- Email: [email protected]
Preoperative Breast Magnetic Resonance Imaging: Applications in Clinical Practice
Canadian Association of Radiologists Journal 63 (2012) 207e214 www.carjonline.org
Magnetic Resonance Imaging / Formation image de resonance magnetique
Preoperative Breast Magnetic Resonance Imaging: Applications in Clinical Practice Supriya Kulkarni, DMRD, DNBa,*, Nitin Singh, MDb, Pavel Crystal, MDa a
Division of Breast Imaging, Joint Department of Medical Imaging, University Health Network, Mount Sinai Hospital and Women’s College Hospital, Princess Margaret Hospital, Toronto, Ontario, Canada b Department of Medical Imaging, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
Abstract Results of large randomized trials have shown that survival rates after breast conserving surgery are equivalent to those obtained by radical mastectomy. Breast conserving surgery with wide local excision in women with early stage breast cancer who are thought to have a single and resectable tumour as determined by clinical examination and conventional imaging followed by postoperative irradiation is the standard of care in early breast cancer. Mapping of local disease is the key element to guide optimal surgery to obtain tumour-free margins, thereby decreasing risk of local recurrence. The usual preoperative workup of breast malignancy consists of clinical breast examination and mammography with or without ultrasound. However, mammography and ultrasound fail to accurately assess tumour extent in as many as a third of patients eligible for breast conserving therapy. It is well established that magnetic resonance imaging is far superior to mammography (with and without ultrasound) for mapping the local extent of breast cancer. Experts advocate its use despite its high costs, high number of false positive findings, and lack of evidence from randomized prospective trials and, notably, fear of ‘‘overtreatment.’’ This article discusses the current role of breast magnetic resonance imaging with its clinical advantages and applications. Resume Les resultats d’essais randomises d’envergure ont demontre que le taux de survie a la suite d’une chirurgie conservatrice du sein equivaut a celui decoulant d’une mastectomie radicale. Chez les femmes ayant rec¸u un diagnostic de cancer du sein a un stade precoce et chez lesquelles l’examen clinique et l’imagerie conventionnelle ont revele une tumeur jugee unique et resecable, la chirurgie conservatrice du sein avec large excision locale suivie d’une irradiation postoperatoire representent le traitement habituel pour les cancers du sein au premier stade. La localisation de la maladie est l’element cle d’une chirurgie optimale qui permet d’obtenir des marges exemptes de tissu tumoral, reduisant ainsi les risques d’une recidive locale. L’evaluation preoperatoire habituelle d’une tumeur maligne du sein consiste en un examen mammaire clinique et une mammographie avec ou sans echographie. Toutefois, jusqu’au tiers des patientes admissibles a une chirurgie conservatrice du sein ne peuvent subir une evaluation exacte de l’ampleur de la tumeur au moyen de la mammographie et de l’echographie. Il est reconnu que l’imagerie par resonance magnetique est de loin superieure a la mammographie (avec ou sans echographie) pour localiser et determiner l’etendue locale du cancer du sein. Les specialistes en preconisent l’utilisation malgre les co^ uts eleves qui s’y rattachent, le grand nombre de resultats faux-positifs ainsi que le manque d’elements probants dans les essais randomises prospectifs et, notamment, la peur du « traitement excessif ». Cet article traite du r^ole actuel de l’imagerie par resonance magnetique du sein, de m^eme que de ses avantages et applications cliniques. Ó 2012 Canadian Association of Radiologists. All rights reserved. Key Words: Preoperative; Breast; Magnetic resonance imaging
Adequate treatment of women with breast cancer relies on accurate depiction of the extent of the index lesion, along with detection of multifocal or multicentric disease. Early breast cancer (stage I or stage II) with an index lesion <3 cm can be treated with either mastectomy or breast conserving
therapy (BCT). BCT consists of wide local excision of the tumour combined with postoperative radiotherapy. The factors that influence the decision of mastectomy vs BCT are tumour size, tumour location, the relation of tumour size to breast volume, multifocality or multicentricity of the tumour,
* Address for correspondence: Supriya Kulkarni, DMRD, DNB, Joint Department of Medical Imaging, University Health Network, Mount Sinai
Hospital and Women’s College Hospital, Princess Margaret Hospital 3-976, 610 University Ave, Toronto, Ontario M5G2M9, Canada. E-mail address: [email protected] (S. Kulkarni).
0846-5371/$ - see front matter Ó 2012 Canadian Association of Radiologists. All rights reserved. doi:10.1016/j.carj.2011.02.007
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Figure 1. (A) A 39-year-old lactating woman with a right palpable finding; dense mammogram with an ill-defined mass. (B) Ultrasound, showing an irregular, suspicious mass. (C) Multifocal multicentric cancer (pathology: invasive ductal carcinoma with an extensive intraductal component).
