-energy mammography, CEDM). The motivation for contrast enhanced mammography was the observation that cancers had been shown to preferentially take up intravenous contrast on breast MRI as its initial breast MRI results demonstrated nearly 100% sensitivity for invasive cancers.7 The hope was that the increased contrast resolution of FFDM, as compared to film mammography, would enable contrast uptake to be demonstrated. However, because contrast resolution was still far inferior to that of CT or MRI, subtraction would have to be utilized. The commonly used method of temporal subtraction, where a pre-contrast image is subtracted from a post-contrast image, was first considered.8 Although temporal subtraction was utilized in the cross-sectional modalities of both CT and MRI with great success, the technique had specific limitations for a projection technique such as mammography. Because of the requirement for the pre-contrast (mask) image to be registered with the post-contrast image, only a single view of one breast could be obtained. Additional views or images of the other breast would require re-injection after the contrast had washed out, necessitating a second study on a different day. An added problem unique to mammography was that evidence from MRI biopsy suggested that breast compression, which is required to minimize movement between the mask image and the postcontrast images, limited contrast uptake to the breast.9 Overcoming this last obstacle by using only limited compression and reducing motion artifacts with image processing, Jong et al.
4 published a series of single projection temporal subtraction contrast enhanced mammography cases in 2003.10 To overcome the limitations inherent in temporal subtraction, the technique of dual-energy subtraction was applied to contrast-enhanced mammography.11 In dual energy subtraction, a pair of low-energy and high-energy images are acquired after contrast administration and used to construct the final recombined image. Because the contrast has already been delivered to the breast, full compression can be used and, because a mask image is not needed, multiple images can be taken in a single examination, allowing both breasts to be studied and lesions to be localized using orthogonal projections. The two source images are combined to make an image that, by equalizing the density of fibroglandular tissue and fat, minimizes the appearance of breast tissue and increases the conspicuity of iodinated contrast agent. The low- and high-energy beams are created by adjusting the peak kilovoltage (kVp) of the x-ray tube and changing the filtration. kVp values between 28 and 32 are typically used for the low energy beam and those between 45 and 49 are typically used for the high-energy beam. In addition, copper filtration is added to the high-energy beam to further harden it and images are combined using a weighted logarithmic subtraction. Prior to its use in contrast mammography, dual energy imaging was utilized in chest radiography systems to increase the visibility of soft tissue by eliminating overlapping bones. More recently, body imagers have become familiar with dual-energy through its application to CT to improve the quantification of contrast uptake for perfusion studies.12 In comparison to temporal subtraction, dual-energy subtraction offers many advantages and has therefore become the standard for contrast enhanced mammography (CEM). Dual-energy CEM-capable devices are commercially available from multiple vendors and are approved for clinical use in most countries, including the U.S. Over 100,000 CEM examinations have been performed to date in both research and clinical settings (Table 1).
5
To perform a CESM examination, a low osmolar iodinated contrast agent, similar to what is used in CT, is administered using a power injector at a rate of 2-3 mL/s. Contrast agents with concentration between 300 mgI/ml and 370 mgI/ml are typically used and the volume of contrast is like that used for an abdominal CT scan, approximately 1.5 mL/kg of body weight. Approximately two minutes after the injection, the patient is positioned as they would for a standard mammogram and a dual-energy image pair is acquired. Acquisition of an image pair typically takes less than 6 seconds and additional projections may then be obtained. A typical 4-view exam takes about 10 minutes to perform, similar to the time needed for a standard 4view mammography exam, although the total ‘room-time’ is slightly more than standard FFDM given the time required to prepare and administer the intravenous contrast administration (Table 2). The order of image acquisition has not been shown to be relevant and can be performed as normally performed at the institution to stimulate a consistent protocol, whether it is FFDM or CESM.
