Pediatric Application of Dynamic Contrast-Enhanced MR Imaging (DCE-MR) in the Management of Extra-Cranial Tumor: Experience in Routine Clinical Practice

Background: Dynamic contrast-enhanced MR imaging (DCE-MR) is becoming a widely accepted complementary method for diagnosing breast cancer and other cancers in adults. It is useful to predict tumor response to anticancer therapy and monitor the tumor response to the therapy. This form of imaging techniques has not been adequately explored in pediatric oncology patients. Objective: To determine the potential role of dynamic contrast-enhanced MR imaging (DCE-MR) in the diagnosis and treatment response monitoring of childhood and young adult extra-cranial tumors in routine clinical setting. Methods: Children with suspected extra-cranial solid tumors, including newly diagnosed or follow-up cases of confirmed tumors, were recruited. DCE-MR was performed with intravenous injection of 0.1 mmol/kg contrast. The enhancement time curves were plotted and the enhancement patterns were categorized into type 1, 2 and 3 curves. Enhancement curve patterns and maximal enhancement intensity were compared with types of tumor in newly diagnosed cases. The preoperative percentiles of inactive area on the colour map were compared with the necrotic areas on histologic sections of the resected specimens in follow-up cases. Pearson Chi-square test and Unpaired two-sample t-test were used for statistical analysis. Results: There were 36 patients, involving 28 malignant and 8 benign cases. There were 14 type 3 curves, (all of them were malignant tumors), 6 type 2 curves and 16 type 1 curves. All findings (accuracy = 93.3%). Conclusion: Type 1 curve was a good predictor of benign lesion. DEC-MR may have a role to play in the monitoring of the progress of treatment and extent of tumor necrosis.


Introduction
Radiologists are often required to provide information on clinical questions such as diagnosis, staging, treatment response, and detection of either residual or recurrent lesions in oncology patients. MRI is a useful tool in assisting the diagnosis, defining the extent of diseases and monitoring the response to therapy. Dynamic contrast-enhanced MR imaging (DCE-MR) is becoming a widely accepted complementary method for diagnosing breast cancer and other cancers in adults [1] [2]. It can help to monitor the effect of anti-angiogenic treatment response [3] [4]. But this form of imaging techniques have not been adequately explored in pediatric oncology patients. There were not many applications in pediatric extra-cranial tumours.
Previous studies using DCE-MR demonstrated that malignant tumors usually showed faster and higher levels of enhancement than normal tissue [2]. This enhancement characteristic indicated that malignant tumors have increased vascularity and endothelial permeability to the contrast molecules than that of normal or less aggressive malignant tissues. Weidner et al. [4] demonstrated that in many tumors such as breast, lung, prostate, and head and neck cancer, the measurements of microvascular density made on histopathological samples correlated closely with clinical stage and acted as an independent prognostic factor of considerable sensitivity. The relationship could be due to the rapid tumor growth which could only be supported by highly active angiogenesis. The more aggressive tumors were therefore associated with higher angiogenesis-related microvasculature abnormalities. On the basis of this histopathological evidence it had been suggested that DCE-MR might be able to provide additional independent indices of angiogenic activity and therefore acted as a prognostic indicator in a broad range of tumor types. DCE-MR time intensity curve (TIC) patterns are categorized to three types: type 1, persistently enhancing (progressive), which is suggestive of less angiogenic; type 2, plateau type, which has an intermediate probability for malignancy; and type 3, washout type, which is indicative of malignancy with a lot of angiogenesis [2] [5]. DCE-MR is also useful to predict tumor response to anticancer therapy and monitoring the tumor response to the therapy [6] [7] [8].
This study tried to explore the possible role of DCE-MR in the diagnosis and treatment response monitoring of childhood and young adult extra-cranial tu-Open Journal of Radiology mors in routine clinical setting.

Subjects
This was a prospective study. From 2014 to 2016, all children and young adults younger than 20 years old attending the oncology clinic with suspected extracranial tumors were recruited for MR examinations. All examinations were done in the Department of Radiology in our local institution, involved patients including newly diagnosed or follow-up cases of malignant tumors. Follow-up cases were those who underwent neoadjuvant chemo-or radiotherapy. This study was approved by the Institutional Review Board in our hospital. Informed consent was obtained from the parents. Newly diagnosed cases with no diagnostic biopsy and follow-up cases with no post-treatment operation were excluded.