and patient preference [1]. The identification of multifocal or multicentric foci of disease results in higher local recurrence rates and is a contraindication for BCT and hence preoperative identification is important for appropriate treatment [2,3]. The 5-year local-recurrence rate after BCT is about 5%, and it doubles if tumour is incompletely excised. Complete gross excision of the tumour maximizes local control, which, in turn, results in better survival [4,5]. Comparative studies of breast magnetic resonance imaging (MRI) and conventional imaging with clinical assessment show consistently that MRI has higher accuracy for determining the extent of disease [6,7]. With remarkable improvement in technique, preoperative MRI is now detecting foci of disease otherwise occult to conventional imaging with a high sensitivity of 94%-100% [8,9]. Documentation of higher tumour load often leads to an alteration of management (wider excisions and more mastectomies), thereby negating the results of several long-standing randomized control trials, which have shown that outcomes with BCT with breast irradiation are similar to those with radical disfiguring surgery [10,11]. At the same time, the very high negative predictive value of breast MRI helps to predict the absence of breast cancer in the same or the contralateral breast with a very high confidence (99.6%) and can be used to justify a more focused therapeutic approach (eg, partial breast irradiation) or avoid prophylactic contralateral mastectomy [12]. It also can help convert a possible ipsilateral mastectomy into a lumpectomy in women with very dense breasts on mammography. In this article, we will review the utilisation of preoperative breast MRI and its impact on management in:
Ipsilateral Tumour Mapping The term preoperative staging is a misleading term, because this ‘‘stage’’ is different from the stage as specified by the American Joint Committee on Cancer. Hence, preoperative mapping is a better term [13]. The International Consensus Consortium II [14] recommends by using an overall size of the lesion (which includes both the in situ and the invasive components of the tumour) and a prognostic size of the tumour, which indicates the invasive component. The overall size is mapping because it pertains to local recurrence rates, and the prognostic size relates to stage and systemic recurrence rates. Results of studies reveal that MRI is the best method for depicting overall size and multifocal and multicentric ipsilateral disease [15]. Multifocality is defined as satellite lesions located within the same quadrant as the index lesion, whereas multicentric disease is defined as a separate focus of cancer
Ipsilateral tumour mapping, Assessment of the contralateral breast, Patients undergoing neoadjuvant therapy, and Preoperative assessment of residual tumour.
We will also briefly highlight the shortcomings of MRI in preoperative imaging.
Figure 2. Involvement of pectoralis muscle with pleural deposits (locally advanced breast cancer).
Preoperative breast MRI / Canadian Association of Radiologists Journal 63 (2012) 207e214
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Figure 3. (A) Left breast mass; heterogeous dense breast tissue with interstitial oedema. (B) Ultrasound, showing irregular suspicious mass. (C) Magnetic resonance image, showing a large tumour mass, with multifocal and multicentric disease. (D) Multicentric disease (pathology: invasive ductal carcinoma with high-grade ductal carcinoma in situ).
Figure 4. (A) Palpable left inferior quadrant mass; history of radiation for gastric lymphoma that involved the left lower chest wall; dense breast tissue; no definite abnormality. (B) Ultrasound, showing a mass with malignant morphology. (C) Magnetic resonance imaging, showing multifocal and multicentric tumour nodules. (D) Pathology: invasive ductal carcinoma with extensive intraductal component.
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Figure 5. (A) Postmantle radiation, with a palpable mass seen on mammography. (B, C) Ducts distended with soft-tissue mass confirmed on biopsy to be intermediate-grade ductal carcinoma in situ. (D) Magnetic resonance imaging, showing very minimal to no enhancement in inferior quadrant.
more than 5.0 cm away from the index lesion or tumours that extended to another quadrant through a discontinuous growth pattern (Figure 1) [13] . Meta-analysis of 19 observational studies that consists of 2610 women showed additional foci of disease in 16%, of which 66% were malignant on histology. Incremental MRI-only detection varies between approximately 1% and 28% for multifocal cancer and between 2% and 15% for multicentric cancer [16], which parallels what is known from landmark histologic studies. The additional foci diagnosed by breast MRI have the same size and the same histology as the cancers detected by conventional imaging. They, however, do exhibit a higher nuclear grading [15] and are associated with a higher biologic aggressiveness [12]. The MRI findings of additional foci of cancer coupled with the findings at the index lesion have impacted surgical therapy in women with breast cancer. A pooled study of 12 studies with more than 1908 women showed that MRI impacted planning in 15%-27% as improved selection of BCT, decreased surgical procedures with tumourfree margins, and detection of contralateral cancer; 11.3% had more extensive surgery than initially planned; 8.1% BCT eligible converted to mastectomy for MRI only lesions; and 5.5% had more extensive surgery due to false-positive findings on MRI [13,16]. High sensitivity of MRI also results in significant false-positive findings, which may necessitate further imaging, needle biopsy, or surgical biopsy [17]. The contraindications to BCT are nipple involvement, chest-wall invasion (Figure 2), inadequate lesion to breast size ratio, and larger than clinically evident size of mass and extensive intraductal component (EIC) of ductal carcinoma in situ (DCIS) surrounding the invasive component These contraindications are best assessed with MRI than other conventional imaging techniques. Preoperative breast MRI has been particularly useful in the following subgroup of women:
Women with heterogeneously dense breast tissue (Figure 3). Women with EIC of DCIS surrounding the invasive component, seen in 30%-40% of all invasive breast carcinomas. EIC occult to conventional imaging is a frequently encountered problem is women with invasive ductal carcinoma and DCIS, and is the most important treatment-related risk factor for recurrent disease. These patients will need a second surgical procedure; a considerable number of these patients end up requiring mastectomies [18]. High-resolution, high-contrast breast MRI accurately depicts DCIS and better demonstrates the extent of disease than mammography (Figure 4). The reported sensitivity of MRI for DCIS has ranged from 77%-96% [19]. False underestimation may occur in
Figure 6. A 55-year-old woman who was a BRCA2 mutation carrier with prior left lumpectomy. Preoperative magnetic resonance imaging (MRI) before prophylactic bilateral mastectomy revealed enhancing lesion in right breast otherwise occult. MRI biopsy showed high-grade ductal carcinoma in situ.