2. Indications:
Inconclusive findings at mammography
The diagnostic accuracy of FFDM is highly dependent on the density of fibroglandular tissue.13 Consequently, a typical mammogram may be difficult to read and may contain
6 masses, asymmetries or focal distortions that are not always associated with underlying breast cancer. Lobbes et al. showed that CESM is an excellent problem solving tool to address inconclusive findings on screening mammography.14 In their study, women recalled from breast cancer screening for inconclusive findings were subjected to CESM. They showed that in 113 women, the overall diagnostic performance relative to FFDM increased when using CESM. CESM achieved the following diagnostic parameters (comparison to FFDM): sensitivity 100% (+3%), specificity 88% (+46%), positive predictive value (PPV) 76% (+37%) and negative predictive value (NPV) 100% (+3%). In short, the most pronounced improvements were observed in specificity and PPV, demonstrating that CESM is especially useful in downgrading mammographic lesions when they were based on false positive recalls. Another interesting observation was the high NPV, suggesting that a negative CESM in these women generally excludes any kind of breast cancer, suggesting follow-up after six or twelve months for inconclusive findings may no longer be necessary. However, their study included only two readers who had experience reading CESM exams. In a subsequent publication, Lalji et al. demonstrated that (with a panel of ten radiologists with varying levels of experience with CESM) in another 199 cases similar improvements in diagnostic performance were observed.15 Readers included those experienced in reading CESM exams, experienced breast radiologists without any prior experience in CESM, and radiology residents. CESM achieved the following diagnostic parameters (comparison to FFDM): sensitivity 97% (+4%), specificity 70% (+34%), and area under the receiver operator curve (ROC) 0.833 (+0.188). These results not only confirmed the initial observations by Lobbes et al., but also demonstrated that CESM requires a minimal learning curve to effectively interpret studies
7 Staging of breast cancer using CESM
Next to breast cancer detection, assessment of disease extent is the most important indication for performing any kind of breast imaging. Accurate disease assessment enables surgeons and patients to reach a decision on the most preferable surgical treatment plan. Both over- and underestimation of disease extent are unwanted. Overestimation may result in the excision of an unnecessarily larger breast volume or may even lead to mastectomy when breast conservative therapy is possible. In contrast, underestimation carries the risk of positive surgical margins, requiring additional surgery to remove residual breast cancer. To date, breast MRI is the most accurate imaging tool to assess disease extent.16 High-quality breast MRI protocols optimize evaluation of enhancing structures (cancer) within the breast. When tumors grow, they require nutrients which, at first, are supplied by simple diffusion.17 When a tumor becomes larger, the center of a cancer becomes hypoxic and secretes vascular growth factors, which triggers the formation of adjacent blood vessels in a process called angiogenesis. However, these vessels are rapidly formed and disorganized, which makes them ‘leaky’ to contrast. Contrast is then able to extravasate into the tumor interstitium, resulting in enhancement of the lesion on breast MRI protocols. CESM is also based on this phenomenon, but utilizes iodine-based contrast agents instead of gadolinium-based ones. Because of the similarities in approach, CESM has been frequently compared to breast MRI. Fallenberg et al. studied differences in tumor size measurement between mammography, CESM, and breast MRI.18 In their study of 80 women, they found that the correlation (as expressed by the PCC: Pearson’s correlation coefficient) between the different imaging modalities and the final histopathological results was highest for CESM (PCC of 0.733, 0.654 for breast MRI, and 0.603 for mammography).
8 However, strong correlation does not simply imply good agreement.19 If a certain test has an inherent structural over- or underestimation, the correlation can be excellent although the measurement error is not calculable in these kinds of analyses. They are, however, visible in Bland-Altman plots, where the mean difference between the test of interest and the gold standard are presented in scatterplots for different tumor sizes, including their variation as expressed by the 95% limits of agreement (LOA). Lobbes et al. studied both correlation and agreement between CESM and breast MRI in 57 cases20 and found that the PCC was excellent for both modalities: 0.905 and 0.915, respectively. The mean difference between CESM and histopathological measurement were also smaller than what was observed on MRI exams: 0.03 mm versus 2.12 mm, respectively. As this difference does not seem to be clinically relevant, the authors also studied whether an additional breast MRI exam would be helpful if the oncologically safe surgical margin was set on 1 cm. They did not find any examples where performing breast MRI after CESM yielded information that was surgically relevant in terms of assessing disease extent. However, it should be emphasized that the number of cases was limited, restricting the authors from studying the difference between CESM and breast MRI in multifocality of breast cancer, which is also an important item in assessing true disease extent. Nevertheless, these initial findings demonstrated that CESM may be a viable modality for the evaluation of disease extent prior to treatment (Figure 1). Symptomatic Patients CESM has been studied in the symptomatic setting as well. A retrospective reader study was performed in 100 symptomatic patients with CESM.21 ROC analysis showed statistically significantly improved overall performance of CESM compared to low-energy image alone (AUC 0.93 versus 0.83 respectively). The sensitivity and specificity of CESM compared to low-energy images alone was also improved (95% versus 84%, p<0.025 and 81% versus 63%, p<0.025). Using a decision-making scale used to rate the usefulness of the recombined
