The additive role of dynamic contrast-enhanced and diffusion-weighted MR imaging in preoperative staging of breast cancer

In women with diagnosed breast cancer, accurate loco-regional staging and preoperative examination are of utmost importance for optimal patient management decisions. MRI may be warranted for correct preoperative staging as recommended from international guidelines. DWI-MRI can be combined with CE-MRI to assess more functional data. So we aimed to evaluate the performance of CE-MRI and qualitative DWI-MRI in preoperative loco-regional staging of malignant breast lesions as regards the local extension of the disease and axillary lymph node status, beyond standard assessment with mammography and ultrasound. This prospective study included 50 female patients with pathologically proven malignant breast lesions (BIRADS VI) coming for preoperative staging. Full-field digital mammography (FFDM) and ultrasound, CE-MRI, and DWI-MRI findings were compared for all patients, and the findings were evaluated independently. Results were then correlated to postoperative histopathology. Fifty women with pathologically proven malignant breast lesions (BIRADS VI) were enrolled in this study; the mean age of this study population was 43.25 years. The 50 patients were divided into 2 groups: 37/50 (74%) underwent upfront surgery and 13/50 (26%) received neoadjuvant therapy before surgery. All patients performed DCE and DWI-MRI breast. Among patients who underwent upfront surgery, DCE-MRI showed the highest correlation with the postoperative pathology size and the overall sensitivity regarding multiplicity. Regarding patients who received neoadjuvant therapy, DCE-MRI was found to have the highest correlation with the postoperative pathology concerning lesion size and multiplicity after completion of the neoadjuvant chemotherapy cycles. CE-MRI can accurately map lesion extension and detect multifocality/multicentricity, thus tailor surgical management options (either conservative surgery or mastectomy). Qualitative DWI can be combined with ultrasonography for better evaluation of the axillary nodal status.


Background
In women with diagnosed breast cancer, accurate locoregional staging and preoperative examination of the whole breast and both axillae are of utmost importance for optimal patient management decisions and correct choice of therapy [1].
The choice between mastectomy and breastconserving surgery with or without axillary evacuation and with or without neoadjuvant chemotherapy depends on numerous factors. These factors include tumor location, grade and size in relation to breast volume, multifocality or multicentricity, and axillary lymph node status [1]. Overestimation can lead to unnecessary mastectomies and unnecessary axillary evacuation. On the other hand, underestimation of tumor extent may lead to reoperations or recurrence [2].
Clinical examination and conventional imaging (mammography and ultrasound) may underestimate tumor size and/or miss small foci in comparison with histopathological examination. Breast MRI with sensitivity close to 100% may be warranted for correct preoperative staging as recommended from international guidelines [2]. It assesses the real extension of cancer by evaluating the index lesion dimensions along with identifying additional malignant foci in the same or contralateral breast, thus tailoring surgery options for each patient [3].
Regarding lymph node evaluation, mammography is typically suboptimal [4]. Non-invasive techniques such as ultrasonography (US) and PET-CT have been suggested for the evaluation of the axilla. MRI has some advantages over other modalities such as having low intra and interobserver variation (compared to US) and not utilizing radiation (compared to PET) [5].
Additional MRI parameters such as DWI-MRI can be combined with DCE-MRI to assess more functional data and to overcome limitations in DCE-MRI specificity [6].
So we aimed to evaluate the performance of CE-MRI and qualitative DWI-MRI in preoperative loco-regional staging of malignant breast lesions as regards the local extension of the disease and axillary lymph node status, beyond standard assessment with mammography and ultrasound.

Patients
This prospective study was conducted over a period of 1 year starting March 2017 till March 2018. The study included 50 women discussed at the MDT with pathologically proven breast cancer (BIRADS VI) who were candidates for further preoperative staging (Fig. 1). The age of patients ranged from 27 to 70 years (mean age 43.25 ± 9.04 SD). They were divided into 2 groups: patients who underwent upfront surgery (n = 37/50, 74%) and those who received neoadjuvant therapy (n = 13/50, 26%).
Exclusion criteria included patients who have contraindication to MRI (cardiac pacemaker, aneurismal clips, bone growth stimulators) and IV contrast (renal impairment, allergic patients, or those known to have history of anaphylactic reaction from contrast media).