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Younger women with lesion with irregular margins on mammography and a size discrepancy of 10 mm between mammography and ultrasonography have added utility of preoperative MRI [23]. Women selected for accelerated partial-breast irradiation (APBI) and intraoperative radiation therapy (IORT). Traditionally, when a separate cancer, occult to conventional imaging, is present in the same breast (multicentric focus), BCT would involve excision of the index lesion, with clear margins that leave behind the undetected multicentric focus, which would be taken care of by the whole breast irradiation (WBI). Over the past several years, there has been growing interest in the use of APBI and IORT as an alternative to WBI. APBI and IORT offer decreased overall treatment time and may allow a decrease in the radiation dose delivered to uninvolved portions of the breast and adjacent organs [24]. Detection of additional foci of disease is of critical importance in patients selected for APBI and IORT because these multicentric foci do not get irradiated. Figure 7. A 46-year-old woman, left biopsy-proven multifocal invasive ductal carcinoma (IDC). Magnetic resonance imaging (MRI), showing enhancing lesion in the right breast, which was localized under MRI guidance; pathology: 0.6-cm IDC surrounded by 2.5-cm DCIS.
a non-high-grade noncomedo type of DCIS, and overestimation may occur due to benign proliferative pathology (Figure 5) [20]. Women with the notoriously difficult to image invasive lobular carcinoma (ILC). Studies show that additional ipsilateral lesions were noted in 32% of cases only with MRI and an additional 7% showed contralateral lesions. Surgical management changed in 28%, of which 88% were found necessary based on pathology. Preoperative breast MRI in women with ILC would reduce BCT failure and re-excisions [21]. High-risk women with breast cancer are likely to benefit from staging MRI because the rate of multifocal and multicentric disease is as high as 45%-50% [22].
Contralateral Breast Cancer Women with diagnosed unilateral breast cancer have a 5 times higher risk of developing contralateral synchronous or metachronous breast cancer than the general population [25]. Numerous risk factors have been implicated for development of bilateral breast cancer: nulliparity; younger age at first breast carcinoma; lobular histology; and multicentricity of first carcinoma and family history, that is, women with a first-degree relative with early age onset breast carcinoma and BRCA mutations (40 times more risk at 10 years) (Figure 6) [26] have a higher risk of developing bilateral breast cancer. In addition, young women treated with irradiation for postpartum mastitis, Hodgkin disease, and tuberculosis also are at an increased risk. The prevalence of synchronous cancer is 1%-3% and that of metachronous cancer is 5%-7%. MRI detects synchronous, contralateral breast cancer that is not detected clinically or
Figure 8. (A) A 51-year-old woman with right biopsy-proven invasive ductal carcinoma (IDC). (B) Left enhancing lesion; magnetic resonance imaging biopsy, IDC.
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Figure 9. (A) Biopsy-proven invasive ductal carcinoma: Preneoadjuvant therapy. (B) After neoadjuvant therapy, showing shrinkage of mass with residual tumour tissue (partial response).
with mammography in 1%-18% of newly affected women (Figure 7). The ACRIN (American College of Radiology Imaging Network) trial 6667 found that MRI detected mammographically and clinically occult cancers in the contralateral breast with a sensitivity of 91% and a specificity of 88%. The negative predictive value of MRI was 99% [27]. The histology for the contralateral malignancies is DCIS in approximately 35% and invasive cancer in 65% [28]. Early detection of in situ or node-negative invasive disease in the contralateral breast can lead to simultaneous treatment of synchronous cancers rather than multiple treatments on separate occasions (Figure 8). Monitoring Preoperative Neoadjuvant Treatment Systemic chemotherapy is known to improve survival for patients with invasive breast cancer and is considered the standard of care for patients who are node positive with large primary tumours and for many patients with high-risk, node-negative disease. A number of trials have compared preoperative chemotherapy with postoperative chemotherapy. Although, there was no difference in disease-free survival and overall survival, more women who received preoperative chemotherapy were able to undergo breast conservation. These findings have led to the increased use of preoperative or neoadjuvant chemotherapy. The National Surgical Adjuvant Breast and Bowel Project B-18 and other studies have demonstrated that response of the primary tumour to treatment, as measured clinically or by histopathology, is associated with both disease-free and overall survival. Thus, preoperative chemotherapy allows the opportunity to monitor the primary tumour response. MRI in women on neoadjuvant treatment is used for the initial determination of extent of disease for proper staging, early identification of poor responders, and identification of the presence, and accurately demonstrates the extent of residual disease before definitive surgery. MRI is more reliable than the conventional methods in the assessment of tumour size and vascularity changes during and after chemotherapy. The addition of advanced imaging techniques,
such as magnetic resonance spectroscopy, to further characterize tumour cellularity, and metabolic features appears promising (Figure 9) [29]. Preoperative MRI Before Re-excision Residual tumour after excisional biopsy has been reported in 32%-63% of cases of breast cancer. The sensitivity, specificity, and accuracy of MRI in showing the presence and extent of residual disease is 61.2%, 69.7%, and 64.6%, respectively [30]. MRI before re-excision can detect additional foci of multifocal or multicentric and contralateral tumour occult to conventional imaging, which, if detected, could change surgical management provided histologic corelation can be established (Figure 10).
Figure 10. Excision for invasive ductal carcinoma referred for magnetic resonance imaging after pathology reports of positive surgical margins; residual tumour was seen around surgical cavity, with extension into the nipple.
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Figure 11. (A) A 45-year-old woman with an axillary mass, which was biopsied and revealed invasive ductal carcinoma (IDC). (B) Magnetic resonance imaging (MRI), showing a second lesion, which underwent MRI wire localization. Pathology, 0.8-cm IDC surrounded by 4.5-cm ductal carcinoma in situ (not seen on MRI); the patient had completion mastectomy.