9 CESM images, the final assessment of the diagnostic imaging, 75% of the cases were deemed a useful or significant aid to diagnosis (with 25% of the cases having no value added from the CESM recombined image). Another retrospective reader study of 116 patients22 compared performance of CESM, FFDM and US and sensitivity of CESM was 100%, which was significantly higher than that of MG (90%, p<0.004) or US (92%, p<0.01). CESM accuracy was 78%, which was also higher than MG (69%, p<0.004) and US (70%, p=0.03). There was no statistically significant difference between AUCs for CESM and US (both 0.83), however both were significantly larger than that of MG (p<0.0004 for each). One clinically used scenario is to offer CESM to those patients with high levels anxiety despite a negative diagnostic evaluation with standard mammography and ultrasound within the past 6 months. These patients include individuals with a personal history of breast cancer, a persistent or new palpable abnormality, chronic/recurrent breast pain, or high-risk family history. A negative CESM study is reassuring to the patient and clinician and can be a quick answer in lieu of a breast MRI (Figure 2). The literature is still pending on this indication, but clinically we have found it reassuring.
Potential Clinical Indications Neoadjuvant Response Monitoring Neoadjuvant systemic therapy (NST) has evolved as a treatment regimen for previously inoperable, locally-advanced breast cancers. Oncologists now utilize NST in women with certain T1cN0 cancers along with stage II and III breast cancers to facilitate breast conversation and/or improve cosmesis. NST also helps clinicians gauge the in vivo sensitivity of the tumor to systemic therapy and has prognostic significance in patients who achieve a pathologic complete response (pCR). Given the increasing prevalence of NST as an initial
10 treatment strategy, an accurate means for detecting residual malignancy to guide surgical planning or other non-operative management is essential. At present, the most accurate modality to monitor response to neoadjuvant chemotherapy in breast cancer is MRI.23, 24
A recent study that included 21 patients demonstrated 91% specificity of CESM in predicting tumor response with a 100% sensitivity in detection of complete tumor response.25 The discordance between radiological response and pathological response was most prevalent in chemoresistent tumors (defined as MD Anderson score III). The study had 6 cases of false negative CESM which lowered the sensitivity of CESM in predicting tumor response to neoadjuvant treatment to 40%. It was speculated that residual cancer cells may remain as small foci in the tumor bed and receive nutrients by diffusion and not from vascular perfusion and therefore result in a false negative enhancement pattern on CESM. Although results are promising, larger studies are necessary to better understand which cohort of patients will best be served through CESM monitoring. Ongoing work by one of the authors (BKP) demonstrates CESM could serve as an alternative to breast MRI to monitor responsiveness of neoadjuvant systemic therapy (Figure 3). In a study of 47 patients with locally-advanced breast cancer who received NST, the lesion size measurements determined through CESM and MRI were highly correlated; equivalence tests demonstrated that the mean tumor size measured by CESM (p=0.0132) or by MRI (p=0.0194) is equivalent to the mean tumor size measured by pathology within -1 and 1 cm range. In our clinical experience, CESM has been particularly useful for those patients who have contraindications to MRI including in those patients who have a pacemaker, severe claustrophobia, metallic foreign bodies, etc.
11 Dense Breasts Dense breasts have been demonstrated to be a strong independent risk factor for breast cancer.26-29 Given new breast density laws in the United States, supplemental screening has been recommended in some dense-breasted women but specific recommendations have not yet been made as to who would benefit from what modality. In addition to tomosynthesis, whole-breast screening ultrasound and molecular breast imaging are available tools for supplemental breast screening (Figure 4). To date, few30 have compared mammography to mammography plus CESM in the dense breasted population. Fallenberg et al. had a study of 118 women, 56% of which were dense breasted, defined as ACR category 3 or 4 based on reader assessed BIRADS categories. Authors found an increase in sensitivity in dense (71.6% versus 93.3%) versus non-dense (85.8% versus 96.5%) breasted women to be statistically significant (p<0.001). Another study31 with 90% (129/143) dense breasted women demonstrated a sensitivity (p < 0.001), specificity (p = 0.016) and accuracy (p < 0.001) significantly higher on CESM compared to standard mammography. Mammography missed malignancy in 27 breasts of which 25 were dense breasts. Of these 25, 20 (80.0 %) breasts were positive on CESM suggesting there may be value added of CESM as supplemental screening tool in dense breasted population however larger studies are needed. Like all screening tests, however, the potential risks (some which are discussed below) need to be weighed in relation to the benefit of the additional cancers detected.
