Radiomic features based on MRI for prediction of lymphovascular invasion in rectal cancer
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To investigate the value of radiomics in predicting lymphovascular invasion (LVI) status of rectal cancer based on MRI.
Materials and methods
The retrospective study included 188 patients based on MRI with histologically confirmed rectal cancer and evaluated LVI status. Clinical factors and image data were collected, and radiomics features were extracted from multi-region (tumor and mesorectum) and single region (tumor), respectively, on T2WI and DWI. Spearman correlation analysis and the LASSO algorithm were used for radiomic feature extraction and selection; preliminarily selection of an optimal classifier by the results of the fivefold cross-validation performance in the six preselected specific machine learning classifier. Multi-regional and single-regional predictive models were both built and evaluated by calculating the area under the ROC curve (AUC) and corresponding accuracy, specificity, sensitivity, etc.
A Ridge Classification model was constructed with 21 features (2 clinical features, 10 radiomics features from mesorectum region, and 9 radiomics features from tumor region) selected by Spearman correlation and LASSO analysis. The multi-regional model shows a good performance in the differentiation of the status of LVI in training data sets (AUC = 0.87, accuracy = 0.79). The model was further validated in the testing data sets, giving an AUC and an accuracy of 0.74 and 0.68, respectively. Furthermore, the performance of single-regional model (AUC = 0.72, accuracy = 0.67) is lower compared to the values given by the multi-regional model.
The radiomics model which we developed demonstrates that multi-regional radiomics features based on multiparametric MRI are useful for preoperatively predicting lymphovascular invasion in patients with rectal cancer.
KeywordsRectal cancer Machine learning Radiomics Lymphovascular MRI
Area under the ROC curve
Extramural venous invasion
Least absolute shrinkage and selection operator
Colorectal cancer (CRC) is the third most common malignant tumor in the world [1, 2], and about one-third to 44% of CRC are occurred in the rectum . The National Comprehensive Cancer Network (NCCN) Guidelines consider lymphovascular invasion (LVI), which is defined as the presence of tumor cells in the lymphatic vessels or blood vessels or both, as a significant negative factor in treatment options and prognostication in rectal cancer [4, 5]. Several investigations have revealed that patients with LVI may associate with lymph-node metastasis and benefit from adjuvant systemic therapy [6, 7, 8, 9]. Hence, it becomes increasingly important to evaluate LVI status preoperatively, so that patients with LVI might benefit from radical surgery and adjuvant treatments [4, 6, 10, 11].
Currently, the LVI status is evaluated by histopathology after resection, which provides no accuracy preoperative evaluation to a treatment option. The biopsy may provide the LVI status before surgery; however, the limited specimen fails to provide the information of the whole tumor [12, 13]. In addition to histopathology, rectal magnetic resonance imaging (MRI) is also an important means in tumor evaluation, which is noninvasively [3, 4, 14]. Previous studies on rectal MRI have demonstrated that the diagnostic performance of extramural venous invasion (EMVI) by MRI was good [15, 16]. However, the intramural blood vessels and lymphatic vessel invasion status, which are parts of the LVI, are failed to evaluate by MRI [17, 18]. Therefore, is there a way to accurately evaluate the LVI status in rectal cancer before treatment?
Radiomics is an emerging method for extracting quantitative features from medical imaging and assisting clinical decision to improve diagnostic, prognostic, and predictive accuracy [13, 19, 20, 21]. The central hypothesis that drives the development of radiomics is based on the tumor microenvironment description, which helps to assess the biological characteristics of the tumor [12, 19]. Rectal MRI is essential for pre- and post-treatment assessment of rectal cancer, as it provides anatomic structures and their relationship with the tumor with a high-spatial resolution [22, 23]. Rectal MRI-based radiomics have been used for treatment response , lymph-node metastasis , and prognostic evaluation . However, MRI-based radiomics for LVI prediction remains underinvestigated in rectal cancer.
