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Contrast-Enhanced Spectral Mammography
Guest Editorial
Contrast-Enhanced Spectral Mammography: An Emerging New Tool in the Clinician’s Arsenal Brad M. Keller, PhD Imaging has evolved to play a unique role in the fight against cancer, as a tool both for screening and detection and for assessing the extent and severity of any cancer found. The ultimate goal of screening is to find cancers smaller and earlier when treatments are most effective. Once a cancer is confirmed with percutaneous core or excisional biopsy, imaging plays a unique role as a noninvasive tool to establish extent of disease and cancer stage, which has substantial downstream implications for appropriate treatment selection. In the case of breast cancer, digital mammography is the primary screening modality for women in the United States, whereas multiple options exist for establishing extent of disease and staging. Establishing the extent of disease in breast cancer involves assessing the size of the primary tumor and whether the cancer has spread to the axillary lymph nodes (1) and looking for synchronous malignancy in the opposite breast. Breast magnetic resonance imaging (MRI) is most commonly used for this indication. Staging evaluation of breast cancer is a clinical decision based on multiple factors including assessing for distant metastatic spread (eg, outside the breast and axillae). Multiple modalities such as computed tomography (CT), positron emission tomography/CT, and bone scintigraphy are used for this indication. Although receptor status and other tumor properties play a role in the treatment decision process, accurate size assessment is critical to determine patient management. For example, in node-negative breast cancer cases, the choice of whether to use systemic adjuvant chemotherapy primarily depends on whether the primary lesion is larger or smaller than 1 cm in diameter (2). Choices of local and neoadjuvant therapy and the appropriateness of breast conservation surgery are also often based on tumor size and stage. Understandably, determining which imaging method allows for the highest agreement between estimated tumor size, subtype, and stage and the pathologic ground truth could lead to improvements in appropriate treatment selection.
Acad Radiol 2014; 21:1361–1362 From the Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, 3600 Market St. Suite 360, Philadelphia, PA 19104-2643. Received September 7, 2014; accepted September 9, 2014. Address correspondence to: B.M.K. e-mail: [email protected] ªAUR, 2014 http://dx.doi.org/10.1016/j.acra.2014.09.002
Research investigating the utility of mammography, MRI, and ultrasound in tumor size assessment has revealed that all three modalities may substantially disagree with pathologic assessment, and differences over 2 cm between radiologic and pathologic sizes can be frequently observed (3,4). Systematic biases can also be observed depending on the choice of imaging modality: use of MRI has a tendency to lead to overestimates of tumor size (3,5), whereas underestimation of size is more common when mammography or ultrasound is used (4,5). Recently, dual-energy contrast-enhanced spectral mammography (CESM) has emerged as a potential new option for breast cancer staging by allowing for improvements in breast cancer tumor visualization (6) and may be equivalent to MRI for tumor size assessment (7,8). CESM, also commonly referred to as contrast-enhanced digital mammography, operates under the principle that iodinated contrast agents injected into the blood stream will have different uptake patterns between hypervascularized breast lesions and background breast parenchyma and that dual-energy subtraction imaging will allow for selective visualization of the distribution of the contrast agent in the breast with minimal anatomic background ‘‘noise’’ to obscure the lesion. In the article by Blum et al. (9) in this issue of Academic Radiology, the authors evaluate and compare lesion size measurements made on CESM and ultrasound to histopathologic assessment on a data set of images from 20 women with histology-proven invasive breast cancer. Using consensus reading, three expert gynecologists and two expert radiologists assessed the tumor size in the ultrasound and CESM images, respectively. Bland–Altman analysis was used to assess the relative agreement and variability between the image-based size assessments made from the two modalities and the gold standard histologic assessment. Overall, Blum et al. found that ultrasound tends to underestimate tumor size, which is in agreement with prior literature (4,5), whereas CESM did not appear to have much systematic bias toward either overestimation or underestimation of tumor size. In contrast, comparison of the Bland–Altman 95% limits of agreement (LOA) suggests that tumor size assessed via CESM (LOA, 18.9 to 19.48 mm) tends to have lower overall agreement to histologic assessment than do size measurements made using ultrasound (LOA, 17.1 to 12.7 mm), although this variability does seem to be sensitive to tumor size, as there 1361
