ABSTRACT: Contrast-enhanced breast magnetic resonance imaging (MRI) is a relatively new but increasingly used modality for the detection of breast cancer. MRI has demonstrated utility in identifying additional tumor foci and extent of disease in patients with known breast cancer. This is especially useful with invasive lobular carcinoma, which is difficult to evaluate on mammography. MRI has been found to identify the primary tumor in 70% to 86% of cases of occult breast cancer. Contrastenhanced breast MRI has shown some usefulness in the detection of residual cancer following surgery but is limited by postoperative changes. In patients who have undergone neoadjuvant chemotherapy, breast MRI is most accurate in those patients in whom there is little or no response to chemotherapy. The use of contrast-enhanced breast MRI for breast cancer screening is controversial. It has only been used in a few small studies of high-risk patients. The limitations of breast MRI include uptake in benign lesions and normal tissue, sensitivity for ductal carcinoma in situ, cost, and availability. This paper will discuss the uses, benefits, and limitations of contrast-enhanced breast MRI in the staging and screening of breast cancer.
Contrast-enhanced breast magnetic resonance imaging (MRI) is a relatively new modality for the detection of breast cancer, but its use has been increasing exponentially with the development of new techniques and applications. This paper will discuss the uses, benefits, and limitations of contrast-enhanced breast MRI in the staging and screening of breast cancer.
Gadolinium-diethylenetriamine penta-acetic acid (DTPA) contrastenhanced MRI to evaluate breast cancer was first described independently by two groups in 1989.[1,2] Since those first studies, a large amount of data has been accumulated, but there is no consensus as to technique, interpretation criteria, and indications for use (as there is for mammography and sonography). Breast MRI does offer a highly sensitive imaging modality for breast cancer without radiation, but MRI is not a replacement for mammography or breast ultrasound. It is, like ultrasound, another problem- solving tool for the detection of breast cancer.
Breast MRI involves evaluation of the breast or breasts prior to and after the administration of gadolinium- DTPA intravenous contrast. Images of the breast(s) are obtained immediately after the administration of the contrast bolus and repeated three to five times over several minutes. This results in multiple images of each slice of breast tissue, demonstrating the change in contrast enhancement over time. The presence, morphology, and pattern of contrast enhancement are evaluated for suspicious lesion(s).
Contrast-enhanced breast MRI is based on the production of angiogenic substances by tumors that result in the development of new vessels to supply the tumor. These new vessels are abnormal. They are permeable, have arterial-to-venous shunting, and are not associated with the concomitant production of lymphatics. This neovasuclarity results in rapid enhancement of the tumor relative to the normal issue. The sensitivity of contrast-enhanced MRI in detecting breast cancer is high, ranging from 88% to 100%,[1,2,4] but the specificity ranges from 37% to 96%.[1,2,4-6] This variable specificity is a limitation in the use of breast MRI.
Imaging of breast implants for rupture or free silicone was the first widely accepted indication for breast MRI. Evaluation of breast cancer patients for tumor extent, occult disease, and posttreatment planning are becoming common applications. Additional uses of breast MRI to further assist in the assessment of questionable mammographic or physical examination findings is emerging. Contrast-enhanced MRI for breast cancer screening is controversial.
Breast Cancer Staging With Contrast-Enhanced MRI
Multifocal or multicentric disease has been demonstrated in 31% of patients with known breast cancer. Residual breast cancer at the lumpeclumpectomy site can result in recurrence. Therefore, successful treatment depends on accurate presurgical knowledge of the extent of the disease. Mammography and sonography can often locate the primary tumor, but small, multifocal, or multicentric lesions may be missed unless they are actively sought out.
In a study comparing imaging modalities for assessing breast cancer, mammography found 90% of the index tumors, ultrasound found 85%, and MRI found 98%. Tumor size was underestimated by 14% on mammography and by 18% on ultrasound, but the size of the tumor at histology was not significantly different from that seen on MRI. In patients with a known primary tumor, breast MRI can better establish the extent of the disease (Figure 1). Contrast-enhanced breast MRI identified additional malignant foci in the ipsilateral breast in 22% to 34% of patients with known breast cancer.[6,7] Mammographically occult synchronous tumors in the contralateral breast were found in 5% of patients.
Invasive Lobular Carcinoma
MRI is especially useful in evaluating invasive lobular carcinoma, as it is difficult to identify on mammography. It has been reported that 19% of patients with invasive lobular carcinoma have no mammographic findings.[ 10] This may be due to the growth pattern of invasive lobular carcinoma, which has been classically described as groups of malignant cells in a one- to two-cell-thick linear arrangement. This neoplasm does not form a sheet of tumor cells, so there is no tumor mass.