Therefore, the aim of this study was to develop a radiomics model for prediction of lymphovascular invasion in rectal cancer based on MRI.
Materials and methods
This study was approved by the ethics committee of The First Hospital of Jilin University, and the informed consent requirement was waived. We retrospectively evaluated patients with rectal cancer in our hospital between January 2016 and December 2018. Inclusion criteria were as follows (a) histologically confirmed rectal adenocarcinoma; (b) rectal MRI were performed before surgery within 2 weeks; (c) LVI were assessed by histopathology after resection. The exclusion criteria included a history of (a) preoperative chemoradiotherapy (CRT), radiotherapy, chemotherapy, or distant metastases, considering that the preoperative treatment maybe changed the LVI status; (b) poor MRI quality; (c) lack of clinic information, such as pretreatment carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9(CA19-9). Finally, we enrolled a total of 188 patients, 80 LVI +, and 108 LVI −. We randomly divide patients into training and testing cohorts in a 2:1 ratio.
Clinicopathologic data, including age, gender, the level of carcinoembryonic antigen (CEA), and carbohydrate antigen19-9 (CA 19-9), were derived from medical records. Laboratory analysis of CEA and CA19-9 was tested within 1 week before surgery. The threshold value for the CEA level was ≤ 5 ng/mL and >5 ng/mL, and the threshold value for the CA19-9 level was ≤ 39U/mL and >39U/mL, according to the normal range used in clinics.
Measurement of conventional radiology evaluation indicators: including the location of primary tumor, lesion involvement length, tumor thickness (measured on oblique axis T2WI), extramural depth of invasion (measured on oblique axis T2WI), mesorectal fascia (MRF, > 1 mm diagnostic negative, ≤ 1 mm positive), and maximum lymph-node short diameter (measured on-axis T2WI).
MRI data acquisition
The enrolled rectal MRIs were all performed on the same MR scanner (3.0T, Philips Ingenia, The Netherlands). And glycerine enema was required for rectal cleansing before scanning. To reduce abdomen motility, 20 mg of anisodamine was injected intramuscularly 30 min before MRI scanning. All patients underwent a rectal MRI protocol including sagittal, axial, oblique axial, and coronal T2-weighted images and DWI. High-resolution T2WI images were obtained using turbo spin-echo with a repetition time (TR) = 3500 ms, echo time (TE) = 100 ms, the field of view (FOV) = 180 × 180 mm, echo train length = 29, matrix = 288 × 256, thickness = 3.0 mm, and gap = 0.3 mm. DWI images were obtained with 2 b factors (0 and 1000 s/mm2), and TR = 2800 ms, TE = 70 ms, FOV = 340 × 340 mm, matrix = 256 × 256, thickness = 4.0 mm, and gap = 1.0 mm. All MRI images were retrieved from the picture archiving and communication system (PACS) for tumor masking and radiomic feature extraction.
Radiomic feature extraction and selection
Extracted features by Philips Radiomics software using pyRadiomics
Including first-order statistics features, shape-based features, gray-level co-occurrence matrix features, gray-level size zone matrix features, gray-level run-length matrix features, neighbouring gray tone difference matrix features, and gray-level dependence matrix features
Calculated based on direct features, through the algorithm of square, square root, logarithm, and exponential
Wavelet transform features
Information about the frequency of similar SIs and describes the wavelet transform of the pixels in the ROI
Laplacian of Gaussian filtered features
Description of texture based on the images filtered by Laplacian of Gaussian
Next, a Spearman correlation analysis of radiomic feature and the label were done. Features with the coefficient lower than absolute value 0.2 or the p value greater than 0.05 were removed accordingly because of the low correlation between these radiomic features and pathological labels.
Finally, at the dimensionality reduction step, least absolute shrinkage and selection operator (LASSO) algorithm  were used.
