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Evidence for Utilizing Magnetic Resonance Imaging to Detect Breast Cancer in the Axilla and Contralateral Breast

Kevin D. Evans, PhD, RT(R)(M)(BD), RDMS, RVS, FSDMS

     *Director/Assistant Professor, Radiologic Sciences and Therapy Division, The Ohio State University, Columbus, Ohio.
    Address correspondence to: Kevin D. Evans, PhD, RT(R)(M)(BD), RDMS,RVS, FSDMS, Director/Assistant Professor, Radiologic Sciences and Therapy Division, The Ohio State University, 453 West 10th Avenue, 340 A. Atwell Hall, Columbus, OH 43210. E-mail: Kevin.Evans@osumc.edu.

ABSTRACT

Cancer of the breast is the leading cancer that affects women in the US population, and has consequently been the subject of widespread research and educational campaigns to improve the rates of early detection and successful treatment. Breast cancer incidence in the United States continues to rise at a steady rate, but aggressive research has improved the ability of clinicians to predict breast tumor behavior based on the size of the tumor. Smaller tumors are less likely to metastasize to the lymph nodes, and it is now recommended that women receive regular screening mammograms and clinical breast examinations to identify tumors at an early stage and improve the probability of successful treatment. Furthermore, the American Cancer Society now endorses complimentary imaging of the breast, including a strong endorsement of magnetic resonance imaging (MRI), to detect lymph node involvement and contralateral disease extension. Those at an increased risk of breast cancer due to genetic predisposition, family history, or medical history may especially benefit from the use of MRI of the breast to detect early disease. Although the widespread utilization of MRI of the breast is challenged by concerns of costs, limited equipment availability, and inherent technical limitations, the consideration of MRI in patients with a greater degree of risk factors may improve early disease detection and successful treatment in these individuals. A literature review of MRI of the breast is provided to offer perspective on breast MRI in clinical practice and its utility in detecting nodal involvement and contralateral disease extension.

Introduction

Breast cancer is a relatively common health risk in women, a fact that has been widely publicized and backed by extensive research. Despite advancements in diagnostic tools and treatments, as well as the wealth of public awareness campaigns undertaken by devoted health advocates, breast cancer rates have been steadily rising at a rate of 0.6% per year since 1986.1 Although breast cancer has not been eradicated, a great deal of information continues to be collected that improves our knowledge of the nature of this disease. For instance, advanced understanding of breast tumors has resulted in the ability to predict the behavior of a malignant breast tumor and its tendency to metastasize, based on the size of the host tumor.2-7 The frequency of metastasis to the axillary nodes in patients with tumors of less than 1.0 cm is 10% to 20%.4,8 Therefore, the importance of providing access to diagnostics that allow for early detection of breast tumors is paramount, and it is likewise critical to evaluate the contralateral breast and axillary lymph nodes to ensure that the disease is properly staged. The importance of utilizing appropriate diagnostic studies to reduce nodal metastasis is demonstrated by the fact that only 20% to 30% of node negative patients will develop a reoccurrence in 10 years compared to 70% of patients with nodal involvement.9 Unfortunately, despite extensive public health campaigns that emphasize regular screening mammography and clinical breast examinations, as well as improvements in patient access to regular diagnostic care, 10% of patients will experience a metastasis of breast cancer into the contralateral breast.10-13

The American Cancer Society (ACS) has been aggressive in endorsing complimentary imaging of the breast to help reduce nodal and contralateral disease extension. Recently, ACS issued a strong endorsement of magnetic resonance imaging (MRI) of the breast. This endorsement of MRI as a valuable diagnostic tool is not without reservations about costs, the lack of standardized techniques and interpretation criteria, the inability to detect microcalcifications, limited equipment availability, and the relatively high rate of high false-positive results.14 Nevertheless, the role of MRI has expanded and is having a substantial impact on disease detection, especially among women with an increased risk of breast cancer, such as those with the breast cancer (BRCA)1 and BRCA2 gene mutations.14 Importantly, it has been shown that some BRCA1 and BRCA2 gene mutations can manifest as either ovarian or breast cancer.14 An additional method for determining patients at high risk for breast cancer is the Gail Model Risk assessment model. Healthcare providers can use the Gail model to determine a short-term and lifetime risk of breast cancer based on menarche, age at birth of first child, number of breast biopsies, family history, and biopsy results.15 Isolating those women with gene mutations and high Gail Model Risk scores allows clinicians to recommend MRI as an additional screening and diagnostic tool. Although MRI is faced with issues of cost and overall sensitivity rates, this tool may be an important imaging option for breast cancer screening and extension of breast cancer involvement to the contralateral breast, as well as the axillary lymph nodes. This article will address the current literature supporting MRI of the breast and will provide a practical overview of this tool in the clinical setting.

