Combined application of pharamcokinetic DCE‐MRI and IVIM‐DWI could improve detection efficiency in early diagnosis of ductal carcinoma in situ

Abstract Purpose Ductal carcinoma in situ (DCIS) is a precursor of invasive ductal breast carcinoma (IDC). This study aimed to use pharamcokinetic dynamic contrast‐enhanced magnetic resonance imaging (DCE‐MRI) and intravoxel incoherent motion diffusion‐weighted imaging (IVIM‐DWI) for the early diagnosis of DCIS. Methods Forty‐seven patients, including 25 with DCIS (age: 28–70 yr, mean age: 48.7 yr) and 22 with benign disease (age: 25–67 yr, mean age: 43.1 yr) confirmed by pathology, underwent pharamcokinetic DCE‐MRI and IVIM‐DWI in this study. The quantitative parameters Ktrans, Kep, Ve, Vp, and D, f, D* were obtained by processing of DCE‐MRI and IVIM‐DWI images with Omni‐Kinetics and MITK‐Diffusion softwares, respectively. Parameters were analyzed statistically using GraphPad Prism and MedCalc softwares. Results All low‐grade DCIS lesions demonstrated mass enhancement with clear boundaries, while most middle‐grade and high‐grade DCIS lesions showed non‐mass‐like enhancement (NMLE). DCIS lesions were significantly different from benign lesions in terms of Ktrans, Kep, and D (t = 5.959, P < 0.0001; t = 5.679, P < 0.0001; and t = 5.629, P < 0.0001, respectively). The AUC of Ktrans, Kep, D and the combined indicator of Ktrans, Kep, and D were 0.936, 0.902, 0.860, and 0.976, respectively. There was a significant difference in diagnostic efficacy only between D and the combined indicator (Z = 2.408, P = 0.016). Conclusion DCE‐MRI and IVIM‐DWI could make for the early diagnosis of DCIS, and reduce the misdiagnosis of DCIS and over‐treatment of benign lesions.


| INTRODUCTION
Breast cancer, the most common female cancer, is highly heterogeneous and is probably caused by numerous changes in the genome of specific cells over extended time periods. 1,2 Changes of normalphenotype breast cells to cancerous-phenotype cells are affected by a series of factors, such as the local and non-native environment, lifestyle, dietary habits, and genetic inheritance, which can disrupt cells' physical characteristics, behavior, and communication pathways. 3 Ductal carcinoma in situ (DCIS) of the breast, a noninvasive and nonobligate precursor lesion, represents a transition from normal tissue to an invasive ductal breast carcinoma (IDC) through a multifactorial process. 2,4 According to the World Health Organization classification of breast tumors in 2012, 5 DCIS lesions could be classified as highgrade, middle-grade, and low-grade tumors, which have varying prognoses due to distinct molecular markers and genetic signatures. 6 High-grade DCIS seems to progress to IDC more rapidly and more frequently than low-grade DCIS, [7][8][9] whereas low-grade DCIS could be more indolent to change or might progress to certain well-differentiated types of cancer. 10 However, DCIS requires surgical locoregional treatment to avoid recurrence or progression to IDC. [11][12][13] Therefore, it is necessary to diagnose DCIS early by noninvasive examinational methods, especially high-grade DCIS.
Preoperatively diagnosed DCIS accounted for only 2% of breast cancers in 1980, but the proportion increased to approximately 20% in 2002 with mammographic imaging techniques. 14,15 Microcalcification, as the main feature of DCIS, is more likely to be detected by mammography than other imaging methods, such as MR. 10,16 However, only 50%-75% of DCIS lesions show microcalcification, 17 which are frequently misdiagnosed on mammographs, with a sensitivity of 27%-80%. 18 Recently, with the application of the Breast Imaging Reporting and Data System (BI-RADS), MRI has become a powerful imaging method for diagnosis of DCIS lesions, with a sensitivity of 96% and the negative-predictive value (NPV) is 98.24%. However, the specificity and positive-predictive value (PPV) of MRI in DCIS are 75.67% and 57.14%, respectively, 19 because DCIS is easily confused with benign lesions in terms of morphology and semi-quantitative features. 20 Excising benign breast lesions is an overtreatment, according to BI-RADS. Therefore, it is necessary to distinguish benign lesions from DCIS of the breast on MRI.
Functional MRI has been widely applied in the diagnosis of breast disease. Pharmacokinetic dynamic contrast-enhanced MRI (DCE-MRI) is a sensitive technique that reflects physiological characteristics of lesion microvasculature. 21 DCE-MRI parameters for quantitative measure of perfusion, including K trans , K ep , V e , and V p , reflect tumor angiogenesis density, vascular permeability, and tumor neoangiogenesis blood flow. 22,23 Additionally, diffusion-weighted imaging (DWI), another noninvasive quantitative MRI method, could reflect tumor cytoarchitecture and distinguish pseudo-random movements. 24 Based on the theory of intravoxel incoherent motion (IVIM), the new DWI analysis model can be performed with >2 b-values with the following parameters: true diffusion coefficient D, the pseudo-diffusion coefficient D*, and the perfusion fraction f. 10 However, DCE-MRI and IVIM-DWI are rarely used to distinguish DCIS from benign lesions of the breast. Herein, we used these techniques to diagnose DCIS to identify DCIS with higher specificity.

