Mami Iima1,2, Masako Kataoka1, Maya Honda1, Ayami Ohno Kishimoto1, Rie Ota1, Akane Ohashi1, Yuta Urushibata3, Thorsten Feiweier4, Masakazu Toi5, and Kaori Togashi1
1Diagnostic Imaging and Nuclear Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan, 2Clinical Innovative Medicine, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, Kyoto, Japan, 3Siemens Healthcare K.K., Tokyo, Japan, 4Siemens Healthcare GMBH, Erlangen, Germany, 5Breast Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
Synopsis
We
investigated the variation of ADC values obtained at diffusion times that are
clinically available for differentiation of human breast tumors. The ADC values
in both malignant and benign breast tumors decreased with increased diffusion
time, and a larger change in ADC values was found in malignant tumors. The
significant association found between ADC change and Ki-67 expression might
indicate the potential of diffusion time-dependent ADC values as a tool to
differentiate these prognostic biomarkers and assess tumor heterogeneity without
the need for contrast agents.
Introduction
Diffusion
MRI is widely used for detection and characterization of breast lesions without
the need for contrast agents, and many previous studies have demonstrated the
clinical utility of ADC in differentiation between malignant and benign breast
lesions or breast tumor subtypes linked to prognostic factors.1
Furthermore,
studies have shown changes in ADC values with different diffusion time and
their utility in tumor characterization in the prostate, head and neck, and
breast tumors.2-5 Increased diffusion hindrance is expected at longer
diffusion time as more water molecules collide with microscopic obstacles
within tissues, such as cell membranes, the density of which increases in
cancer tissues. Improvements in MRI gradient hardware have allowed the
acquisition of shorter diffusion times (such as oscillating gradient spin-echo (OGSE)) with some clinical
scanners. Measuring ADC values at different diffusion times can provide
important information about the degree of diffusion hindrance and in turn the
nature of the lesions. It may also provide information about the different
expression levels of prognostic biomarkers in human breast tumors. Thus, our
purpose was to investigate the variability of clinical ADC measurements and
their association with diffusion times using OGSE and pulsed gradient spin-echo (PGSE) in human breast tumors.Methods
OGSE and PGSE sequences were performed on a dedicated-breast polyvinylpyrrolidone phantom (covering typical ADC values from malignant to benign lesions6) and patients using a clinical 3-T system (MAGNETOM Prisma, Siemens Healthcare, Erlangen, Germany) equipped with a dedicated 16-channel breast array coil. This
prospective study investigated 72 breast tumors (36 malignant and 36 benign).
Data acquisition utilized diffusion-weighted echo planar prototype
sequences with b-values of 0 and 700 s/mm2. OGSE was
performed with trapezoid cosine waveforms (frequency = 40 Hz; effective
diffusion time (Deff) =5.1ms) and PGSE (Deff=96.6 ms); repetition time/echo time, 7,500ms/125ms;
field of view, 330×330 mm2; matrix, 112×112; slice thickness,
3.0 mm; acquisition time averaged over 8 averages, 2.5 min for each, OGSE
and PGSE. Two independent radiologists placed ROIs in lesions on the ADC maps,
and mean ADC values were calculated. An ADC change was
calculated as (ADCOGSE − ADCPGSE) / ADCOGSE×100 (%). Agreement of ADC values or ADC change between two independent
radiologists was calculated using intraclass correlation coefficients (ICC). Wilcoxon test was used for
the comparison of ADC values between different diffusion times. ADC values and ADC change with diffusion time were compared between samples that were positive
and negative for expression of prognostic biomarkers (ER, PgR, Her2, Ki-67)
using Mann-Whitney
tests.Results
As expected, ADC values in PVP phantom showed no difference for Gaussian
diffusion, validating the OGSE and PGSE protocols. Excellent agreement between
independent readers was observed for ADC values and ADC change (ICC:
0.91–0.98), so each value was averaged for further analysis. The ADC values in
malignant lesions were significantly lower than those in benign lesions at both
diffusion times, and ADC values significantly decreased with increased
diffusion times (P <
0.01 and < 0.01, Fig.1a). A significant association was found between ADC change and Ki-67 status (P < 0.05, Fig. 1b). No significant difference was found in other prognostic biomarkers or subtypes of breast cancer. Figures 2–3 demonstrate representative ADC maps at
different diffusion times. A mild ADC decrease was observed at the center of the
cancer, whereas ADC sharply decreased in the peripheral region (Fig. 2).
In contrast, very small ADC changes were observed in a benign phyllodes tumor
(Fig. 3) .
The
diagnostic performance of ADCPGSE was slightly better than that of
ADCOGSE or ADC change, with no significant difference (AUC: 0.97,
0.94, and 0.96, respectively, Fig.4).Discussion
The
observed decrease of ADC values with diffusion time in breast tumors was in
agreement with the literature, as well as with our previous investigation.2-5 This confirms the hypothesis that diffusion hindrance increases with diffusion
time in tumors, as more molecules hit many boundaries such as cell membranes
that are water-permeable, to which ADC is highly sensitive.7 The
lower ADC values observed in malignant than benign tumors suggest a dependence
of water molecule displacement on tissue type, as shown in Fig. 5. The
difference of apparent diffusion distance between malignant and benign tumors
was smaller in OGSE than in PGSE, and using OGSE might diminish the contrast
for differentiation of tumor type. The association of ADC change with Ki-67
expression might reflect differences in the proliferative activity of some
tumors and help to assess prognostic biomarkers for breast cancer without the
use of contrast agents.Conclusion
The
diffusion time
dependence of ADC measurements for differentiation of prognostic biomarkers in
human breast tumors was investigated. The ADC values in breast tumors varied
with diffusion time, suggesting the necessity of reporting diffusion times in corresponding
studies. The significant association of ADC change with Ki-67 expression might
help to differentiate these prognostic biomarkers, determine treatment plans,
and assess tumor heterogeneity without the need for contrast agents. Acknowledgements
This work was supported by MEXT
KAKENHI Grant No. 18K15588. References
(1) Iima M, Honda M, Sigmund EE, et
al. Diffusion MRI of the breast: Current
status and future directions. J Magn Reson Imaging. 2019 Sep 14.
(2)
Reynaud O et al.
Surface-to-volume ratio mapping of tumor microstructure using
oscillating gradient diffusion weighted imaging. Magn Reson Med. 2016
Jul;76:237-47.
(3)
Lemberskiy G, Rosenkrantz AB, Veraart J et al.
Time-Dependent Diffusion in Prostate Cancer. Invest Radiol. 2017
Jul;52(7):405-411.
(4)
Iima M et al. Time makes the difference: Comparison
of ADC values obtained with OGSE and PGSE sequences for differentiation of
human breast tumors. ISMRM 2018.
(5)
Iima M et al. Time-dependent diffusion MRI to distinguish
malignant from benign head and neck tumors J Magn Reson Imaging. 2019
Jul;50(1):88-95.
(6) Wagner F et al. Temperature and concentration calibration of aqueous polyvinylpyrrolidone (PVP) solutions for isotropic diffusion MRI phantoms.PLoS One. 2017 Jun 19;12(6):e0179276.
(7)
Springer CS Jr1. Using 1H2O MR to measure and map
sodium pump activity in vivo. J Magn Reson. 2018 Jun;291:110-126.