MRI of the Breast

Breast imaging with MRI requires the administration of a contrast agent and a dedicated breast coil for use with existing MRI equipment.16 Since the advent of MRI of the breast as a diagnostic option, this tool has been continually refined and has become increasingly sensitive due to advances in coil design and contrast agents.

Breast Coil
As with any MRI examination, the breast coil is designed to detect a radiofrequency signal. The coil acts as an antenna that picks up the radio waves emitted from the body as a result of being exposed to the strong magnetic field of the MRI device. The utilization of a multicoil array with a geometric design allows for tumor detection with a high signal-to-noise ratio that covers both breasts, the chest wall, and the axilla. It is important to note that axilla imaging with MRI may be limited due to the smaller field of view compared to conventional imaging equipment. Additionally, the ability of MRI to provide images of great detail may be limited by the patient's relative comfort with the procedure. Patient comfort is often compromised by the limited space provided in the bore and the need to place the patient prone with the torso elevated during the study.16 As with any imaging technique, the closer the breast tissue is to the coil, the better the detail and ultimate resolution of the image. Finally, the size of the patient may also present some challenges in obtaining a quality image.

Contrast Agents
The use of advanced contrast agents to provide higher definition of vascular tumor growth has improved the sensitivity of studies with the goal of early tumor detection. The radiographic contrast agent gadolinium-DPTA is a T1 shortening agent that reflects the vascular density and permeability of cancer based on the extent to which it collects in the tissue. Peak enhancement of gadolinium-DPTA occurs within the first 2 minutes after bolus injection of the agent. Consequently, the protocol for image acquisition must be repeated at 1-minute intervals or shorter as the signal intensity changes.16 This results in images that capture subtle changes in the signal that is emitted from questionable areas in the breast tissue. The use of specially designed breast coils, coupled with the administration of gadolinium-DPTA, has enhanced the ability of MRI to provide valuable screening and diagnostic images in high-risk women.

Kinetic Studies
Kinetic analysis requires the intravenous administration of contrast agent injected over a period of time, and has become an invaluable tool that provides a quantitative assessment of the behavior of a suspected lesion.17 Three types of kinetic maps have been identified to characterize contrast uptake in kinetic analysis:

  • Type I: Continuous progressive enhancement of the area over time, which is typical of benign lesions.
  • Type II: A plateau curve that is a combination of Type I and III, which may be observed in both benign and malignant lesions.
  • Type III: A washout curve, indicating that the area quickly takes up the contrast agent and promptly washes it out. This behavior has been attributed to the angiogenic nature of malignancies with many microvessels feeding the tumor.17

Protocol for Breast MRI

Although variability may exist among institutions and types of equipment manufacturers, it is important to provide a sample protocol for performing breast MRI. The first phase of the examination involves collection of bilateral 3D T1-weighted, spoiled-gradient sequence images of the patient. Next, imaging is preformed with bilateral 2D T2-weighted, fast spin echo with fat saturation. This is followed by 3D T1-weighted, spoiled-gradient sequence with fat saturation.18 This series of images provides excellent soft-tissue contrast and allows for visualization of architectural distortion with superior detail.

Lastly, bilateral dynamic 3D T1-weighted, spoiled-gradient images with fat saturation are obtained after contrast injection.18 Dynamic images provide documentation of how contrast media is absorbed and washed out of the tissue. This analysis is important in the detection of angiogenesis or microcirculation associated with tumor development. Contrast agent spilling into adjacent breast tissue increases the signal intensity that can be detected on the image. In addition, dynamic imaging with MRI allows for the evaluation of the morphology of lesions. Similar to mammography, features such as irregular borders, speculation, enhancement of the tissue, and inhomogeneity are all hallmarks of malignancy.