MRI Quantitative Analysis
Post data analysis was conducted using Functool software. A region of interest (ROI) was placed in the lumen of the nearest large artery to evaluate the arterial input function. Consecutively, perfusion and tissue-blood ratio were calculated and colour mapping was generated. ROIs were drawn around its highest vascu-  The curve patterns and maximal enhancement intensity (SI max ) were correlated with the type of tumours (pathological confirmed) in first diagnosed cases.
For those follow-up cases of tumors after neoadjuvant chemo or radiotherapy, MR was performed within a few days before the operation. The tumour inactive area was defined by the area of lack of signal changes on the color map and TIC curve. The percentile of tumour inactive area was defined as the ratio between inactive area and the overall tumour volume. The preoperative percentile of inactive area on the colour map was compared with the necrotic areas on histologic sections of the resected specimens.

Statistical Analysis
Statistical analyses were performed using SPSS version 15.0. Pearson Chi-square was used to test the dependence of types of tumor upon types of curve. The observed frequency (O) and the expected frequency (E) for each type of curves were used to calculate the χ 2 value.
Unpaired two-sample t-test was used to analyse the relationship between type of tumor and the SI max ( 1 x = SI max mean of benign tumor, 2 x = SI max mean of malignant tumor, s1 = SD of benign tumor, s2 = SD of malignant tumor, N1 = samples size of benign tumor, N2 = samples size of malignant tumor) The calculated T statistic value was used to decide if there is a significant difference in the SI max between the benign and Open Journal of Radiology malignant tumor.
A p-value < 0.05 (two-tail) was considered to be statistically significant.

Results
A total of 36 studies (M = 29, F = 7) were performed, with average age 9.87 yrs old and with ages ranging from 1 month to 20 years old. There were 28 malignant cases and 8 benign cases (Table 1).

Newly Diagnosed Cases
There were 21 newly diagnosed cases including 3 intra-abdominal, retroperitoneal

Discussion
In our study, most of the tumors were peripheral solid tumors of musculoskeletal or blastoma origins. The initial result was encouraging. We found that type 3 curve pattern applied to many newly diagnosed malignant extra-cranial solid tumors irrespective of their location, such as Ewing sarcoma, pPNET, Langerhans Open Journal of Radiology  Osteogenic sarcoma often requires biopsy for definitive diagnosis. Evaluating response of bone sarcoma to initial chemotherapy by imaging methods is a challenge. Even with large necrotic area inside the tumor bulk, the tumor may not shrink significantly. This is due to the extensive osteoid and bony matrix which will remain static after chemotherapy [10]. At present, the gold standard for as-  [20]. One study showed DCE-MR was a prognostic factor for event-free survival and overall survival before treatment, and was indicative of histologic response to neoadjuvant therapy [21]. In the assessment of the percentile of necrosis and thus the degree of response to the chemotherapy in our follow up scans, all of our cases correlated well with the pathology findings. Our findings in osteogenic sarcoma were comparable with the other studies.
We demonstrated that all benign tumors showed type 1 curves and all of their maximal enhancement signals (SI max ) were less than 350. Though limited in number, the cases in our study showed that the negative predictive value of type 1 curve for malignant tumor was 100%. It is therefore tempting to suggest that type 1 curve together with SI max < 350 may be reliable indicators to differentiate benign from malignant tumors in pre-treatment cases. This is particularly useful for the planning of operation.
However, there were limitations in our study. Our sample size and characteristics of the samples were small. Our samples were a mixture of different tumors. The number of paired pre and post-treatment patients were small and limited. A larger sample size is desirable to further confirm our findings and to improve statistical power. In one case of intra-abdominal carcinoma of pancreas, type 2 curve was found. We considered that the TIC for this kind of tumor was not specific. DCE-MR might not be useful in this kind of intra-abdominal tumor. In one case of arm pPNET tumor, the presence of axillary lymph node impaired the blood flow, thus affecting our accuracy.

Conclusion
Despite small sample size, our results were very encouraging. In routine clinical practice, our study showed that DEC-MR might be useful in the differentiation of benign and malignant extra-cranial solid tumor in children and young adults.
Based on our findings, type 1 curve with SI max less than 350 is suggested as an additional indicator to assist in the differentiation of benign tumors in pre-treatment cases. We also think that DEC-MR may have a possible role in the monitoring of treatment response in extra-cranial childhood solid tumors. The lack of irradiation has an advantage over CT or PET in pediatric applications.
However, a larger study is needed to further confirm our findings.