Radiomic model construction and evaluation
At the model construction and evaluation step, six linear classification algorithms were investigated, including Passive Aggressive Classifier, Perceptron, Ridge Classifier, SGD Classifier, Logistic Regression, and Linear Support Vector Classifier for training and prediction. First, in the model training stage, we used fivefold cross validation to evaluate the performance of six specific machine learning classifiers in the training cohort with ‘accuracy’ as the optimization metric, preliminarily selected the prediction model with the best prediction performance, and then evaluated the model in the training and test cohorts with the area under the ROC curve (AUC), etc.
All statistical analyses were performed using SPSS 24.0 (IBM Corp). Chi-square test was used to compare the differences in categorical variables (gender, the location of primary tumor, the level of CEA and CA19-9, and MRF status), while an independent sample t test or Mann–Whitney U test, as appropriate, was used to compare the differences in continues variables (age, lesion involvement length, tumor thickness, and extramural depth of invasion).
Receiver-operating characteristic (ROC) curves were generated to assess the diagnostic performance of the radiomic models in predicting LVI status by calculating the area under the ROC curve (AUC) and corresponding accuracy, specificity, sensitivity, and so on were calculated.
The reported statistical significance levels are all two-sided, with the statistical significance set at 0.05.
Characteristic of patients in the training and testing cohort
n = 53
n = 72
n = 27
n = 36
Gender, no. (%)
57.0 (51.0, 62.5)
61.5 (52.2, 69.8)
62.8 ± 10.5
59.4 ± 11.7
The location of the tumor, no. (%)
The tumor involved length (CM)
5.2 ± 1.7
5.1 ± 2.1
5.3 ± 2.7
4.9 ± 2.1
Tumor thickness (CM)
1.4 (1.1, 1.7)
1.3 (1.1, 1.6)
1.2 ± 0.4
1.3 ± 0.5
Extramural depth of invasion (MM)
5.0 (3.0, 8.0)
4.0 (1.0, 8.0)
Maximum lymph node short diameter (MM)
6.0 (5.0, 9.0)
5.0 (3.0, 6.0)
5.9 ± 2.8
4.6 ± 3.0
CEA level, no (%)
CA19-9 level, no (%)
MRF, no. (%)
No significant differences in LVI prevalence were found between the two cohorts (P = 0.952). Overall, 42.4% and 42.9% of cases were LVI positive in the training and testing cohorts, respectively.
Radiomic feature extraction and selection
For each VOI, a total of 1653 three-dimensional (3D)-based radiomic features were extracted. These radiomic features quantified tumor characteristics using tumor size and shape, intensity statistics, and texture. For each patient, we integrated all of the 4959 radiomic features from three VOIs together.
Feature coefficients of trained model
Maximum lymph-node short diameter (mm)
Radiomic model construction and evaluation
Performance of multi- and single-regional radiomic models on fivefold cross validation, training, and testing data sets
Fivefold cross validation
Training data sets
Testing data sets
The AUC, accuracy, F1, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the multi-regional model is better than that of the single-regional model, except PPV in testing data sets.
This retrospective study investigated a radiomic model based on MRI for the preoperative prediction of LVI status in patients with rectal cancer. We constructed and compared the single and multi-regional radiomic models for discriminate LVI invasion of rectal cancer patients. Our results suggest that MRI radiomic signature is significantly correlated with LVI. The multi-regional radiomic model was performed better than that of the single-regional model in preoperative prediction of LVI, with acceptable accuracy.