High-Risk Screening The sensitivity of mammography in high-risk populations with dense breast tissue has been shown to be as low as 30-60%.32-34 MRI, on the other hand, demonstrates a sensitivity of 77100% in high-risk, dense-breasted women and is therefore a more compelling modality. If, as
12 studies have already demonstrated, CESM has equal sensitivity to MRI,18, 35, 36 CESM may play an important role in high-risk screening like MRI. There is limited literature on the use of CESM in the high-risk screening population.37 In our limited experience, were have occasionally used CESM for evaluating women who meet the 20% lifetime risk of breast cancer threshold where MRI is contraindicated or evaluating same day add-ons when MRI appointments are unavailable. Further research is needed.
3. Advantages of CESM
In terms of diagnostic accuracy, CESM is consistently superior to FFDM. In a recent metaanalysis of eight studies, Tagliafico et al. showed that the pooled sensitivity was 98% (95% CI 96-100%), with a more moderate pooled specificity of 58% (95% CI 38-77%).38 The pooled ROC curve showed an AUC value of 0.93. Some of the other potentially eligible publications needed to be excluded since they did not provide absolute numbers in terms of true negative/positive or false negative/positive findings. Jochelson and Lobbes addressed this limited specificity in a letter to the editor, observing that three of the eight included papers were from one single group.39 This group yielded a mammography specificity 15%, which lead Jochelson and Lobbes to question the validity of the resultant CESM specificity of merely 40%. Therefore, the pooled estimates were recalculated excluding these three studies and resulted in a pooled specificity estimate of 78% (95% CI 56-90%). Other studies have compared combinations of mammography, ultrasound, and CESM. Dromain et al. showed that the sensitivity for mammography with ultrasound was significantly lower than the combination mammography/ultrasound/CESM: 71% versus 78%, p=0.006, respectively).40) Luczynska et al. showed that the sensitivity for detecting breast cancer was highest for CESM (100%), followed by ultrasound (92%), and then FFDM
13 (90%).22%) Although this paper did not purely compare mammography/ultrasound with CESM, it is safe to assume that the combination of mammography/ultrasound would yield comparable results as CESM. This is already suggested by the results of Houben et al., who showed that in recalls from screening, CESM detected an additional 3-4% of cancer foci purely based on the information provided by the recombined CESM images. 41 As some of these CESM-detected tumor foci were very small, it is questionable whether they would have been detected by performing additional breast ultrasound. Future studies should therefore also investigate the diagnostic accuracy of CESM combined with targeted ultrasound.
Miscellaneous
There are several other benefits of performing CESM, especially compared to breast MRI. Access to MRI units is limited in many parts of the world and the acquisition of breast MR images is costly while CESM is more likely to be more accessible to a larger population.42 With multiple vendors now entering the CESM arena, more units could be cost-effectively upgraded with CESM options.
Next, CESM’s acquisition time is shorter: the image
acquisition per CESM exposure is only slightly longer than FFDM (mean exposure times 5.6s versus 1.1s, respectively),43 although additional time is required when preparing the patient for intravenous access and contrast administration. Future studies should include robust costeffectiveness analyses to demonstrate the superiority of CESM over breast MRI in this area as well. From a patient’s perspective, Hobbs et al. study the differences in preference and toleration between CESM and MRI. Although patients graded breast compression/positioning and contrast administration less favorable for CESM, in general, they still expressed a preference for CESM over breast MRI.44
14
4. Disadvantages of CESM
CESM also has some relevant disadvantages when compared to other breast imaging modalities.