Often, what is seen on mammography is the body's desmoplastic response to the tumor. The most common mammographic appearance is an asymmetry or ill-defined mass that is the same density as the surrounding breast tissue and is hard to differentiate from the normal parenchyma. Sonography can identify almost 90% of cases of invasive lobular carcinoma, but often, ultrasound is only done when a mammographic or clinical abnormality is present in the area. Invasive lobular carcinoma is more likely to be multicentric and bilateral than ductal carcinoma. These factors combine to make diagnosis and treatment of invasive lobular carcinoma difficult.
MRI is useful in evaluating patients with invasive lobular carcinoma. MRI has identified additional tumor foci in 22% to 40% of patients with known invasive lobular carcinoma[ 12,13] and contralateral foci in 9% of patients. Although MRI has been seen to be sensitive for lobular carcinoma, reports have indicated false-negative MRI findings. A few cases have been reported in which there is little or no contrast enhancement.[8,14]
The enhancement pattern seen in invasive lobular carcinoma may also make detection difficult. A discrete mass was found with contrast-enhanced breast MRI in 30% to 56% of invasive lobular carcinoma cases, and 39% to 61% demonstrated multifocal or regional enhancement.[13,15] This regional enhancement can be confused with fibrocystic or glandular uptake and may be underidentified. The extent of disease on pathology has been seen to correlate with the MRI findings in 85% of patients. Due to MRI findings, 50% of patients with invasive lobular carcinoma undergoing preoperative breast MRI had a change in their surgical management.[ 16] MRI can be a useful addition to the evaluation of invasive lobular carcinoma and should be considered for preoperative evaluation of the disease (Figure 2).
Need for Cautious Interpretation
The identification of more extensive disease can determine if the patient is a candidate for mastectomy or breast-conservation therapy. Of the patients with additional foci, 13% to 21% had their treatment changed to mastectomy or to lumpectomy with wider local excision because of MRI findings.[7,16] Breast MRI can also determine chest wall invasion better than mammography or ultrasound. Tumor involvement of the chest wall, regardless of primary tumor size, changes the disease stage to IIIB.
However, prudence should be used with the application of breast MRI in evaluating breast cancer patients. There is overlap of contrast enhancement in benign and malignant breast processes on MRI, and 4% to 21% of the patients undergoing preoperative breast MRI have false-positive findings necessitating additional biopsy and worry.[7,9,16,17] The patient needs to realize that there is a possibility of false-positive and falsenegative findings with MRI. Physicians should help patients understand what this may mean in regard to their treatment plan.
The high sensitivity of contrastenhanced breast MRI has created the impression that it is the gold standard for evaluation of breast cancer. The assumption is made that any enhancing area on MRI is a carcinoma. It is important to recognize that 29% to 80% of lesions with suspicious enhancement on MRI are benign on histology.[ 7,9,16,17] Some patients have become so concerned by the presence of an abnormality on breast MRI that they go directly to prophylactic mastectomy, at which point no malignancy may be found in the specimen.[ 9,17] Liberman et al found that 9% of patients with a suspicious MRI finding underwent prophylactic contralateral mastectomy, compared to 3% with no findings.
Occult Breast Cancers
Axillary metastasis without clinical or mammographic evidence of the primary has been reported to occur in less than 1% of cases of breast cancer.[ 18] If the primary tumor cannot be found, the patient often undergoes modified radical mastectomy followed by chemotherapy.[18,19] Many surgeons are hesitant to perform a mastectomy without demonstrated breast malignancy. No evidence of carcinoma is found in one-third of these "blind" mastectomy specimens.
Although the number of patients is small, studies of occult breast cancer have found that 70% to 86% of the primary tumors can be identified on contrast-enhanced breast MRI.[19,20] The majority of the cancers appeared as focal-enhancing lesions with spiculated or irregular borders. False-positive findings included patients with no tumor found at pathology or cancer found in areas of the breast that were not the same as the enhancing lesion. Finding the primary tumor allowed 37% to 41% of these women to undergo breast-conservation therapy.[ 19,20] Tumor was found in 81% of the specimens in patients with MRI findings. The lack of an enhancing lesion on MRI changed the treatment plan to axillary lymph node dissection and breast radiation therapy in a few of the study cases.
Not all lesions seen on MRI are malignant, and biopsy is necessary before a final treatment course can be determined. Generally, once the lesion is found, the mammograms are reassessed and an ultrasound is performed. If the lesion is seen on ultrasound, then a faster and less expensive ultrasound-guided biopsy can be performed. Otherwise, MRI-directed biopsy can be performed at facilities with the appropriate equipment.