LVI is regarded as an important negative factor in treatment options and prognostication in rectal cancer from multiple statistically published trials. The previous study which was reported by Liu et al. found that the DCE-MRI-based radiomic features and LVI status were correlated in breast cancer, and indicated that the radiomic features were effective in predicting the LVI status of patients with invasive breast cancer before surgery . However, it is still a challenge for LVI preoperative prediction in rectal cancer. In the clinic, rectal MRI was suggested to reflect EMVI in rectal cancer, which is only one part of LVI [15, 16, 17, 18]. Kim Y et al., who have investigated the visually assessed features, considered that the LVI presents when the mesorectal perivascular infiltrative signal was visible on pelvic MR imaging, and the sensitivity of MR-reported LVI status was 68.2% . While the radiomic model in our study showed a better predictive performance than MRI-reported LVI status by Kim. The better performance in our research might be due to that the radiomic features which was derived from multi-regional VOIs in multiparametric MR images could provide comprehensive information on LVI status, including intramural, extramural blood vessels, and lymphatic vessels in rectal cancer.
Previous studies showed multi-regional MRI radiomics allowing for a more comprehensive characterization of the tumor heterogeneity. This may offer potential to improve the prediction performance [31, 32]. LVI, which is defined as the presence of tumor cells in the lymphatic vessels or blood vessels or both, include intramural, extramural blood vessels, and lymphatic vessels. In addition to the region of the tumor, the surrounding mesorectal tissues may also exhibit abnormal microscopic changes in the microvascular and lymphatic networks, extracellular matrix, and interstitial pressure, which cannot be ignored [33, 34]. Hence, we investigated whether multi-regional radiomics, including both tumor and mesorectum, could provide more features to discriminate LVI positive from LVI-negative lesions. When the current multi-regional radiomics signature was introduced into the prediction model, the performance improved than that of the single-regional model . This suggests that the multi-regional radiomic signature could enhance the prediction of LVI in rectal cancer patients. In addition, our study used a 3 D VOI radiomic features by segmenting the tumor and mesorectum layer-by-layer. The 3D features provided more comprehensive information about lesions and improved the prediction accuracy of radiomic analysis compared with 2D features. Previous studies have shown that the 3D VOI provided more information about the heterogeneity of the whole lesion than the 2D region of interest (ROI) [35, 36].
How to select a modeling method is important for the performance of the radiomic model. Hence, a variety of machine learning methods should be used and the implementation should be fully documented , and then compare the performance of different algorithms. In our study, Ridge Classifier used in the features extraction of multi-region and linear SVC used in the feature extraction of single region were found to produce the most accurate model on fivefold cross-validation data set, respectively, can predict the LVI and maybe assist clinical decision-making.
There are some limitations to this study. First, the sample was divided into training and testing cohorts, but lacked of external testing validation. It likely led to overfitting. And all the enrolled MRIs were performed on the same MR scanner, which may also reduce the robustness of the prediction models. In the future, the study cohort should mixed different MRI scanners’ data sets to enhance robustness. Moreover, a multicenter study with a larger sample size and external validation is warranted. Second, the study did not evaluate T1 W and enhanced MR images, and only the VOIs of T2WI and DWI were calculated. However, in clinic, the T2WI and DWI play vital role in tumor evaluation, which have a proven high diagnostic accuracy [23, 37]. Third, LVI status was only classified as positive or negative in this study. LVI status was further categorized into four grades based on the number of lymphovascular structures invaded, according to Jass classification (expanding vs infiltrative) [17, 18]. Further study should investigate the relationship between radiomic feature scores with grades of LVI. Finally, this research was a retrospective study. Therefore, there is an inevitable selectivity bias. In the future, we will design a prospective study of radiomic data related to rectal cancer.
In conclusion, the radiomic model which we developed demonstrates that multi-regional and multiparametric radiomic features based on MRI are useful tools for preoperatively predicting lymphovascular invasion in patients with rectal cancer.
This study has received funding by Jilin Province Science and Technology Department Science and Technology Innovation Talents Cultivation Program (20180519008JH), Jilin Provincial Department of Finance (2018SCZWSZX-02, P8022740001, JLSCZD2019-062), Jilin Province Development and Reform Commission (2017C020), and Prevention and Control of Major Diseases Science and Technology Action Plan of China [ZX07-c20160036].
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