Radiation exposure in CESM Because CESM consists of two image acquisitions (i.e. a low- and a high-energy image), the radiation dose is higher in comparison to FFDM. Dromain et al. were the first to report on CESM radiation dose and observed a 20% higher dose in comparison to FFDM.40 In a subsequent publication by Fallenberg et al. an even lower dose for CESM was reported when compared to FFDM (1.72 mGy versus 1.75 mGy, respectively).30 In the Fallenberg study, however, FFDM units of multiple vendors and both computed radiography and digital radiography images were used as reference standard. These studies were of limited clinical value, however, as they were performed on prototype CESM units where exposure settings had to be set manually, depending on breast thickness and glandularity (with the aid of a table with predefined exposure variables). In commercial, non-prototype CESM units, these parameters are determined by the automated exposure control (AEC).
Badr et al. also
observed a 54% increase in radiation dose compared to FFDM (2.65 mGy versus 1.72 mGy, respectively).45 Nevertheless, these results were based on numbers produced by the unit itself. Jeukens et al. were the first to validate machine-generated numbers using well-validated phantom measurements and observed an 81% increase in radiation dose in their clinical data set using the commercially available unit from GE Healthcare (Senographe* Essential with the SenoBright* CESM upgrade, GE Healthcare, Chalfont, UK).43 For a single exposure, the AGD for a CESM exam was 2.80 mGy, versus 1.55 mGy for a single FFDM exposure. These
15 findings were in line with previous results by Badr et al. and also in line with subsequent results found by James et al.46 James et al. used a commercially available unit from Hologic (Selenia Dimensions, software version 1.8.3, Malborough, MA, USA) and found that the AGD for CESM was 3.0 mGy versus 2.1 mGy for FFDM. Although the radiation dose of a CESM exam is higher than the FFDM radiation dose, it should be emphasized that the overall CESM dose is still within internationally accepted radiation dose limits and that the chances of inducing breast cancer through these exams is neglible. The health detriment caused by radiation exposure can be estimated from the AGD and the lifetime attributable risk (LAR) factors for breast cancer incidence and mortality. As was demonstrated by Jeukens et al., LAR for a unilateral, single FFDM or CESM exposure had a small risk of only 0.002-0.0003% per 100,000 women for breast cancer incidence, respectively.43 However, one should note that the lifetime risk of breast cancer incidence is much higher and, according to the American Association of Physicists in Medicine, an effective radiation dose beneath 50 mGy will not have adverse consequences.
Application of iodine based contrast agents in CESM
Unwanted side-effects, including hypersensitivity reactions and the occurrence of CIN, can occur when using iodine-based contrast agents. Hypersensitivity reactions can vary from mild and self-limiting up to severe anaphylactic shock but the risk of developing severe hypersensitivity reactions is small nowadays. With the latest generation of non-ionic iodinated contrast media, the incidence of hypersensitivity reactions has decreased, with an estimated incidence of 0.7-3.1%. Severe hypersensitivity reactions occur in only 0.02-0.04% of contrast administrations.47
Death caused by the administration of iodinated contrast agents is
extremely rare and generally reported in patients with severe and extensive co-morbidity.
16 However, women undergoing breast imaging for whatever reason generally do not fit into this latter category. As a practical example, Houben et al. recently observed hypersensitivity reactions in women undergoing CESM in 0.6% of the cases, with most reactions being mild and self-limiting after a prolonged observation period.41 Hence, the use of iodine based contrast agents in CESM is generally safe with respect to the risk of introducing hypersensitivity reactions. Nevertheless, institutions using CESM should familiarize themselves with the identification of hypersensitivity reactions and should train their staff to adequately cope with these stressful situations, for example through frequent simulator trainings. A second disadvantage of using iodinated contrast agents in CESM is that it might cause CIN, which is reported to occur in 1% to 20% of cases, depending on the population studied in various publications.48 CIN is defined as “as condition in which an impairment of renal function (i.e., an increase of serum creatinine by more than 25% or 44 umol/L) occurs within three days after intravascular administration of an iodine based contrast agent and in the absence of an alternative aetiology”.49 To identify patients at risk for developing CIN, questionnaires are usually employed to determine which patients should have their renal function assessed through blood testing. Nevertheless, CIN and its clinical impact is a topic of ongoing debate.50,
51
Since CIN cannot be treated, many national guidelines suggest
prehydration protocols in patients with impaired renal function that require contrast administration. A recent study by Nijssen et al. demonstrated that refraining from prehydration is a non-inferior and cost-saving approach in the prevention of CIN compared with preventative prehydration in this category of patients.52 Hence, countries should reconsider their national guidelines but an extensive review of CIN and its role in clinical practice is beyond the scope of this review.