Because MRI usually is performed weeks after the initial excisional biopsy, differentiating contrast enhancement due to residual cancer from postsurgical inflammatory change is difficult. Benign postoperative enhancement usually is thin and rim-like around the seroma cavity. Any enhancement that appears nodular or irregular would need additional workup. The time interval between lumpectomy and MRI influences the specificity of MRI, with the greatest specificity of 75% being achieved when MRI is performed between 28 and 35 postoperative days [31]. Conclusion In summarizing the available data, in comparison with conventional imaging, breast MRI increases the detection of tumour foci in addition to the known index lesion within the ipsilateral breast and synchronous tumour in the contralateral breast, which has significant impact on surgical planning, particularly in the specific subgroups of women previously described. With such a high-detection rate comes the controversy of the high number of false positives, which may lead to overtreatment. Results of studies show that addition of MRI to preoperative workup causes more-extensive surgery, additional utilisation of resources, and delay in surgery, with no impact in overall survival benefit (Figure 11) [32]. The recently published COMICE (Comparative Effectiveness of MRI in Breast Cancer) trial negates the impact of MRI on the re-excision rates in women with preoperative MRI compared with those with no preoperative MRI [33]. However, this study commenced during the time when there was an absence of accurate MRI-guided interventions. Their cases had extremely wide surgical margins, and the impact of MRI in such cases may not be significant. However, in institutes where surgical techniques aim at removal of smaller resection volumes, the impact of MRI can be significant in reducing re-operation rates [34]. Despite the lack of randomized trials to show survival benefit or improved surgical outcome (re-excision and recurrence rates) and the additional workup of false positives, MRI is a modality of significant clinical impact, which
leads us to the exciting era of APBR and IORT. MRI has been shown to reduce the positive margin rate in women with ILCs without increasing mastectomy rates [34]. The high staging accuracy of breast MRI makes it an attractive method for assessing tumour distribution and for measuring response to preoperative chemotherapy. In centres with expertise in MRI interpretation and intervention, it can be a phenomenal adjunctive tool for patient care. The high negative predictive value of MRI might reduce the number of unnecessary mastectomies and allay patient anxiety. Preoperative MRI should be interpreted by taking into account clinical breast examination, mammography, and sonography, and does not replace a good traditional workup of lesions. All findings that would impact surgical planning should be worked up and verified with image-guided biopsy, and this would potentially reduce the chances of overtreatment due to MRI-only findings [35]. Centres that run a breast MRI program should ensure proper equipment and imaging technique, and provide training necessary to achieve high-quality breast MRI, and should have the ability to perform MRI-guided biopsy or needle localization for MRI only detected lesions. All workups should be completed within a time frame of a maximum 1 month to avoid surgical delay. As radiologists, our job is to give maximum information with appropriate workup. Women newly diagnosed with breast cancer should always be informed of the potential risks and benefits of preoperative MRI. The MRI-only lesions cannot be ignored. Evolving understanding of these subclinical MRI-only lesions and improvement of MRI intervention will pave the way for MRI-guided lumpectomies, which allows breast conservation. A multidisciplinary approach should be instituted to address any changes in management that result from preoperative MRI, thus providing appropriate care and allaying women’s and their physicians’ anxieties regarding overtreatment of women with breast cancer. References [1] Lee JM, Orel SG, Czerniecki BJ, et al. MRI before reexcision surgery in patients with breast cancer. AJR Am J Roentgenol 2004;182:473e80.
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[2] Kurtz JM, Jacquemier J, Amalric R, et al. Breast conserving therapy for macroscopically multiple cancers. Ann Surg 1990;212:38e44. [3] Kurtz JM. Factors influencing the risk of local recurrence in the breast. Eur J Cancer 1992;28:660e6. [4] Clarke M, Collins R, Darby S, et al. Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15 year survival: an overview of the randomized trials. Lancet 2005;366:2087e106. [5] Bartelink H, Horiot JC, Poortmans P, et al. Recurrence rates after treatment of breast cancer with standard radiotherapy with or without additional radiation. N Engl J Med 2001;345:1378e87. [6] Tan JE, Orel SG, Schnall MD, et al. Role of magnetic resonance imaging and magnetic resonance imaging-guided surgery in the evaluation of patients with early-stage breast cancer for breast conservation treatment. Am J Clin Oncol 1999;22:414e8. [7] Tillman GF, Orel SG, Schnall MD, et al. Effect of breast magnetic resonance imaging on the clinical management of women with earlystage breast carcinoma. J Clin Oncol 2002;20:3413e23. [8] Gilles R, Guinebretiere JM, Lucidarme O, et al. Nonpalpable breast tumors: diagnosis with contrast enhanced subtraction dynamic MR imaging. Radiology 1994;191:625e31. [9] Harms SE, Flamig DP, Hesley KL, et al. MR imaging of the breast with rotating delivery of excitation off resonance: clinical experience with pathologic correlation. Radiology 1993;187:493e501. [10] Veronesi U, Cascinelli N, Mariani L, et al. Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 2002;347: 1227e32. [11] Fisher B, Anderson S, Bryant J, et al. Twenty year follow-up of a randomized trial comparing total mastectomy, lumpectomy, and lumpectomy plus irradiation for the treatment of invasive breast cancer. N Engl J Med 2002;347:1233e41. [12] Kuhl C, Kuhn W, Braun M, et al. Pre-operative staging of breast cancer with breast MRI: one step forward, two steps back? Breast 2007;16:S34e4. [13] Hollingsworth AB, Stough RG, O’Dell CA, et al. Breast magnetic resonance imaging for preoperative locoregional staging. Am J Surg 2008;196:389e97. [14] Holland R, Veling SH, Mravunac M, et al. Histologic multifocality of Tis, T1-2 breast carcinomas: implications for clinical trials of breast conserving surgery. Cancer 1985;56:979e90. [15] Schnall MD, Blume J, Bluemke DA, et al. MRI detection of distinct incidental cancer in women with primary breast cancer studied in IBMC 6883. J Surg Oncol 2005;92:32e8. [16] Houssami N, Ciatto S, Macaskill P, et al. Accuracy and surgical impact of magnetic resonance imaging in breast cancer staging: systematic review and meta-analysis in detection of multifocal and multicentric cancer. J Clin Oncol 2008;26:3248e58. [17] Houssami N, Hayes DF. Review of preoperative magnetic resonance imaging (MRI) in breast cancer: should MRI be performed on all women with newly diagnosed, early stage breast cancer? CA Cancer J Clin 2009;59:290e302.