2.A | Study population
where C t (t) is the concentration of the agent in the voxel at time t, while C p is the concentration of the agent in the plasma volume. V e is the proportional volume of the extravascular extracellular distribution space (EES). K trans is the volume transfer constant between the plasma and EES. V p is the proportional blood plasma volume. K ep is the diffusion rate constant EES to plasma.
The following biexponential (IVIM) equation was used: where S b is the mean signal intensity, S 0 is the signal reference, b stands for the b-value, and f is the fraction of perfusion. D* is the diffusion of the perfusing fraction and D is the diffusion of the nonperfusing fraction.
The K trans , K ep , V e , and V p maps were obtained by postprocessing of DCE-MRI images with Omni-Kinetics software. The D, f, and D*maps, as IVIM-DWI parameters, were generated by MITK-Diffusion software postprocessing.     Fig. 5(a-b)].

3.B.2 | Comparison of parameters among different DCIS grades
No obvious differences in K trans , K ep , V e , and V p (in DCE-MRI), and D, f, and D* (in IVIM) values of lesions were found, indicating different DCIS grades (Table 3).

3.B.3 | Diagnostic efficiency test of parameters
ROC curves were used to evaluate the diagnostic efficiency of parameters between DCIS and benign lesions [ Table 4, Fig. 6]. All AUCs of K trans , K ep , and D exceeded 85%, and all of the sensitivity and specificity values were >80%. The cutoff value of every diagnostic parameter calculated on generating ROC curves is listed in  distinguish DCIS from benign lesions in morphology. It is very likely to misdiagnose DCIS lesions as benign lesions during a semiyearly assessment. Therefore it is clinically meaningful to distinguish between DCIS and benign lesions.
Breast MRI is used preoperatively with increasing frequency in women with DCIS, where it has shown high sensitivity for detection, especially in cases of high-grade lesions. 10 In our study, most middle-and high-grade DCIS lesions were NMLE, which was consistent with Greenwood's standpoint that most DCIS lesions manifested NMLE in enhanced MRI. 27 Due to the lack of typical morphological features of malignant lesions in DCIS, and its misinterpretation as benign lesions, 28      efficiency for differentiating DCIS lesions from benign lesions, which was in agreement with results from the previous reports. [29][30][31] As a novel DWI technique, IVIM-DWI reveals microscopic biological structures and diffusion of water protons in tissue, without the intravenous contrast agent. 33 Using a series of multiple b-values, DWI signals could show the perfusion of the capillary network in the low bvalue range (b < 100-150 s/mm 2 ), and the diffusion of water protons in the high b-value range. 34 In the current study, IVIM-DWI was an effective tool for diagnosing DCIS and other benign breast lesions by means of parameter D. In the biexponential IVIM-DWI model, D value could exclude the influence of cell structure and the microcirculatory perfusion effect. 35 Furthermore, D had a higher diagnostic efficiency than parameters f and D*, which was consistent with other literature reports. 35,36 The cutoff value of D was 1.177 × 10 −3 mm 2 /s, with an AUC of 0.860, sensitivity of 81.82%, and specificity of 84.00%. These values were higher than those reported by Mao et al. 37 , probably because of differences between studied samples.
An indicator that combined K trans , K ep , and D had a higher diagnostic efficiency than any single parameter. Therefore, combining the DCE-MRI and IVIM-DWI methods could increase the accuracy of DCIS diagnosis, which was consistent with the study by Ma in terms of the diagnosis of breast tumors. 38 Statistical analysis showed that, there was no significant difference in diagnostic efficiency among the combined index, K trans , K ep , and D, except for the diagnostic efficiencies of the combined index and D. As a DWI method, IVIM-DWI had some value in diagnosing DCIS, although the ability to identify DCIS and IDS was weaker than that of the combined index. 39 There were some limitations in our study. The number of cases was relatively small, and the interpretability of the results was limited. The differences in parameters among lower-grade, high-grade, and middle-grade DCIS have not been proven conclusively because of the limited numbers of cases. Despite these limitations, our results suggested that DCE-MRI and IVIM-DWI could contribute to the diagnosis of DCIS.

| CONCLUSION
In summary, our study showed significant differences in K trans and K ep of DCE-MRI, and D of IVIM between DCIS and benign lesions.
DCE-MRI and IVIM-DWI were helpful for the early diagnosis of DCIS, which could prevent a missed diagnosis of DCIS, and overtreatment of benign lesions as well.