Cancer 05
Cancer 05
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                                  Bones are made of two regions, outer and inner regions. The outer region is compact and enclosed by cancel-
                                  lous tissues while the inner region consists of blood-producing m   aterial1. Bone cancer can originate from any
                                  part of the bones and can occur due to hereditary factors or previous radiation exposure. The benign cancer
                                  occurs commonly and is asymptomatic until the disease spreads or injuries the other body parts. The malignant
                                  cancer can lead to the patient’s death unless treated at the early s tage2. Since most of the cancers are asympto-
                                  matic, early diagnosis and treatment is critical to stop spreading to the other regions of the body. Bone cancer
                                  is divided into primary and secondary types. If the unrestricted cell growth is not treated during the primary
                                  type, cancer can develop unwanted new cells which may later lead to death. In the primary type, cancer starts
                                  from cells of bone whereas in the secondary type, cancer starts from other body regions and then affect the cells
                                          one3. Primary detection of bone cancer has a chance of reducing the death rate. In the beginning stage,
                                  of the b
                                  the symptoms of bone cancer may include bowel movement change, formation of new lumps, weight loss,
                                  bone loss, pain and, weakness in b   ones4. Proper treatment of cancer requires information like the history of
                                  patients, physical examination, and imaging techniques (e.g., X-ray2, Computed Tomography (CT)5, Magnetic
                                  Resonance Imaging (MRI)6, and Positron Emission Tomography (PET)7). Radiologists prefer medical imag-
                                  ing procedure for the detection of cancer due to the management of time, low cost and early detection. The
                                  preprocessing, segmentation, feature extraction, and classification stages are incorporated in medical devices
                                  for early d iagnosis8. Moreover, the pre-processing stage includes, either bilateral, median or Gaussian filter to
                                  remove the noise from the images9,10. After the noise removal, cancer regions can be segmented either using the
                                  threshold based11, region based11,12 or edge based segmentation13 methods. The segmentation techniques like
                                  Prewitt, Canny, Sobel, K-means and region growing were used to analyze the osteosarcoma type of bone cancer
                                  in X-ray i mages2,10,13. The K-means and edge detection segmentation algorithms have also been used for bone
                                 cancer14. After segmenting the cancer regions, seven Gray Level Co-occurrence Matrix (GLCM) features were
                                  extracted from the image. These features were then trained and tested using the K-nearest neighbors (KNN)
                                  classifier with a resulting accuracy of 98.18%14. The fusion of K-means with the fuzzy C-means segmentation
                                 1
                                  Department of Sensor and Biomedical Technology, School of Electronics Engineering, Vellore Institute
                                 of Technology, Vellore 632014, India. 2Department of Communication Engineering, School of Electronics
                                 Engineering, Vellore Institute of Technology, Vellore 632014, India. *email: rsivakumar@vit.ac.in
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                                           of the MRI images was used to calculate the mean intensity to identify the cancer and non-cancer images. The
                                           accuracy rate was 98% with a sensitivity of 65.21% and a specificity of 98.47%15. The X-ray images of 105, with
                                           65 cancers and 40 normal, were used to extract the histogram of the gradient with GLCM features. Using the
                                           support vector machine (SVM) classifier, an accuracy of 92.5% was a chieved16. The 36 X-ray images were used
                                           to extract the cancer border clarity and GLCM features and these features were then used to classify the benign
                                           and cancerous image using random forest and SVM classifiers with the resulting testing accuracy of 85% and
                                           81%, respectively. Among these two classifiers, random forest performed well compared to SVM which may be
                                           due to the use of small dataset and decision tree in a random forest classifier whereas SVM uses only the linear
                                           kernel, hence random forest works faster and performs good result17. Recently, the development of Artificial
                                           Intelligence (AI) has becoming more advanced in medical image analysis18–20. Deep neural networks (DNNs) are
                                           used as computational models to acquire training to learn the features of the images from a large set of datasets,
                                           resulting in reduction of false positive and false negative rates and thereby increasing the accuracy rate during
                                           the testing s tage20,21. The previous works on DNN primarily focused on X-ray2,9 and MRI i mages2,22,23 for bone
                                           cancer diagnosis while usage of CT images is rare due to the limited numbers of publicly available database5,24,25.
                                           The 2899 X-ray images were used to evaluate the 3 way classification (benign, intermediate and malignant)
                                           using Convolutional neural network (CNN) classifier and achieved the testing accuracy of 73.4%9. To classify
                                           the normal and bone cancer images, the 1060 MRI images were divided into training (70%), validation (20%)
                                           and testing (10%). EfficientNet B0 was then used for the image classification and achieved the testing accuracy
                                           of 72%6.The 39 MRI images with histopathological confirmation were used to predict the malignancy in the
                                           bone cancer using DNN. The dataset were splitted into training (70%), validation (10%), testing (20%) and then
                                           ResNet50 model was used to classify the benign and malignant type of bone cancer with the resulting testing
                                           accuracy of 95%23. The 832 CT scans, with 732 for training, 40 for validation and 60 for testing, were used to
                                           segment and classify the cancer regions using 2D and 3D UNet model and 3D ResNet, respectively. This model
                                           achieved the testing sensitivity of 82.7% with 0.617 false positive rate5.