[18] Orel SG, Mendonca MH, Reynolds C, et al. MR imaging of ductal carcinoma insitu. Radiology 1997;202:413e20. [19] Shiraishi A, Kurosaki Y, Maehara T, et al. Extension of ductal carcinoma in situ: histopathological association with MR imaging and mammography. Magn Reson Med Sci 2003;2:159e63. [20] Schouten van der Velden AP, Schlooz-Vries MS, Boetes C, et al. Magnetic resonance imaging of ductal carcinoma in situ: what is its clinical application? A review. Am J Surg 2009;198:262e9. [21] Mann RM, Hoogeveen YL, Blickman JG, et al. MRI compared to conventional diagnostic work-up in the detection and evaluation of invasive lobular carcinoma of the breast: a review of existing literature. Breast Cancer Res Treat 2008;107:1e14. [22] Sardanelli F, Podo F, D’Agnolo G, et al. results. Radiology 2007;242: 698e715. [23] Deurloo EE, Klein Zeggelink WF, Teertstra HJ, et al. Contrastenhanced MRI in breast cancer patients eligible for breast-conserving therapy: complementary value for subgroups of patients. Eur Radiol 2006;16:692e701. [24] Biagioli MC, Harris EE. Accelerated partial breast irradiation: potential roles following breast-conserving surgery. Cancer Control 2010;17: 191e204. [25] Roubidoux MA, Helvie MA, Lai NE, et al. Bilateral breast cancer: early detection with mammography. Radiology 1995;196:427e31. [26] Metcalfe K, Lynch HT, Ghadirian P, et al. Contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. J Clin Oncol 2004;22:2328e35. [27] Lehman CD, Gatsonis C, Kuhl CK, et al. MRI evaluation of the contralateral breast in women with recently diagnosed breast cancer. N Engl J Med 2007;356:1295e303. [28] Brennan ME, Houssami N, Lord S, et al. MRI screening of the contralateral breast in women with newly diagnosed breast cancer: systematic review and meta-analysis of incremental cancer detection and impact on surgical management. J Clin Oncol 2009;27:5640e9. [29] Le-Petross HC, Hylton N. Role of breast MR imaging in neoadjuvant chemotherapy. Magn Reson Imaging Clin N Am 2010;18:249e58, viiieix. [30] Lee JM, Orel SG, Czerniecki BJ, et al. MRI before reexcision surgery in patients with breast cancer. AJR Am J Roentgenol 2004;182:473e80. [31] Frei KA, Kinkel K, Bonel HM, et al. MR imaging of the breast in patients with positive margins after lumpectomy: influence of the time interval between lumpectomy and MR imaging. AJR Am J Roentgenol 2000;175:1577e84. [32] Solin LJ. Counterview: pre-operative breast MRI (magnetic resonance imaging) is not recommended for all patients with newly diagnosed breast cancer. Breast 2010;19:7e9. [33] Turnbull L, Brown S, Harvey I, et al. Comparative Effectiveness of MRI in Breast Cancer (COMICE) trial: a randomised controlled trial. Lancet 2010;375:563e71. [34] Morris E. Should we dispense with preoperative breast MRI? Lancet 2010;375:528e30. [35] Sardenelli F. Overview of the role of pre-operative breast MRI in the absence of evidence on patient outcomes. Breast 2010;19:3e6.
Magnetic Resonance Imaging / Formation image de resonance magnetique
Preoperative Breast Magnetic Resonance Imaging: Applications in Clinical Practice Supriya Kulkarni, DMRD, DNBa,*, Nitin Singh, MDb, Pavel Crystal, MDa a
Division of Breast Imaging, Joint Department of Medical Imaging, University Health Network, Mount Sinai Hospital and Women’s College Hospital, Princess Margaret Hospital, Toronto, Ontario, Canada b Department of Medical Imaging, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada
Abstract Results of large randomized trials have shown that survival rates after breast conserving surgery are equivalent to those obtained by radical mastectomy. Breast conserving surgery with wide local excision in women with early stage breast cancer who are thought to have a single and resectable tumour as determined by clinical examination and conventional imaging followed by postoperative irradiation is the standard of care in early breast cancer. Mapping of local disease is the key element to guide optimal surgery to obtain tumour-free margins, thereby decreasing risk of local recurrence. The usual preoperative workup of breast malignancy consists of clinical breast examination and mammography with or without ultrasound. However, mammography and ultrasound fail to accurately assess tumour extent in as many as a third of patients eligible for breast conserving therapy. It is well established that magnetic resonance imaging is far superior to mammography (with and without ultrasound) for mapping the local extent of breast cancer. Experts advocate its use despite its high costs, high number of false positive findings, and lack of evidence from randomized prospective trials and, notably, fear of ‘‘overtreatment.’’ This article discusses the current role of breast magnetic resonance imaging with its clinical advantages and applications. Resume Les resultats d’essais randomises d’envergure ont demontre que le taux de survie a la suite d’une chirurgie conservatrice du sein equivaut a celui decoulant d’une mastectomie radicale. Chez les femmes ayant rec¸u un diagnostic de cancer du sein a un stade precoce et chez lesquelles l’examen clinique et l’imagerie conventionnelle ont revele une tumeur jugee unique et resecable, la chirurgie conservatrice du sein avec large excision locale suivie d’une irradiation postoperatoire representent le traitement habituel pour les cancers du sein au premier stade. La localisation de la maladie est l’element cle d’une chirurgie optimale qui permet d’obtenir des marges exemptes de tissu tumoral, reduisant ainsi les risques d’une recidive locale. L’evaluation preoperatoire habituelle d’une tumeur maligne du sein consiste en un examen mammaire clinique et une mammographie avec ou sans echographie. Toutefois, jusqu’au tiers des patientes admissibles a une chirurgie conservatrice du sein ne peuvent subir une evaluation exacte de l’ampleur de la tumeur au moyen de la mammographie et de l’echographie. Il est reconnu que l’imagerie par resonance magnetique est de loin superieure a la mammographie (avec ou sans echographie) pour localiser et determiner l’etendue locale du cancer du sein. Les specialistes en preconisent l’utilisation malgre les co^ uts eleves qui s’y rattachent, le grand nombre de resultats faux-positifs ainsi que le manque d’elements probants dans les essais randomises prospectifs et, notamment, la peur du « traitement excessif ». Cet article traite du r^ole actuel de l’imagerie par resonance magnetique du sein, de m^eme que de ses avantages et applications cliniques. Ó 2012 Canadian Association of Radiologists. All rights reserved. Key Words: Preoperative; Breast; Magnetic resonance imaging
Adequate treatment of women with breast cancer relies on accurate depiction of the extent of the index lesion, along with detection of multifocal or multicentric disease. Early breast cancer (stage I or stage II) with an index lesion <3 cm can be treated with either mastectomy or breast conserving
therapy (BCT). BCT consists of wide local excision of the tumour combined with postoperative radiotherapy. The factors that influence the decision of mastectomy vs BCT are tumour size, tumour location, the relation of tumour size to breast volume, multifocality or multicentricity of the tumour,
* Address for correspondence: Supriya Kulkarni, DMRD, DNB, Joint Department of Medical Imaging, University Health Network, Mount Sinai
Hospital and Women’s College Hospital, Princess Margaret Hospital 3-976, 610 University Ave, Toronto, Ontario M5G2M9, Canada. E-mail address: [email protected] (S. Kulkarni).
