Addition of Diffusion-Weighted Imaging to Dynamic Contrast Enhanced MRI: can it help differentiate benign from malignant jaw lesions?

Objective: To explore the diagnosis value of adding diffusion-weighted imaging (DWI) to dynamic contrast enhanced MRI (DCE-MRI) in distinguishing benign from malignant jaw lesions. Materials and Methods: This retrospective study was involved 53 patients (23 benign, 30 malignant) with jaw lesions conrmed by pathology were analyzed. DWI and DCE-MRI were performed in all patients. The Apparent Diffusion Coecient (ADC) value as well as the DCE-MRI parameters [time to peak (T peak ), wash in rate (WIR), wash out rate (WOR), relative enhancement, and maximum enhancement] were measured for each patient. The optimal cut-off value of ADC values and DCE-MRI parameters were determined by using a receiver operating characteristics (ROCs), and the area under ROC curve (AUC) was evaluated. P < 0.05 was considered to indicate a signicant difference. Results: Among the ve parameters of DCE-MRI, the WOR displayed the most signicantly difference with a threshold value of 4.90 l/s between benign and malignant group (P<0.05). When only WOR was used as the basis for diagnosis, the sensitivity, specicity, and AUC were 77.20%, 78.00%, and 0.800, respectively (Fig.3, 4). However, sensitivity (77.20% vs 83.30%), specicity (78.00% vs 87.20%) and accuracy (0.80 vs 0.85) signicantly improved with the addition of ADC values in the evaluation of jaw lesions, which manifested better than that by using WOR alone. Conclusion: The high WOR of DCE-MRI may have a malignant tendency, but in the evaluation of jaw disease, the addition of ADC value can improve the diagnostic value.

a threshold value of 4.90 l/s between benign and malignant group (P<0.05). When only WOR was used as the basis for diagnosis, the sensitivity, speci city, and AUC were 77.20%, 78.00%, and 0.800, respectively ( Fig.3, 4). However, sensitivity (77.20% vs 83.30%), speci city (78.00% vs 87.20%) and accuracy (0.80 vs 0.85) signi cantly improved with the addition of ADC values in the evaluation of jaw lesions, which manifested better than that by using WOR alone.
Conclusion: The high WOR of DCE-MRI may have a malignant tendency, but in the evaluation of jaw disease, the addition of ADC value can improve the diagnostic value.

Background
Imaging of lesions within the maxilla and mandible is often fraught with di culty owing to the similarity in the imaging appearance of a diverse array of pathological processes , (1,2) . Array of lesions with the jaw reveal similar localization features, most of which arising in the posterior body and lower ramus of the mandible (3,4) . Even though conventional imaging, such as computed tomography (CT) and magnetic resonance imaging (MRI) can represent the pertinent reference such as the location, relationship to the tooth, margins of the lesion, size of the lesion and solid or cystic performance of the lesion, which of the imaging ndings can narrow the differential diagnosis, many lesions still often exist considerable conventional imaging overlap (2,(5)(6)(7) . Assessing the biological behavior among the mandible and maxilla lesions is the rst step for clinical diagnosis and management. (8) Previous studies involving the roles of functional MRI, such as diffusion-weighted imaging (DWI) and dynamic contrast-enhanced (DCE) MRI already have a wild application (7,9,10) , such as the brain, prostate, and breast, and head and neck (11)(12)(13) .
The usefulness of DWI has been reported (14,15) ,and the type of time-intensity curve (TIC) generated by DCE-MRI is of a great value as well (16) . However, these are not as accurate as quantitative or semiquantitative parameters. In this study, we try to introduce array of semi-quantitative parameters measured by DCE-MRI such as wash in rate(WIR), time to peak(T peak ) , wash out rate (WOR). To our knowledge, the exploration of the combination of DWI and DCE-MRI in the jaw lesions has not been emphasized previously in the literature. Therefore, our study aims to determine whether the addition of DWI to DCE-MRI can help distinguish between benign and malignant jaw lesions.

Methods
Our retrospective study was approved by the institutional review committee of the Shanghai Ninth People's Hospital and the informed consent requirement was waived. A total of 53 patients (29 male, 24 female; mean age, 41.5 years) were enrolled between January 2017 and May 2019. All patients were examined with gadolinium-enhanced dynamic MR imaging and DWI at our hospital. Histopathologic diagnoses were made on the basis of ndings in specimens obtained at surgical resection. The exclusion criteria were as follows: (1) with interfering the diagnosis; (2) with a previously diagnosed head and neck cancer; or (3) with treatment of a head and neck lesion (surgical management or radiotherapy) before the MRI scan. Two radiologists selected representative regions of interest (ROIs) by consensus (X.Z. and J.B.W., with 5 and 10 years of experience in maxillofacial imaging and contrast-enhanced MRI, respectively). For ADC measurements, freehand ROI was drawn, taking care to exclude obvious necrotic or non-perfused areas by visual correlation with pre-and post-contrast T1 weighted images and to avoid the most peripheral portions because of partial volume effects of adjacent tissue. Three ROIs were manually placed within each lesion, and the averaged ADC value was obtained. For post-processing of DCE-MRI, we placed ROIs (approximately 25-50 mm 2 ) over the lesion and time-intensity curve (TIC) for each ROI was generated.
The TIC (axis co-ordinate, time; vertical, signal intensity) with the most prominent enhancement was selected as the representation for each lesion. The following DCE-MRI parameters were automatically calculated for each patient: T peak (time to enhancement peak minus the time at which the maximum slope tangent intersects the x-axis), relative enhancement (the difference between post -pre enhancement on the y-axis), maximum enhancement (time to peak enhancement extend the value at which the maximum slope tangent intersects the y-axis), wash in rate (maximum slope, tangent at the ascending part of the time-intensity curve), wash out rate (minimum slope, tangent at the descending part of the time-intensity curve).