Evidence of an Emerging Role of MRI to Diagnosis Breast Cancer Extension

Although MRI has an important role in following patients who have already undergone a mammogram or a breast ultrasound, new emerging roles for this diagnostic modality have been identified that may enhance the ability to diagnose the stage of disease. For instance, bilateral MRI of the breast is valuable in determining ipsilateral breast cancer extension (Figures 1 and 2).19 Research studies have shown that MRI with intravenous injection of gadolinium-DPTA has a sensitivity of 83% to 100% in detecting tumors that are only a few centimeters in size.20 The other area of impact on patient outcomes is the use of MRI to locate positive axillary nodes (Figures 3-7).18 However, as mentioned earlier in this article, axillary nodes may be difficult to visualize due to coil construction and patient positioning.


Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Figure 7
 

Literature Review

To further explore the emerging role of MRI breast imaging, an evidenced-based review of the current literature is essential. The distillation of results from published studies provides the necessary framework to determine the reliability of MRI and the future direction of MRI in the detection of contralateral breast and nodal extension of breast cancer. In both of these applications, MRI breast imaging has made a substantial impact among women exhibiting an elevated risk of breast cancer.

The use of MRI to detect local and ipsilateral extension of breast cancer is most useful in patients who are at risk for a synchronous contralateral cancer, which is defined as occurring within 3 months, 6 months, or 1 year after diagnosis of the primary tumor.21 Importantly, it has been demonstrated that contralateral breast cancer metastasis is likely regardless of detection with mammography, physical examination, or both in approximately 2% to 20% of women with breast cancer.20 Moreover, patients with bilateral breast cancer are more likely to have a genetic disposition for this disease and decreased overall survival.22

Utilization of MRI to detect metastatic activity in axillary lymph nodes is best accomplished by imaging nodes on T2-weighted sequences that have an intermediate-to-high signal intensity. On the postcontrast, T1-weighted sequences show vivid homogenous enhancement or rim enhancement.23 It has also been noted that the size of lymph nodes measured by MRI cannot be used to make the MRI diagnosis.23 Given these pearls of wisdom, a review of current research adds an additional layer of useful information in alerting clinicians to the importance of using MRI for the detection of contralateral breast involvement and nodal extension of breast cancer.

Contralateral Breast Cancer Screening
A series of case studies, which admittedly represents the lowest level of clinical evidence in terms of the degree of rigorousness, demonstrated the successful use of breast MRI imaging in detecting contralateral breast involvement, tumor recurrence, and staging of disease in 3 patients. In this series of case studies, 2 patients presented with normal mammography studies and breast ultrasound examinations of the contralateral breast after receiving a diagnosis of breast cancer approximately 2 years prior to the analysis. The patients underwent breast MRI, and the resulting contrast images revealed a small area of increased contrast uptake that was found to be a metastatic lesion.24 The third patient in the case series was undergoing MRI for disease staging to determine the appropriate course of therapy for diagnosed breast cancer and subsequently reported pain in her contralateral breast coexistent with a palpable lump. She was referred for breast MRI after suspicious mammograms and ultrasound findings of this same area. Again, on contrast images only, the rapid uptake of this contralateral area of the breast was discovered to contain a metastatic lesion.24 Although these case studies are limited, and it should be emphasized that these findings only represent the outcomes of these individual patients, the case series does illustrate the value of contrast-enhanced MRI of the breast to detect a reoccurring cancer in these individuals.

Cohort studies of MRI breast imaging in the detection of contralateral breast cancer are also available and represent a higher level of evidence. One cohort study was conducted on a group of 17 patients with biopsy-confirmed breast cancer. A 1.5 Tesla MRI study was conducted with T1, administration of gadolinium-DPTA, and T2-weighted images, which successfully isolated 5 of the 17 patients with contralateral breast cancer extension. In these 5 patients with contralateral breast cancer extension, a total of 10 lesions were identified. Of the contralateral lesions imaged, 9 were confirmed as malignancies. Additionally, 4 of the 17 patients suffering from invasive breast cancer also were found to have contralateral extension (24%).25

The increased resolution that can be obtained with single breast imaging represents a possible quality compromise in conducting bilateral studies. However, this cohort study highlights the utility of bilateral studies in investigating the potential for contralateral lesions. This analysis was limited by the size of the population studied, and larger studies are now being called for to provide a better level of evidence in considering the compromise between the higher resolution of single breast imaging and the ability to detect contralateral lesions in bilateral studies.