0846-5371/$ - see front matter Ó 2012 Canadian Association of Radiologists. All rights reserved. doi:10.1016/j.carj.2011.02.007
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Figure 1. (A) A 39-year-old lactating woman with a right palpable finding; dense mammogram with an ill-defined mass. (B) Ultrasound, showing an irregular, suspicious mass. (C) Multifocal multicentric cancer (pathology: invasive ductal carcinoma with an extensive intraductal component).
and patient preference [1]. The identification of multifocal or multicentric foci of disease results in higher local recurrence rates and is a contraindication for BCT and hence preoperative identification is important for appropriate treatment [2,3]. The 5-year local-recurrence rate after BCT is about 5%, and it doubles if tumour is incompletely excised. Complete gross excision of the tumour maximizes local control, which, in turn, results in better survival [4,5]. Comparative studies of breast magnetic resonance imaging (MRI) and conventional imaging with clinical assessment show consistently that MRI has higher accuracy for determining the extent of disease [6,7]. With remarkable improvement in technique, preoperative MRI is now detecting foci of disease otherwise occult to conventional imaging with a high sensitivity of 94%-100% [8,9]. Documentation of higher tumour load often leads to an alteration of management (wider excisions and more mastectomies), thereby negating the results of several long-standing randomized control trials, which have shown that outcomes with BCT with breast irradiation are similar to those with radical disfiguring surgery [10,11]. At the same time, the very high negative predictive value of breast MRI helps to predict the absence of breast cancer in the same or the contralateral breast with a very high confidence (99.6%) and can be used to justify a more focused therapeutic approach (eg, partial breast irradiation) or avoid prophylactic contralateral mastectomy [12]. It also can help convert a possible ipsilateral mastectomy into a lumpectomy in women with very dense breasts on mammography. In this article, we will review the utilisation of preoperative breast MRI and its impact on management in:
Ipsilateral Tumour Mapping The term preoperative staging is a misleading term, because this ‘‘stage’’ is different from the stage as specified by the American Joint Committee on Cancer. Hence, preoperative mapping is a better term [13]. The International Consensus Consortium II [14] recommends by using an overall size of the lesion (which includes both the in situ and the invasive components of the tumour) and a prognostic size of the tumour, which indicates the invasive component. The overall size is mapping because it pertains to local recurrence rates, and the prognostic size relates to stage and systemic recurrence rates. Results of studies reveal that MRI is the best method for depicting overall size and multifocal and multicentric ipsilateral disease [15]. Multifocality is defined as satellite lesions located within the same quadrant as the index lesion, whereas multicentric disease is defined as a separate focus of cancer
Ipsilateral tumour mapping, Assessment of the contralateral breast, Patients undergoing neoadjuvant therapy, and Preoperative assessment of residual tumour.
We will also briefly highlight the shortcomings of MRI in preoperative imaging.
Figure 2. Involvement of pectoralis muscle with pleural deposits (locally advanced breast cancer).
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Figure 3. (A) Left breast mass; heterogeous dense breast tissue with interstitial oedema. (B) Ultrasound, showing irregular suspicious mass. (C) Magnetic resonance image, showing a large tumour mass, with multifocal and multicentric disease. (D) Multicentric disease (pathology: invasive ductal carcinoma with high-grade ductal carcinoma in situ).
Figure 4. (A) Palpable left inferior quadrant mass; history of radiation for gastric lymphoma that involved the left lower chest wall; dense breast tissue; no definite abnormality. (B) Ultrasound, showing a mass with malignant morphology. (C) Magnetic resonance imaging, showing multifocal and multicentric tumour nodules. (D) Pathology: invasive ductal carcinoma with extensive intraductal component.