Methods
All patients (n = 50/50) had previously reported sonomammography and underwent dynamic MRI with DWIs.

Technique of DCE and DWI-MRI
MRI was performed using (Philips) 1.5 T MRI system. The examination was performed using a bilateral breast surface coil with the patient in the prone position. The imaging studies included (1) localizer: axial T1-weighted turbo spin echo (TR/TE = 307/4.6 ms), axial T2-wighted turbo spin echo (TR/TE = 4.3 s/91 ms), and axial shorttime inversion recovery (STIR) (TR/TE = 5.2 s/71 ms; inversion time = 170 ms) as well as sagittal turbo spin echo weighted sequences; (2) pre-contrast series: seven dynamic acquisitions, one before and one after intravenous injection 0.1 mmol/kg body weight of contrast material (gadolinium-diethylene tri amino penta acid; Gd-DTPA), using the dynamic THRIVE sequence (T1 high-resolution isotropic volumetric examination) (TR/ TE = 5/2 ms); (3) post-contrast series: seven dynamic acquisitions, one before and one after intravenous injection 0.1 mmol/kg body weight of contrast material (gadolinium-diethylene tri amino penta acid; Gd-DTPA), using the dynamic THRIVE sequence (T1 high-resolution

Image analysis
Image analysis and interpretation were done by a singleconsultant radiologist with more than 10 years of experience in advanced breast imaging techniques, guided by the results of clinical data but blind to the sonomammography findings and the postoperative pathologic diagnosis.

Image analysis and interpretation of MRI
We characterized each malignant (or additional suspicious) lesion in reference to MRI BIRADS atlas 2013 morphology descriptors [7]. Any detected lesion was assessed for the size, extent, and multiplicity, as well as relation to the skin, nipple, and chest wall with kinetic assessment done. Axillary lymph nodes were also assessed for their shape, size, cortical thickness, and uniformity. The presence or absence of diffusion restriction was mentioned according to the qualitative assessment (i.e., the signal pattern in DWI and ADC map) [8]. The final T and N stages of each patient were estimated by sonomammography and MRI according to the AJCC guidelines of breast cancer staging [9]. Regarding the (T) stage, in case of multifocal disease, the overall area was measured, while in case of multicentricity, the size of the largest lesion was used, and in cases of neoadjuvant group, the post-neoadjuvant residual lesion size was the one used for correlation with the final postoperative pathology specimen.

Statistical analysis
Data were coded and entered using the statistical package SPSS (Statistical Package for the Social Sciences) version 25. Data was summarized using the mean, standard deviation, median, minimum, and maximum in quantitative data and using frequency (count) and relative frequency (percentage) for categorical data. Standard diagnostic indices including sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic efficacy were calculated as described by [10]. Correlations between quantitative variables were done using Spearman correlation coefficient [11]. P value less than 0.05 was considered as a statistically significant.

Group 1: upfront surgery
The ages ranged from 27 to 70 years with a mean age 43.25 ± 9.04 (mean=/-SD). The histopathological types   The mean size of the malignant mass lesions was measured by ultrasound, DCE-MRI, and DWI-MRI, and the sizes were correlated with the postoperative pathology size (Table 1). A statistically significant correlation was found between the sizes of the lesions measured by dynamic MRI and ultrasound (p values < 0.001and 0.001, respectively), yet a higher correlation (R 0.858) was calculated for dynamic MRI as seen in the scatter dot ( Fig. 2).
Regarding lesion multiplicity, additional lesions were seen by SM and DCE-MRI in 15 and 17 cases, respectively (5 and 9 TP, respectively), when only 12 cases were confirmed by the postoperative pathology and DCE-RI showed higher sensitivity. DWI-MRI was found to be unreliable in the assessment of lesion multiplicity ( Table 2).
According to the postoperative specimen pathology, 15 cases showed pathological axillary lymph nodes. The axillary lymph node status was overestimated on ultrasound and MRI; 16 on US (11 TP and 5 FP) and 19 on CE-MRI (12 TP and 7 FP). On the other hand, the lymph node status was underestimated by DWIs, and only 13 nodes were reported as pathological (9 TP and 4 FP). CE-MRI and ultrasound identified an additional pathological infraclavicular LN that was missed on DWI-MRI. DWI detected pathological axillary LN not detected by CE-MRI. Results are shown in Table 2.
Comparison of diagnostic indices of sonomammography, DCE-MRI, and DWI-MRI regarding lymph node status and multiplicity of malignant lesions is shown in Table 3. The accuracy measures of sonomammography were found to be the highest among the imaging modalities used to assess axillary LNs. On the other hand, regarding multiplicity, the accuracy measures of CE-MRI were found to be higher than those of sonomammography.
The T and N stages of the cases in this group are shown in Table 4.