KELLER
tended to be a higher level agreement between image-based and pathology size assessment in smaller tumors. Finally, the authors note that tumor size measurements made on CESM are not strongly influenced by a woman’s breast density, implying that CESM may be most useful in staging women with dense breast tissue. Ultimately, the authors state that the use of CESM can lead to more accurate tumor size estimates relative to ultrasound; however, given that disagreement between CESM and pathology can be greater than between ultrasound and pathology, more evaluation is needed before such a statement can be conclusively made. The study has several other limitations of note, including the fact that consensus reads were done, which precludes intra- and inter-reader variability assessment. The impact of modality choice on ultimate treatment decisions and patient outcomes will also need to be assessed before the question of which modality is best for staging can be definitively answered. That said, the work by Blum et al. does add to the understanding of the performance of CESM and provides some initial evidence that CESM may be useful in certain specific contexts, particularly in staging women with complex breast tissue and for quantifying the size of smaller, early-stage, breast cancers. Addressing the challenge of reader variability in the quantitative assessment of tumors, whether in terms of cancer detection, staging, or response assessment, is going to be a critical focus of the field moving forward. As such, empirical investigation of the accuracy and precision of new and emerging modalities, such as CESM, and of the imaging protocols used in practice will set a valuable precedence for the community to decide on standards and practices for appropriate use, such as which lesion types should be assessed by which modalities and the minimum performance expected when particular protocols are used. There will also likely be an increasing role for computer-aided and automated methods in lesion characterization, especially in the context of tumor size and treatment response assessment, where reader variability is potentially the highest.
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Academic Radiology, Vol 21, No 11, November 2014
In conclusion, imaging plays and will continue to play a key role in tumor staging, and therefore treatment selection, and thus the continued assessment of emerging technologies will be critical to increase concordance between radiologic and pathologic assessments of tumor extent, improving the treatment decision process and patient care.
ACKNOWLEDGMENTS The author would like to thank his colleagues Dr. Elizabeth S. McDonald, Dr. Emily Conant, and Dr. Despina Kontos of the University of Pennsylvania for their critical review of the article.
REFERENCES 1. Kopans DB. Breast imaging. 3rd ed. Baltimore, MD: Lippincott Williams & Wilkins, 2007. 2. National Institutes of Health Consensus Development Panel. National Institutes of Health Consensus Development Conference statement: adjuvant therapy for breast cancer, November 1–3, 2000. J Natl Cancer Inst 2001; 93(13):979–989. 3. Schouten van der Velden AP, Boetes C, Bult P, et al. The value of magnetic resonance imaging in diagnosis and size assessment of in situ and small invasive breast carcinoma. Am J Surg 2006; 192(2):172–178. 4. Heusinger K, Lohberg C, Lux MP, et al. Assessment of breast cancer tumor size depends on method, histopathology and tumor size itself*. Breast Cancer Res Treat 2005; 94(1):17–23. 5. Gruber IV, Rueckert M, Kagan KO, et al. Measurement of tumour size with mammography, sonography and magnetic resonance imaging as compared to histological tumour size in primary breast cancer. BMC Cancer 2013; 13:328. 6. 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. 7. Lobbes MB, Lalji U, Houwers J, et al. Contrast-enhanced spectral mammography in patients referred from the breast cancer screening programme. Eur Radiol 2014; 24(7):1668–1676. 8. Fallenberg EM, Dromain C, Diekmann F, et al. Contrast-enhanced spectral mammography versus MRI: initial results in the detection of breast cancer and assessment of tumour size. Eur Radiol 2014; 24(1):256–264. 9. Blum KS, Rubbert C, Mathys B, et al. Use of contrast-enhanced spectral mammography for intramammary cancer staging: preliminary results. Acad Radiol 2014; 21:1363–1369.