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Figure 5. (A) Postmantle radiation, with a palpable mass seen on mammography. (B, C) Ducts distended with soft-tissue mass confirmed on biopsy to be intermediate-grade ductal carcinoma in situ. (D) Magnetic resonance imaging, showing very minimal to no enhancement in inferior quadrant.
more than 5.0 cm away from the index lesion or tumours that extended to another quadrant through a discontinuous growth pattern (Figure 1) [13] . Meta-analysis of 19 observational studies that consists of 2610 women showed additional foci of disease in 16%, of which 66% were malignant on histology. Incremental MRI-only detection varies between approximately 1% and 28% for multifocal cancer and between 2% and 15% for multicentric cancer [16], which parallels what is known from landmark histologic studies. The additional foci diagnosed by breast MRI have the same size and the same histology as the cancers detected by conventional imaging. They, however, do exhibit a higher nuclear grading [15] and are associated with a higher biologic aggressiveness [12]. The MRI findings of additional foci of cancer coupled with the findings at the index lesion have impacted surgical therapy in women with breast cancer. A pooled study of 12 studies with more than 1908 women showed that MRI impacted planning in 15%-27% as improved selection of BCT, decreased surgical procedures with tumourfree margins, and detection of contralateral cancer; 11.3% had more extensive surgery than initially planned; 8.1% BCT eligible converted to mastectomy for MRI only lesions; and 5.5% had more extensive surgery due to false-positive findings on MRI [13,16]. High sensitivity of MRI also results in significant false-positive findings, which may necessitate further imaging, needle biopsy, or surgical biopsy [17]. The contraindications to BCT are nipple involvement, chest-wall invasion (Figure 2), inadequate lesion to breast size ratio, and larger than clinically evident size of mass and extensive intraductal component (EIC) of ductal carcinoma in situ (DCIS) surrounding the invasive component These contraindications are best assessed with MRI than other conventional imaging techniques. Preoperative breast MRI has been particularly useful in the following subgroup of women:
Women with heterogeneously dense breast tissue (Figure 3). Women with EIC of DCIS surrounding the invasive component, seen in 30%-40% of all invasive breast carcinomas. EIC occult to conventional imaging is a frequently encountered problem is women with invasive ductal carcinoma and DCIS, and is the most important treatment-related risk factor for recurrent disease. These patients will need a second surgical procedure; a considerable number of these patients end up requiring mastectomies [18]. High-resolution, high-contrast breast MRI accurately depicts DCIS and better demonstrates the extent of disease than mammography (Figure 4). The reported sensitivity of MRI for DCIS has ranged from 77%-96% [19]. False underestimation may occur in
Figure 6. A 55-year-old woman who was a BRCA2 mutation carrier with prior left lumpectomy. Preoperative magnetic resonance imaging (MRI) before prophylactic bilateral mastectomy revealed enhancing lesion in right breast otherwise occult. MRI biopsy showed high-grade ductal carcinoma in situ.
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Younger women with lesion with irregular margins on mammography and a size discrepancy of 10 mm between mammography and ultrasonography have added utility of preoperative MRI [23]. Women selected for accelerated partial-breast irradiation (APBI) and intraoperative radiation therapy (IORT). Traditionally, when a separate cancer, occult to conventional imaging, is present in the same breast (multicentric focus), BCT would involve excision of the index lesion, with clear margins that leave behind the undetected multicentric focus, which would be taken care of by the whole breast irradiation (WBI). Over the past several years, there has been growing interest in the use of APBI and IORT as an alternative to WBI. APBI and IORT offer decreased overall treatment time and may allow a decrease in the radiation dose delivered to uninvolved portions of the breast and adjacent organs [24]. Detection of additional foci of disease is of critical importance in patients selected for APBI and IORT because these multicentric foci do not get irradiated. Figure 7. A 46-year-old woman, left biopsy-proven multifocal invasive ductal carcinoma (IDC). Magnetic resonance imaging (MRI), showing enhancing lesion in the right breast, which was localized under MRI guidance; pathology: 0.6-cm IDC surrounded by 2.5-cm DCIS.
a non-high-grade noncomedo type of DCIS, and overestimation may occur due to benign proliferative pathology (Figure 5) [20]. Women with the notoriously difficult to image invasive lobular carcinoma (ILC). Studies show that additional ipsilateral lesions were noted in 32% of cases only with MRI and an additional 7% showed contralateral lesions. Surgical management changed in 28%, of which 88% were found necessary based on pathology. Preoperative breast MRI in women with ILC would reduce BCT failure and re-excisions [21]. High-risk women with breast cancer are likely to benefit from staging MRI because the rate of multifocal and multicentric disease is as high as 45%-50% [22].
Contralateral Breast Cancer Women with diagnosed unilateral breast cancer have a 5 times higher risk of developing contralateral synchronous or metachronous breast cancer than the general population [25]. Numerous risk factors have been implicated for development of bilateral breast cancer: nulliparity; younger age at first breast carcinoma; lobular histology; and multicentricity of first carcinoma and family history, that is, women with a first-degree relative with early age onset breast carcinoma and BRCA mutations (40 times more risk at 10 years) (Figure 6) [26] have a higher risk of developing bilateral breast cancer. In addition, young women treated with irradiation for postpartum mastitis, Hodgkin disease, and tuberculosis also are at an increased risk. The prevalence of synchronous cancer is 1%-3% and that of metachronous cancer is 5%-7%. MRI detects synchronous, contralateral breast cancer that is not detected clinically or
Figure 8. (A) A 51-year-old woman with right biopsy-proven invasive ductal carcinoma (IDC). (B) Left enhancing lesion; magnetic resonance imaging biopsy, IDC.