Assessment of the relation to the skin and nipple
There was no skin invasion detected on both SM and CE-MRI while the nipple was involved in 2 cases by SM and in 6 cases by CE-MRI. In the postoperative pathology, 2 cases showed skin invasion and one case showed nipple affection. DWI-MRI was found to be unreliable in the estimation of the skin and nipple involvement due to its poor resolution.

Other findings
Suspicious microcalcifications were seen in 4 cases on the mammography with the corresponding area of nonmass enhancement in 3 of them on DCE-MRI. The 4 cases had corresponding area of DCIS in the postoperative pathology.
The mean size of the malignant mass lesions postneoadjuvant therapy was measured by ultrasound, DCE-MRI, and DWI, and the sizes were correlated with the postoperative pathology size (Table 5). A statistically Regarding lesion multiplicity, additional lesions detected by SM and DCE-MRI correctly correlated with the postoperative pathology specimen results (n = 3/13 (23.1%)). DWI-MRI was found to be unreliable in the assessment of lesion multiplicity (Table 6).
Regarding post-neoadjuvant chemotherapy axillary lymph node status, sonomammography and DCE-MRI showed similar results (5 cases with pathological LNs) that were identical to those identified in the postoperative pathology. In DWI-MRI, pathological LNs were found in 4 cases only. Regarding additional pathological LNs, 2 additional pathological infraclavicular and supraclavicular LNs were detected by both ultrasound and DCE-MRI, upgrading the N stage of those cases. Both cases were missed by DWI-MRI ( Table 6).
The T and N stages of the cases in this group are shown in Table 7.

