Synopsis

Previous studies have demonstrated the application of CEST to breast malignancies and its potential to aid tumor characterization. However, artifacts can develop in breast CEST imaging due to strong lipid signals. In this work, CEST-Dixon sequence is used for fat free CEST imaging to characterize suspicious lesions in patients. The CEST effects are higher in the ER- IDC than the ER+ IDC, benign and normal groups. The results also indicate positive correlation of CEST with the Ki-67 level. Thus, CEST-Dixon has a potential for improved non-invasive characterization of breast lesions, potentially differentiating more aggressive from less aggressive tumors.

Introduction

Methods

5 healthy female volunteers and 10 female patients prior to biopsy (later confirmed with 8 malignancies and 2 non-malignant lesions) were recruited. The confirmed malignancies included 6 Invasive Ductal Carcinoma (IDC), 1 IDC and Encapsulated Papillary Carcinoma (EPC), and 1 Invasive Mucinous Carcinoma (IMC). The non-malignant lesions included 1 Atypical Ductal Hyperplasia (ADH) and 1 Fibroadenoma. Two IDC patients were excluded from analysis due to the observable motion or the small size of lesion. The IMC patient was also excluded from the analysis because IMC and IDC are different tumor types. The local Institutional Review Board (IRB) approved the study.

The scans were performed on a 3 T scanner (Ingenia, Philips Healthcare) using a 16-channel bilateral breast coil. The CEST images were acquired using a 2D multi-shot T₁-weighted TFE sequence with 3-point multi-echo Dixon acquisition (Fig.1, TR/TE₁/ΔTE=5.1/1.57/1.0 ms). The CEST saturation consisted of 10 hyperbolic secant pulses, 49.5 ms each, with inter-pulse delay 0.5 ms and B_1rms=1.2 μT. 33 points in the Z-spectrum from -6 ppm to 6 ppm were acquired. Other imaging parameters included centric ordering, voxel size=2×2×5 mm³, FA=10°. After Dixon fat/water separation, water-only images were processed on a pixel-by-pixel basis. Field inhomogeneity was corrected using an averaged B₀ map from all frequency offsets produced by mDixon post-processing. CEST maps were generated by integrating MTR_asym in three ranges: (i) 0.8-1.2 ppm for hydroxyl groups, (ii) 1.8-2.2 ppm for amine groups and (iii) 3.3-3.7 ppm for amide groups. ROIs were placed manually on normal and/or malignant tissues identified by a fellowship trained breast-imaging radiologist. The patients are further stratified into three groups: ER-negative (ER-) IDC group (N=2), ER-positive (ER+) IDC group (N=3) and benign group (N=2). The ER- breast cancer lacks of the estrogen receptor, which is an index for sensitivity to endocrine treatment and is more aggressive than the ER+ breast cancer.⁷

Results

Figure 2 demonstrates that CEST-Dixon leads to much smoother Z-spectrum in the normal fibroglandular tissue and the overall influence of fat is removed. For comparison, Z-spectrum and APT maps using acquisition echoes close to In-Phase condition leads to large negative MTR_asym at frequencies around 3.5 ppm (Fig. 2a,b). Z-spectrum using acquisition echoes close to Out-of-Phase is even worse (Fig. 2c,d). This complex behavior was discussed in an earlier publication.⁸ Moreover, the Z-spectrum from water-only images displays higher suppression levels near water resonance, almost zero, as should be expected (Fig. 2f).

Figure 3 shows the representative hydroxyl CEST maps and ROI averaged Z-spectra and MTR_asym for a healthy volunteer (Fig. 3a,b), a triple-negative IDC patient (Fig. 3c,d) and a non-triple-negative IDC patient (Fig. 3e,f). The MTR_asym in the three CEST frequency ranges of all the subjects are summarized in Figure 4. It can be seen that the ER- IDC group results in higher CEST effects in all the three frequency ranges than the ER+ IDC, benign and normal groups. Moreover, the hydroxyl range has the largest difference between the ER- IDC and the other groups. However, the ER+ IDC, benign and normal groups tend to have similar CEST effects, which suggest that the ER+ IDC group is indistinguishable from normal and benign groups in the three frequency ranges.

In Figure 5, the tumor MTR_asym in the three frequency ranges are plotted against the Ki-67. It is evident that the MTR_asym increases as Ki-67 level increases for all the frequency ranges. The R² values were 0.95, 0.87 and 0.36 for hydroxyl, amine and amide frequency ranges, respectively. These results are one of the first correlations of CEST with Ki-67 in-vivo.

Conclusion

Acknowledgements

References

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