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Figure 9. (A) Biopsy-proven invasive ductal carcinoma: Preneoadjuvant therapy. (B) After neoadjuvant therapy, showing shrinkage of mass with residual tumour tissue (partial response).
with mammography in 1%-18% of newly affected women (Figure 7). The ACRIN (American College of Radiology Imaging Network) trial 6667 found that MRI detected mammographically and clinically occult cancers in the contralateral breast with a sensitivity of 91% and a specificity of 88%. The negative predictive value of MRI was 99% [27]. The histology for the contralateral malignancies is DCIS in approximately 35% and invasive cancer in 65% [28]. Early detection of in situ or node-negative invasive disease in the contralateral breast can lead to simultaneous treatment of synchronous cancers rather than multiple treatments on separate occasions (Figure 8). Monitoring Preoperative Neoadjuvant Treatment Systemic chemotherapy is known to improve survival for patients with invasive breast cancer and is considered the standard of care for patients who are node positive with large primary tumours and for many patients with high-risk, node-negative disease. A number of trials have compared preoperative chemotherapy with postoperative chemotherapy. Although, there was no difference in disease-free survival and overall survival, more women who received preoperative chemotherapy were able to undergo breast conservation. These findings have led to the increased use of preoperative or neoadjuvant chemotherapy. The National Surgical Adjuvant Breast and Bowel Project B-18 and other studies have demonstrated that response of the primary tumour to treatment, as measured clinically or by histopathology, is associated with both disease-free and overall survival. Thus, preoperative chemotherapy allows the opportunity to monitor the primary tumour response. MRI in women on neoadjuvant treatment is used for the initial determination of extent of disease for proper staging, early identification of poor responders, and identification of the presence, and accurately demonstrates the extent of residual disease before definitive surgery. MRI is more reliable than the conventional methods in the assessment of tumour size and vascularity changes during and after chemotherapy. The addition of advanced imaging techniques,
such as magnetic resonance spectroscopy, to further characterize tumour cellularity, and metabolic features appears promising (Figure 9) [29]. Preoperative MRI Before Re-excision Residual tumour after excisional biopsy has been reported in 32%-63% of cases of breast cancer. The sensitivity, specificity, and accuracy of MRI in showing the presence and extent of residual disease is 61.2%, 69.7%, and 64.6%, respectively [30]. MRI before re-excision can detect additional foci of multifocal or multicentric and contralateral tumour occult to conventional imaging, which, if detected, could change surgical management provided histologic corelation can be established (Figure 10).
Figure 10. Excision for invasive ductal carcinoma referred for magnetic resonance imaging after pathology reports of positive surgical margins; residual tumour was seen around surgical cavity, with extension into the nipple.
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Figure 11. (A) A 45-year-old woman with an axillary mass, which was biopsied and revealed invasive ductal carcinoma (IDC). (B) Magnetic resonance imaging (MRI), showing a second lesion, which underwent MRI wire localization. Pathology, 0.8-cm IDC surrounded by 4.5-cm ductal carcinoma in situ (not seen on MRI); the patient had completion mastectomy.
Because MRI usually is performed weeks after the initial excisional biopsy, differentiating contrast enhancement due to residual cancer from postsurgical inflammatory change is difficult. Benign postoperative enhancement usually is thin and rim-like around the seroma cavity. Any enhancement that appears nodular or irregular would need additional workup. The time interval between lumpectomy and MRI influences the specificity of MRI, with the greatest specificity of 75% being achieved when MRI is performed between 28 and 35 postoperative days [31]. Conclusion In summarizing the available data, in comparison with conventional imaging, breast MRI increases the detection of tumour foci in addition to the known index lesion within the ipsilateral breast and synchronous tumour in the contralateral breast, which has significant impact on surgical planning, particularly in the specific subgroups of women previously described. With such a high-detection rate comes the controversy of the high number of false positives, which may lead to overtreatment. Results of studies show that addition of MRI to preoperative workup causes more-extensive surgery, additional utilisation of resources, and delay in surgery, with no impact in overall survival benefit (Figure 11) [32]. The recently published COMICE (Comparative Effectiveness of MRI in Breast Cancer) trial negates the impact of MRI on the re-excision rates in women with preoperative MRI compared with those with no preoperative MRI [33]. However, this study commenced during the time when there was an absence of accurate MRI-guided interventions. Their cases had extremely wide surgical margins, and the impact of MRI in such cases may not be significant. However, in institutes where surgical techniques aim at removal of smaller resection volumes, the impact of MRI can be significant in reducing re-operation rates [34]. Despite the lack of randomized trials to show survival benefit or improved surgical outcome (re-excision and recurrence rates) and the additional workup of false positives, MRI is a modality of significant clinical impact, which
leads us to the exciting era of APBR and IORT. MRI has been shown to reduce the positive margin rate in women with ILCs without increasing mastectomy rates [34]. The high staging accuracy of breast MRI makes it an attractive method for assessing tumour distribution and for measuring response to preoperative chemotherapy. In centres with expertise in MRI interpretation and intervention, it can be a phenomenal adjunctive tool for patient care. The high negative predictive value of MRI might reduce the number of unnecessary mastectomies and allay patient anxiety. Preoperative MRI should be interpreted by taking into account clinical breast examination, mammography, and sonography, and does not replace a good traditional workup of lesions. All findings that would impact surgical planning should be worked up and verified with image-guided biopsy, and this would potentially reduce the chances of overtreatment due to MRI-only findings [35]. Centres that run a breast MRI program should ensure proper equipment and imaging technique, and provide training necessary to achieve high-quality breast MRI, and should have the ability to perform MRI-guided biopsy or needle localization for MRI only detected lesions. All workups should be completed within a time frame of a maximum 1 month to avoid surgical delay. As radiologists, our job is to give maximum information with appropriate workup. Women newly diagnosed with breast cancer should always be informed of the potential risks and benefits of preoperative MRI. The MRI-only lesions cannot be ignored. Evolving understanding of these subclinical MRI-only lesions and improvement of MRI intervention will pave the way for MRI-guided lumpectomies, which allows breast conservation. A multidisciplinary approach should be instituted to address any changes in management that result from preoperative MRI, thus providing appropriate care and allaying women’s and their physicians’ anxieties regarding overtreatment of women with breast cancer. References [1] Lee JM, Orel SG, Czerniecki BJ, et al. MRI before reexcision surgery in patients with breast cancer. AJR Am J Roentgenol 2004;182:473e80.
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