Follow-up Post-Neoadjuvant Chemotherapy
Neoadjuvant chemotherapy is given to patients after the diagnosis of malignancy has been made but prior to definitive surgical treatment, to decrease the size of the tumor. Recurrence rates and positive margins have been reported to be similar to those seen in patients with early-stage cancers.[ 21] Therefore, for a woman with advanced disease, neoadjuvant chemotherapy can enable the use of breast-conservation therapy as an alternative to mastectomy without a difference in survival.
The extent of response to chemotherapy and amount of residual tumor determines the treatment options in this setting. Delineating the response poses a clinical challenge. Traditionally, palpation, mammography, and sonography have been used, but edema and necrosis at the tumor site may hinder measurement of the tumor's true size. Clinical breast exam has been found to underestimate residual disease. In one study, the average tumor size after neoadjuvant chemotherapy was 2.2 cm on clinical breast exam and 3.0 cm on final pathology; 63% of patients who were thought to have had a complete response to chemotherapy on clinical exam had residual tumor on final pathology.
Mammography does not show much better results. Vinnicombe et al found that five of eight patients with complete response to chemotherapy on mammography had residual tumor at excision. Mammographic assessment of response is more difficult in denser breasts, with ill-defined tumors, or in areas of architectural distortion alone. Sonography may be more accurate with well-defined tumors but may still produce erroneous results. If conventional imaging evaluation is done during the course of chemotherapy, then this underestimation of response may cause continuation of ineffective therapy and delay in definitive treatment.
MRI provides not only an anatomic evaluation of the tumor but also a physiologic one. Necrosis and edema do not influence the MRI findings. As the MRI findings are based on the vascularity of the tumor, the effect of chemotherapy agents that inhibit tumor angiogenesis can be seen (Figure 3). In one study, specificity for partial response to chemotherapy was 93%, with 82% accuracy. In addition, studies have found that MRI is better at determining the lack of response to neoadjuvant chemotherapy than at determining the extent of response.[22,26]
Rieber et al found that 56% of patients with a partial response to chemotherapy had an average MRI tumor measurement of 1.1 cm over the tumor size on final pathology. Among patients with complete response on MRI, 67% had residual tumor up to 5 cm in diameter at excision. This underestimation was more marked in invasive lobular carcinoma, with seven of nine patients showing larger tumors at final pathology than expected by MRI. This discrepancy may cause difficulty for the surgeon when selecting between mastectomy and lumpectomy. The result may be positive surgical margins with increased recurrence.
The change in appearance on postchemotherapy MRI may be due to decreased tumor size, change in tumor cellularity, or change in tumor vascularity. Diminished contrast enhancement following chemotherapy would support a reduction in tumor vascularity. Decrease in peak contrast uptake and flattening of the contrast uptake curve have been seen in tumors following chemotherapy.[22,26] The shape of the contrast uptake curve is a factor in the evaluation of an enhancing lesion to determine if it is suspicious for malignancy. Due to the neovascularity, there is a greater vascular supply to the carcinoma, resulting in contrast reaching the tumor faster than the surrounding normal parenchyma. This rapid "wash in" is accompanied by a rapid "wash out" in highly suspicious lesions as the contrast moves out of the tumor through arterial venous shunting. Therefore, a tumor would be expected to have an early, steep rise to peak enhancement with a decrease in enhancement almost as quickly. The change in the contrast uptake curve may account for the underestimation of response to chemotherapy and may mask satellite lesions. If neoadjuvant chemotherapy is being considered, a prechemotherapy MRI would permit identification of the extent of the disease and allow for more accurate posttreatment evaluation.
MRI prior to initiating neoadjuvant chemotherapy is especially important if the disease is multicentric or diffuse. These lesions are not very conspicuous and become even less so with decreased contrast enhancement resulting from neoadjuvant chemotherapy. MRI can also suggest that the carcinoma is more extensive than what is found at final pathology. Rosen et al found that contrast-enhanced MRI overestimated tumor size by 1 cm or more in 33% of their patients. Most of these were nonfocal lesions.[ 22] Enhancement in diffuse disease may mimic benign breast enhancement, causing it to appear larger. MRI evaluation during the chemotherapy course may readily demonstrate a lack of response and allow earlier changes to the treatment regimen. Rieber et al found that more reliable results were obtained with contrast-enhanced breast MRI imaging performed at least 6 weeks after the initiation of chemotherapy.