Contrast-Enhanced Spectral Mammography: An Emerging New Tool in the Clinician’s Arsenal Brad M. Keller, PhD Imaging has evolved to play a unique role in the fight against cancer, as a tool both for screening and detection and for assessing the extent and severity of any cancer found. The ultimate goal of screening is to find cancers smaller and earlier when treatments are most effective. Once a cancer is confirmed with percutaneous core or excisional biopsy, imaging plays a unique role as a noninvasive tool to establish extent of disease and cancer stage, which has substantial downstream implications for appropriate treatment selection. In the case of breast cancer, digital mammography is the primary screening modality for women in the United States, whereas multiple options exist for establishing extent of disease and staging. Establishing the extent of disease in breast cancer involves assessing the size of the primary tumor and whether the cancer has spread to the axillary lymph nodes (1) and looking for synchronous malignancy in the opposite breast. Breast magnetic resonance imaging (MRI) is most commonly used for this indication. Staging evaluation of breast cancer is a clinical decision based on multiple factors including assessing for distant metastatic spread (eg, outside the breast and axillae). Multiple modalities such as computed tomography (CT), positron emission tomography/CT, and bone scintigraphy are used for this indication. Although receptor status and other tumor properties play a role in the treatment decision process, accurate size assessment is critical to determine patient management. For example, in node-negative breast cancer cases, the choice of whether to use systemic adjuvant chemotherapy primarily depends on whether the primary lesion is larger or smaller than 1 cm in diameter (2). Choices of local and neoadjuvant therapy and the appropriateness of breast conservation surgery are also often based on tumor size and stage. Understandably, determining which imaging method allows for the highest agreement between estimated tumor size, subtype, and stage and the pathologic ground truth could lead to improvements in appropriate treatment selection.
Acad Radiol 2014; 21:1361–1362 From the Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, 3600 Market St. Suite 360, Philadelphia, PA 19104-2643. Received September 7, 2014; accepted September 9, 2014. Address correspondence to: B.M.K. e-mail: [email protected] ªAUR, 2014 http://dx.doi.org/10.1016/j.acra.2014.09.002
Research investigating the utility of mammography, MRI, and ultrasound in tumor size assessment has revealed that all three modalities may substantially disagree with pathologic assessment, and differences over 2 cm between radiologic and pathologic sizes can be frequently observed (3,4). Systematic biases can also be observed depending on the choice of imaging modality: use of MRI has a tendency to lead to overestimates of tumor size (3,5), whereas underestimation of size is more common when mammography or ultrasound is used (4,5). Recently, dual-energy contrast-enhanced spectral mammography (CESM) has emerged as a potential new option for breast cancer staging by allowing for improvements in breast cancer tumor visualization (6) and may be equivalent to MRI for tumor size assessment (7,8). CESM, also commonly referred to as contrast-enhanced digital mammography, operates under the principle that iodinated contrast agents injected into the blood stream will have different uptake patterns between hypervascularized breast lesions and background breast parenchyma and that dual-energy subtraction imaging will allow for selective visualization of the distribution of the contrast agent in the breast with minimal anatomic background ‘‘noise’’ to obscure the lesion. In the article by Blum et al. (9) in this issue of Academic Radiology, the authors evaluate and compare lesion size measurements made on CESM and ultrasound to histopathologic assessment on a data set of images from 20 women with histology-proven invasive breast cancer. Using consensus reading, three expert gynecologists and two expert radiologists assessed the tumor size in the ultrasound and CESM images, respectively. Bland–Altman analysis was used to assess the relative agreement and variability between the image-based size assessments made from the two modalities and the gold standard histologic assessment. Overall, Blum et al. found that ultrasound tends to underestimate tumor size, which is in agreement with prior literature (4,5), whereas CESM did not appear to have much systematic bias toward either overestimation or underestimation of tumor size. In contrast, comparison of the Bland–Altman 95% limits of agreement (LOA) suggests that tumor size assessed via CESM (LOA, 18.9 to 19.48 mm) tends to have lower overall agreement to histologic assessment than do size measurements made using ultrasound (LOA, 17.1 to 12.7 mm), although this variability does seem to be sensitive to tumor size, as there 1361