Statistical analysis
Statistical analysis was carried out using SPSS 23.0 (2012, Chicago, USA). Descriptive statistics, such as the age of male and female patients, and disease duration in patients, were compared with Mann-Whitney U test for independent samples. 95% con dence intervals (CIs) were calculated using logistic regression models to determine the association of DCE-MRI parameters between benign and malignant jaw, as well as the ADC value. To nd the feasible threshold of ADC value and DCE-MRI parameters to distinguish malignant from benign lesions, we conducted receiver operator characteristics (ROCs) analysis. We plotted the sensitivity versus 1-speci city for each cut-off value to generate the ROC curve, and the areas under the ROC curve (AUC) were assessed. We then conducted and compared the AUC of the DCE-MRI parameters, then add the ADC value to the most signi cantly parameter of DEC-MRI to evaluate the diagnostic ability. p < 0.05 was considered as statistically signi cant.
Malignant group showed higher WOR, WIR, but lower T peak and ADC value compared with the benign group (p<0.05) ( g.6-9). The optimal cut-off value of WOR value was 4.9 l/s ( Table 2), which suggested a malignant diagnosis with WOR > 4.9 l/s and a benign diagnosis with WOR ≤ 4.9 l/s. Maximum or relative enhancement is not helpful to distinguish benign and malignant lesions (P>0.05). In addition to DCE-MRI parameters, the ADC value displayed a threshold value of 1.05×10 −3 mm 2 /s ( Table 2), which suggested a malignant diagnosis with ADC value ≤ 1.05×10 −3 mm 2 /s (Fig 1) and a benign diagnosis with ADC value >1.05×10 −3 mm 2 /s (Fig 2).

Discussion
Our ndings show that adding DWI to DCE-MRI can improve diagnostic value in mandible and maxilla tumors. With the addition of ADC, it may be possible to avoid missing cancers and performing unnecessary surgery or biopsy for benign lesions in the jaw. DWI quanti es the diffusional mobility of water protons with apparent diffusion coe cient (ADC). DCE-MRI provides information related to the physiology of the microcirculation and vascularity. As with most DWI applications, tumor cell density is higher, and more cell membranes theoretically have a greater impediment to diffusion, consequently, a lower ADC. On the contrary, ADC is higher . Given the heterogeneous group of benign and malignant lesions, there will clearly be exceptions and overlap in ADC value as well as the WOR results. A single parameter threshold cannot be used in all circumstances, and the establishment of threshold for speci c diagnosis is required. Among a wild range of head and neck lesions, previous studies have established an optimal ADC threshold of 1.3 × 10 −3 mm 2 /s for diagnosis between benign and malignant lesions (17) , and the ADC value of malignant tumors, benign solid masses, and cystic lesions of 0.93 ×10 −3 mm 2 /s ± 0.18, 1.57 × 10 −3 mm 2 /s± 0.26, and 2.01 × 10 −3 mm 2 /s ± 0.21, respectively (18) . For speci c mandible and maxilla lesions, our results found the ADC value of benign and malignant group of 1.55×10 −3 mm 2 /s ± 0.83, 0.95×10 −3 mm 2 /s ± 0.37, respectively, which was more speci c than the previous reports.
T peak is believed to represent microvascular counts, and in head and neck tumors, the threshold between benign and malignant tumors has been described as about 120 seconds (19) . However, there is no clear data on the identi cation of speci c jaw lesions. The data from this group showed a threshold of 75.78 seconds for the "benign and malignant tumors" group, which is more suitable for maxillary and mandibular lesions than previously reported. WOR represents a difference in medium concentration between the intravascular and extravascular phases; tumors with high cellularity exhibit higher wash out rate values (20) . Previous authors reported that enhanced areas of benign lesion-broblastoma showed a gradual enhancement on DCE-MRI, which corresponded to solid components and/or intramural nodules, and the solid area reached 600 After s gradually disappears or maintains an enhanced level. The maximum enhancement level, our results showed that the mean WOR of benign lesions was 4.09 l / s ± 6.10, while in the malignant group, the mean WOR was 21.4 l / s ± 31.37, signi cantly higher than the benign group. Due to the high cell density in malignant tumors, the WOR threshold for benign and malignant groups was 4.9 l / s, corresponding to previous studies. Other parameters of DCE-MRI in our study, including maximal enhancement and relative enhancement, did not reveal signi cant differences in the identi cation of benign and malignant lesions of the jaw. By adding the ADC value, the sensitivity, speci city, and accuracy are signi cantly improved, which is better than using WOR alone. In addition, because DWI combined with DCE-MRI can improve the diagnostic accuracy, whether traditional MRI combined with DWI and DCE-MRI can improve the diagnostic accuracy is still to be further exploration.
Our study had the following limitations: First, due to the low incidence rate and the strict exclusion criteria of the study, we included a relatively small number of jaw lesions, thereby further prospective and multicenter studies need to validate our ndings. Second, the reproducibility of ADC values between MR pulse sequences remains controversial. As such, the cutoff level for the ADC value derived from our results might not be transferable to other institutions. In addition, given the heterogeneous origin of benign and malignant lesions with jaw, data from larger studies are required to de ne in speci c pathological entities.
In conclusion, the high WOR of DCE-MRI may have a malignant tendency, but in the evaluation of jaw disease, the addition of ADC value can improve the diagnostic value. DWI combined with DCE-MRI parameters can better distinguish benign and malignant lesions in the mandible than single parameters, which is of great signi cance for preoperative diagnosis of jaw lesions.          The ROC showed the diagnosis of benign and malignant lesions based on WOR and ADC value demonstrated an AUC of 0.80, and 0.81, respectively.