Another cohort study was conducted from a sample of 182 patients that underwent a 1.5 Tesla MRI study. Bilateral studies were conducted in these individuals and, as a result, 15 patients were found to have contrast-enhancing lesions in the contralateral breast. Of this group of 15 women, 7 were confirmed to have malignant contralateral lesions (3.8%).26 This study was designed as a feasibility study of conducting bilateral studies and to demonstrate the importance of detecting contralateral lesions. The investigators studied a larger population than previous analyses, and the yield in detecting contralateral lesions was a small percentage of the overall population, which again raises the issue in exchanging the higher resolution of single breast imaging for the possibility of detecting contralateral involvement. It should be noted that the investigators also examined results in patients with a risk for contralateral breast lesions based on family history, index cancer histology, breast density, and age of first diagnosis. Importantly, no significance was attached to these risk factors in helping to isolate those patients who would benefit from a bilateral study.26

Another cohort study was conducted in 118 patients with an average age of 52 years, all of whom were imaged with a 1.5 Tesla MRI and gadolinium contrast. A total of 28 contralateral lesions were detected in this population, and the diagnostic strategy yielded a sensitivity of 100% and specificity of 94% in detecting malignancies.27 The study included a long-term follow-up of subjects, and found that the incidence of contralateral breast cancer was maintained after 2 years. This landmark study demonstrated the high level of accuracy with bilateral studies to detect contralateral breast lesions. Although results from these cohort studies are compelling, randomized, controlled studies are now needed to confirm these findings.

Axillary Nodes Breast Cancer Screening
The level of evidence that has been provided for the use of MRI to evaluate lymph nodes begins with a number of cohort research studies. One study was conducted in the United Kingdom and included 90 patients who were diagnosed with breast cancer. The study used a 1.0 Tesla magnet to provide staging information in these patients. Using gadolinium, 75 of the patients were shown to have abnormal enhancement postcontrast within their axillary nodes. Interestingly, nodes larger than 5 mm yielded a postcontrast signal that was greater than the signal emanating from surrounding soft tissue. Overall, gadolinium in conjunction with breast MRI yielded a sensitivity of 90% and a specificity of 82%.28 The authors noted that these results were limited by the extent of the effectiveness of the coil over the axillary area, as well as interference from cardiac motion. However, this cohort analysis was one of the first studies designed to determine the accuracy of breast MRI in staging cancer.

Another cohort study conducted in Japan compared internal mammary nodal dimensions to the actual dissected node in 16 women diagnosed with breast cancer. A 1.5 Tesla MRI was used to obtain noncontrast images of the patients, and a comparison was made between the diameter and shape of the nodes as depicted on the MR image and the diameter and shape of the nodes after resection. The researchers found that MRI was better able to distinguish nodal size and pathology in nodes that were larger than 2 mm. Additionally, investigators found that MRI demonstrated a 90.7% accuracy and a 93.3% sensitivity for detecting metastasis utilizing internal mammary nodes that were greater than 5 mm. This compelling study is important in that it selected the internal mammary nodes for analysis, which pose the greatest challenge in imaging with mammography and sonography. It is hopeful that these results can be replicated in a larger patient population, or in those with a greater extent of nodal pathology.29

A Norwegian study compared breast MRI results with pathology reports in 65 patients diagnosed with invasive breast cancer, with the aim of demonstrating the utility of contrast enhancement and nodal dimensions to make an accurate diagnosis of metastatic lymph node involvement. The researchers found that postcontrast enhancement was the best predictor of nodal involvement, with a signal intensity of greater than 100% on the first postcontrast image. Nodal dimensions did not increase in accuracy, and MRI postcontrast enhancement correctly classified the extent of nodal involvement with an 88% accuracy.30 Importantly, this study was limited by the inability to isolate information specific to each node and the fact that the diagnosis was made at the patient level.

Another study conducted in Switzerland moved beyond the use of gadolinium as a contrast agent by introducing ultrasmall super paramagnetic iron oxide (USPIO). Researchers obtained consent from 20 patients who received a drip infusion of USPIO followed by MRI with gadolinium for imaging. A sensitivity of 83% was demonstrated in those patients imaged with USPIO and gadolinium.31 However, researchers were unable to visualize nodes of less than 2 mm. It appears that in this patient population, USPIO was helpful but would not provide additive value in identifying the primary breast tumor. Researchers did report adverse reactions in 18% of patients who were injected with USPIO, including lumbar and thoracic pain that was associated with the flow rate of the USPIO infusion, but these effects subsided with a reduction in flow rate. Investigators determined that these effects were manageable within the context of USPIO use in this analysis. The approval of USPIO by the US Food and Drug Administration is currently pending, and future research with a larger patient population would be helpful in determining the extent to which USPIO is useful in tracking micrometastatic debris within lymph node tissue.