Discussion
An accurate loco-regional staging and preoperative assessment of breast cancer are considered of key importance to guide treatment decisions [12]. MRI is a valuable technique and has been increasingly used particularly in  cases in which sonomammography are inconclusive or yield discrepancies (Fig. 3). It may improve the analysis of the local extent of breast cancer [13], thus increasing the rates of complete resection and reducing the number of re-operations [14]. Therefore, in this study, we aimed to evaluate the performance of CE-MRI and qualitative DWI-MRI in preoperative loco-regional staging of malignant breast lesions as regards the local extension of the disease and axillary lymph node status, beyond standard assessment with mammography and ultrasound.
We started the analysis of the upfront surgery group by correlating the size of the malignant lesion with the postoperative pathology results. CE-MRI showed the highest correlation while DWI showed the lowest (Fig. 4).
In a study performed by Gundry, tumor size was underestimated on both mammography and ultrasound (14 and 18 %, respectively); however, the size of the tumor at histology was not significantly different from that seen on MRI [15].
In our study, CE-MRI was able to detect the DCIS component of the malignant lesions in the form of area of non-mass enhancement giving better extent of the tumor size and consequently superior staging results over the sonomammography.
Kim et al. also stated that MRI was more accurate compared to mammography in the assessment of the DCIS size [16]. According to Hwang et al., MRI was  superior to mammography in the detection of invasive components within DCIS [17].
Regarding lesion multiplicity in our study, the accuracy measures of CE-MRI were found to be higher than those of sonomammography with an overall accuracy of 83.78% for MRI and 67.57% for sonomammography with reference to the postoperative pathology results (Fig. 5). DWI-MRI was found to be unreliable due to its poor resolution in the detection of the small satellite lesions.
Additional lesions (multifocal or multicentric disease) have been shown in 31% of women with breast cancer. Even though mammography and ultrasonography can often detect the primary tumor, small additional lesions may be missed [15].
Selvi et al. stated that MRI is well known for its increased diagnostic value in detecting multifocal, multicentric, or contralateral disease unrecognized on conventional exams [18]. Moreover, the metaanalysis of 50 studies (10,811 women with breast cancer) performed by Lee et al. showed that MRI findings prompted conversion from lumpectomy to mastectomy in 12.8% of cases [4].
Appropriate evaluation of regional lymph node status (N) is important for staging, treatment planning, and prognosis [4]. In reference to the postoperative pathology results of axillary lymph nodes, the accuracy measures of sonomammography were found to be the highest among the imaging modalities, with an overall accuracy of 75.68% as compared to CE-MRI and DWI-MRI with the same accuracy of 72.97% (Figs. 5 and 6).
According to Lee et al., high-resolution US is useful in the evaluation of lymph nodes at all levels while MRI can in addition detect internal mammary and supraclavicular adenopathy [4].
Kujis et al. also showed in a meta-analysis study done to demonstrate whether MRI can replace SLNB to exclude axillary lymph node metastasis, a false-negative rate of 8.61 % of the SLNB [20].
We then assessed the post-neoadjuvant group. We started the analysis of our cases by correlating the postneoadjuvant therapy size of lesions with the postoperative pathology results. In our study, CE-MRI was found to be the best among the imaging modalities, with a p value of 0.013 (Fig. 7). According to a study that included 160 patients who received neoadjuvant chemotherapy, the results showed that MRI correlated better with the size of the breast tumor remnants found in the assessment of the surgical specimen than did mammography and ultrasound [14]. Menzes et al. results suggest that DWI and ADC are useful for predicting tumor response to NAC in breast cancer patients [21].
Rosen et al. stated that the treatment options in the neoadjuvant setting depend on the amount of residual tumor. Palpation and conventional imaging (mammography and sonography) have been traditionally used, yet the tumor's true size may be hindered by edema and necrosis at the tumor site [22].
Mammographic assessment becomes 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 [15].
MRI provides anatomic and physiologic evaluation of the tumor, so the findings are not influenced by necrosis and edema. And since the findings are based on the vascularity of the tumor, the effect of chemotherapy agents can be seen through inhibiting tumor angiogenesis [15]. However, some studies emphasize on the tendency of MRI to overestimate lesion size, particularly in women with invasive lobular carcinoma and DCIS [21].
Regarding post-neoadjuvant chemotherapy lymph nodes status in our study, sonomammography and DCE-MRI had the same statistical results, correlating with the postoperative pathology specimen results. DCE-MRI is correlating better with the postoperative pathology specimen results regarding post-neoadjuvant chemotherapy lesions multiplicity.
MRI prior to NAC is essential especially if there is multicentric or diffuse disease. As a result of therapy, these lesions become less conspicuous with decreased contrast enhancement [15].
According to a study of 163 patients, preoperative MRI showed 91.04% sensitivity in detecting additional lesions either in the ipsilateral or contralateral breast [18].
Direct skin invasion and involvement of the nipple, pectoralis muscle, or chest wall should be mentioned in radiology reports because their presence changes surgical planning [4].
DCE-MRI and sonomammography correlated well with the postoperative pathology specimen regarding nipple affection while both overestimated the skin involvement. DWI-MRI was found to be unreliable in the estimation of both due to its poor resolution.
According to Gundry, breast MRI can 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 [15].
We had few limitations in this study, the small number of patients we included, especially in the postneoadjuvant group.

Conclusion
CE-MRI can accurately map lesion extension and detect multifocality/multicentricity, thus tailor surgical management options (either conservative surgery or mastectomy) for each patient. Qualitative DWI can be combined with ultrasonography for better evaluation of the axillary nodal status of those patients. Combining both allows rather reliable, accurate preoperative locoregional staging of malignant breast disease, avoiding either over or under staging, ensuring that appropriate management is provided for each case.