17 False positive findings caused by CESM
During CESM, enhancing lesions may be observed on recombined images that were deemed unsuspicious or otherwise not visible on low-energy images. The PPV of enhancement of lesions in a CESM exam warrants tissue sampling of these lesions, regardless of their morphology. This creates a situation in where the usage of CESM results in additional tissue sampling of lesions that turn out to be benign (i.e. false-positive findings). The presence of false-positive findings has been described in several publications. Badr et al. showed that enhancement was observed in 33% of 27 benign lesions.45 Jochelson et al. observed two false-positive findings in 52 cases (of note, 13 were observed in the breast MRI group)36) and Lobbes et al. detected five false-positive findings in a population of 113 women recalled from screening.14 Most of these false-positive lesions are caused by fibroadenomas (Figure 5). although a vast variety of benign lesions have been reported as false-positive CESM findings. Although these might lead to unnecessary tissue biopsy, the current biopsy protocols are extremely safe, with the two most important complications being hematomas or infection at the biopsy site. The incidence of biopsy-related complications is estimated to be 0.2%.41
At present, there have been no studies with published results on CESM-guided stereotactic biopsy or localization.53Although rare, CESM may demonstrate enhancing lesions on recombined images that do not have a correlate on low-energy (mammographic) images. Hence, conventional stereotactic biopsy is not possible, creating the necessity to perform CESM-guided biopsy procedures. Although technical developments are in progress, it is currently not possible to perform these kinds of interventions. As a workaround, breast MRI is generally employed in these cases to determine if the enhancing abnormality is real and not an artifact. Subsequently, an MRI-guided biopsy procedure can be scheduled if the lesion is real
18 and accessible through MRI-guided biopsy. From our clinical experience, the occurrence of such cases is rare and the abovementioned workaround has always lead to a final diagnosis in these challenging cases.
5. Conclusions
CESM is a growing technique for breast cancer detection and diagnosis that has levels of sensitivity and specificity on par with contrast-enhanced breast MRI. Because of its similar performance and ease of implementation, CESM is being adopted for multiple indications previously reserved for MRI, such as problem-solving, disease-extent in newly diagnosed patients and evaluating the treatment response of neoadjuvant chemotherapy.
CESM is
currently being studied for screening both high-risk and medium-risk patients. CESM is also more efficient and less costly than MRI due to reduced equipment costs and shorter examination times. Future studies with larger patient numbers are necessary to validate the initial literature.
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Poster
25
Table 1 Acquisition of the CESM images
26
Table 2
27
A
B
Figure 1 80-year-old female with new palpable right breast abnormality.
Diagnostic ultrasound
imaging showed 3.5 cm irregular mass in the left 1:00 breast underlying palpable abnormality. Ultrasound biopsy demonstrated high grade DCIS. Low energy (A) CESM shows no mammographic abnormality. Recombined (B) CESM and MRI (C) demonstrate a large 10 cm area of non-mass enhancement. Surgical pathology at time of mastectomy confirmed 10 cm of DCIS.
28
Figure 2.
62-year-old woman with negative outside imaging (MG and US) for palpable
abnormality in left subareolar breast. Low energy (A) and recombined (B) CESM images confirm negative study. Clinical management was recommended with negative follow up on imaging and clinically 24 months later.
29
Figure 3.
38-year-old female with ultrasound guided biopsy demonstrating ER negative,
PR negative HER2 positive IDC of a palpable right breast mass. Low energy (A) and recombined (B) pretreatment CESM images demonstrate multicentric disease with mass (arrows) and intervening nonmass enhancement spanning the central and medial breast. Post treatment low energy (C) and recombined (D) images demonstrate no residual enhancement. Surgical pathology from mastectomy specimen confirmed no residual carcinoma.
30
Figure 4. 64-year-old female with dense breast on standard low energy mammogram. Recombined image clearly shows an irregular moderately enhancing mass (arrow) in the central breast, mid depth. This was biopsy proven IDC, NOS at the time of ultrasound guided biopsy.
31
4
Figure 5
46-year-old woman with mass on screening mammography. A) Oval mass with
indistinct margins on FFDM(arrow). B) CESM prior to biopsy demonstrates heterogenous enhancement in the lobulated mass in the upper outer quadrant on recombined image (arrow). C) US guided percutaneous biopsy demonstrated a benign fibroadenoma (arrow).