A French study was conducted in 16 patients to determine if several imaging characteristics from breast MRI-enhanced images could detect nodal malignancy. Variables under analysis included nodal contours, high T2 signal intensity, gadolinium enhancement, and nodal geometry. Although this study was limited by its small patient population, the researchers did observe that nodes with high T2 signals, gadolinium enhancement, and abnormal morphology were significantly more likely to be identified pathologically than those that did not demonstrate these imaging characteristics.32 A larger study is needed to replicate these results, thus future guidelines can be developed to guide the use of these diagnostic tools in clinical practice.

Another study documented a population of 22 women who underwent imaging studies with USPIO to depict potential axillary lymph node metastasis. Data were generated prospectively, as 2 radiologists graded the resulting images in terms of nodal dimensions, morphology, signal intensity, contrast enhancement, and the uptake of USPIO. When both radiologists agreed upon a diagnosis, available patient data and nodal data were compared to actual surgical pathology reports. The imaging tools used in this study resulted in a 98% accuracy in determining the correct diagnosis and a sensitivity of 100% when comparing patient data and the nodal level of diagnosis based on pathology reports.33 Although this study was limited by the small population analyzed and the relative strength of the MRI magnet, these findings are quite exciting in demonstrating the accuracy and sensitivity of USPIO in determining the potential for lymph node metastasis. A similar analysis in a larger population, which would yield a greater number of malignant lymph nodes, is now needed to determine the utility of USPIO in detecting lymph node involvement.

Furthermore, the use of MRI with a magnet strength of 1.5 Tesla or greater may also provide more sensitive information. Diagnoses in this study were determined from images printed on film, and the use of digital images holds the promise of using magnification and other digital enhancement techniques that could allow for the consistent evaluation of nodes smaller than 5 mm.

Conclusions

This evidence-based review of the current literature reveals a great potential role for MRI of the breast in clinical practice, especially in those women who are at high risk for contralateral breast cancer reoccurrence and those who require noninvasive staging to determine axillary lymph node involvement. Some of the overarching issues that need to be addressed are the use of bilateral studies to include both these important diagnostic challenges. Continued equipment innovations will resolve current challenges encountered with MRI stemming from a lower resolution in some analyses and the limited field of view. In the presence of expanded studies that confirm the sensitivity and specificity of MRI of the breast, this diagnostic tool may be recommended for use on a routine basis in women at a high risk for breast cancer and for the detection of tumors with an aggressive metastatic behavior, and could provide substantial value beyond mammography and breast ultrasound. Future studies are needed to support the development of accurate diagnostic guidelines for assessing gadolinium-DPTA uptake in breast tumors, in addition to the uptake of USPIO in lymph nodes. Although the ACS has been an advocate of MRI of the breast, it is possible that this diagnostic tool is most suitable in women at high risk for breast cancer extension. The ultimate test for the widespread utilization of breast MRI in high-risk patients would be the ability to demonstrate a reduction in mortality and a very low percentage of false-positive biopsy results.17

Recommendations
It has been stated that in nonfatty breasts, ultrasound and MRI are more sensitive than mammography for invasive cancer.34 As presented in this article, an additional role may be developing for MRI to assess breast cancer extension in those women demonstrating substantial risk factors. It is clear that additional research is needed to determine the accuracy and sensitivity of the use of gadolinium-DPTA and USPIO as contrast agents to enhance the activity of micrometastatic activity within breast tissue. Meanwhile, a combination of imaging modalities, such as sonography and MRI, has been suggested as a way to maximize accuracy in evaluating suspicious lymph nodes.35 The impact of further technological developments and a greater weight of evidence to support breast imaging with MR holds great promise to influence mortality and morbidity rates in women at risk for breast cancer.

Acknowledgements

Dr Evans is indebted to Kristina Woodworth for her assistance with this article.

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Comments/Questions

What did you think of this article?
Evidence for Utilizing Magnetic Resonance Imaging to Detect Breast Cancer in the Axilla and Contralateral Breast

 
» Comment From: dhoover » Posted on: 11/01/2007 15:25 PM
It was great to get free CE - I needed them
 
» Comment From: mrivcd » Posted on: 11/09/2007 1:09 AM
Good article, I learned that there is still more research to be done in breast MRI.
 
» Comment From: melanie » Posted on: 11/29/2007 10:31 AM
good job
 
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