KELLER
tended to be a higher level agreement between image-based and pathology size assessment in smaller tumors. Finally, the authors note that tumor size measurements made on CESM are not strongly influenced by a woman’s breast density, implying that CESM may be most useful in staging women with dense breast tissue. Ultimately, the authors state that the use of CESM can lead to more accurate tumor size estimates relative to ultrasound; however, given that disagreement between CESM and pathology can be greater than between ultrasound and pathology, more evaluation is needed before such a statement can be conclusively made. The study has several other limitations of note, including the fact that consensus reads were done, which precludes intra- and inter-reader variability assessment. The impact of modality choice on ultimate treatment decisions and patient outcomes will also need to be assessed before the question of which modality is best for staging can be definitively answered. That said, the work by Blum et al. does add to the understanding of the performance of CESM and provides some initial evidence that CESM may be useful in certain specific contexts, particularly in staging women with complex breast tissue and for quantifying the size of smaller, early-stage, breast cancers. Addressing the challenge of reader variability in the quantitative assessment of tumors, whether in terms of cancer detection, staging, or response assessment, is going to be a critical focus of the field moving forward. As such, empirical investigation of the accuracy and precision of new and emerging modalities, such as CESM, and of the imaging protocols used in practice will set a valuable precedence for the community to decide on standards and practices for appropriate use, such as which lesion types should be assessed by which modalities and the minimum performance expected when particular protocols are used. There will also likely be an increasing role for computer-aided and automated methods in lesion characterization, especially in the context of tumor size and treatment response assessment, where reader variability is potentially the highest.
1362
Academic Radiology, Vol 21, No 11, November 2014
In conclusion, imaging plays and will continue to play a key role in tumor staging, and therefore treatment selection, and thus the continued assessment of emerging technologies will be critical to increase concordance between radiologic and pathologic assessments of tumor extent, improving the treatment decision process and patient care.
ACKNOWLEDGMENTS The author would like to thank his colleagues Dr. Elizabeth S. McDonald, Dr. Emily Conant, and Dr. Despina Kontos of the University of Pennsylvania for their critical review of the article.
REFERENCES 1. Kopans DB. Breast imaging. 3rd ed. Baltimore, MD: Lippincott Williams & Wilkins, 2007. 2. National Institutes of Health Consensus Development Panel. National Institutes of Health Consensus Development Conference statement: adjuvant therapy for breast cancer, November 1–3, 2000. J Natl Cancer Inst 2001; 93(13):979–989. 3. Schouten van der Velden AP, Boetes C, Bult P, et al. The value of magnetic resonance imaging in diagnosis and size assessment of in situ and small invasive breast carcinoma. Am J Surg 2006; 192(2):172–178. 4. Heusinger K, Lohberg C, Lux MP, et al. Assessment of breast cancer tumor size depends on method, histopathology and tumor size itself*. Breast Cancer Res Treat 2005; 94(1):17–23. 5. Gruber IV, Rueckert M, Kagan KO, et al. Measurement of tumour size with mammography, sonography and magnetic resonance imaging as compared to histological tumour size in primary breast cancer. BMC Cancer 2013; 13:328. 6. 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. 7. Lobbes MB, Lalji U, Houwers J, et al. Contrast-enhanced spectral mammography in patients referred from the breast cancer screening programme. Eur Radiol 2014; 24(7):1668–1676. 8. Fallenberg EM, Dromain C, Diekmann F, et al. Contrast-enhanced spectral mammography versus MRI: initial results in the detection of breast cancer and assessment of tumour size. Eur Radiol 2014; 24(1):256–264. 9. Blum KS, Rubbert C, Mathys B, et al. Use of contrast-enhanced spectral mammography for intramammary cancer staging: preliminary results. Acad Radiol 2014; 21:1363–1369.