                                               The Computer aided design (CAD) system were presented to distinguish the benign and malignant type of
                                           bone cancer in 79 CT images. Active contour model were used to segment the cancer regions and then GLCM
                                           features were extracted to train and test using the Random Forest classifier and obtained the overall testing accu-
                                           racy of 91.47%24. The K-mean clustering segmentation algorithm was used to segment the cancer regions in 3
                                           MRI and 3 CT images. The surface area of the cancer regions were evaluated using the algorithm and compared
                                           with the radiologist performance. The relative difference of algorithm and radiologists ranges from 0.63 to 1.75%
                                           for MRI images and 0.34 to 1.51% for CT images25. As CT is the primary scan after X-ray, hence is necessary
                                           to conduct a thorough investigation using the CT scans for detecting early bone cancer. Usually, CT scans pre-
                                           ferred over other medical imaging modalities due to the excellent spatial resolution and lesser scanning t ime12.
                                           CT is also the best imaging method to visualize the complex bone structures in the early stage for detecting the
                                           bone metastasis12,26. The current study deals with commonly affected bone cancers for the early detection of
                                           parosteal osteosarcoma27, enchondroma28, and o      steochondroma29 types of bone cancer. Perosteal osteosarcoma
                                           is the primary malignant type which arises on the surface of the bone30. The common location is metaphyseal to
                                           diaphyseal junction or the diaphysis part of the long bone like humerus, tibia, mandible, and femur31. Enchon-
                                           droma commonly occurs in the cartilage inside the b         one32 and osteochondroma occurs in the end of growth
                                           plate of long b  one33. The goal of this study is to detect bone cancer at a preliminary stage by utilizing the larger
                                           datasets of CT images and applying the image processing and deep learning (DL) techniques to detect the cancer
                                           with higher accuracy rate. More specifically, using 1141 bone CT images, the current study utilized K-means
                                           clustering, canny edge detection segmentation, and CNN models to classify the normal and cancerous images.
                                           Methods
                                           The proposed method involved detection and classification of bone cancer. The cancer region has more intensity
                                           than the other regions in the image24,34. Figure 1 shows the flowchart of the step involved in detecting the cancer
                                           region from the CT image for classifying the normal and cancer affected bones.
                                           Image collection
                                           The bone cancer images are obtained from publicly available databases: radiopeadia (radiopeadia.org) and can-
                                           cer_imaging_archive (cancerimagingarchive.net). The dataset used in this study consists of 1141 CT scan images
                                           (730 CT scans from radiopeadia and 411 CT scans from cancer_imaging_archive), with 530 bone cancer images
                                           and 511 normal images.
                                           Pre‑processing
                                           The image was converted into a grayscale prior to applying the fi    lter34. There exists many filters (e.g., Average,
                                           Median, Gaussian, Weiner filters) for noise reduction during the pre-processing s tage25. Among these, the median
                                           filter had a better performance for early-stage detection of the bone cancer images24. Moreover, this is a non-linear
                                           method that is effective in removing the salt and pepper noise while preserving the e dges25,34.
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K-means clustering
Normal Abnormal
Figure 1. Flowchart illustrating the steps involved in the detection of bone cancer.
                                 procedure of computing the distance metric and updating the centroid location is repeated until there is no
                                 change in centroid l ocation35,36. This algorithm was mainly used to segment the cancer region from the original
                                 CT image.
                                                                                                      Gy
                                                                               Angle(θ) = tan−1          ,
                                                                                                      Gx
                                 where Gx represents horizontal edges, Gy represents vertical edges, and A represents the filtered bone cancer
                                 image that convolves with the 3 × 3 convolutional kernel to detect the horizontal and vertical edges. The non-
                                 maxima suppression is used to narrow the edges of the image. If the gradient of the pixel is lesser than the lower
                                 threshold value, then the pixel is neglected and if the gradient of the pixel is greater than the higher threshold
                                 value, the pixel is accepted36. If the gradient of the pixel lies between lower and upper threshold value and the
                                 pixel is connected to edge, then only the pixel is accepted10,36.
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Figure 2. The AlexNet architecture for detecting normal and cancerous CT bone i mages38,40.
                                            rectifier linear unit (ReLU) activation function is used. The convolutional layers utilize specific number of filters
                                            (along with ReLU) to extract the relevant features from the input image. The maxpooling layer (an optional layer),
                                            is then used to remove the computational complexity while preserving the features. Followed by convolutional
                                            and pooling layers, there are 3 fully connected layers that flatten the features of the image. A dropout layer exists
                                            between fully connected layer to prevent the over fitting problems. The last layer is the fully connected layer
                                            that uses softmax activation function to analyze the probabilities of each class36,38–40. The layer specifications
                                            like filter size, kernel size, stride, input shape and output shape of the AlexNet architecture is shown in Table 1.
                                                In the current study, various CNN models like A       lexNet41, ResNet5042, ResNet10143, VGG1643, VGG1943,
                                                            42           44                42,43
                                           InceptionV3 , Xception , DenseNet121 , EfficientNet B         06 and EfficientNet B
                                                                                                                                  245 were applied to classify the
                                            CT image either into normal or cancer. Each CNN model was trained to perform two-way classification (normal
                                            and malignant). The input image size, number of epochs, loss function, and learning optimizer were the same
                                            for all the CNN models to facilitate the comparison in terms of accuracy and computational processing time.
                                            The size of the input image was 227 × 227 and the batch size was set to 32. Adam optimizer was used with the
                                            learning rate of 0.001, due to its better convergence, less memory requirements and computationally efficient
                                            compared to Stochastic and RMSprop optimizers46. Since the model focuses on two way classification, binary
                                            cross entropy loss f unction47 was used for all CNN models during the training, validation and testing stages. These
                                            models were implemented in Python using Jupyter Notebook version 6.4.12. The accuracy of the classification
                                            model was calculated using the equation:-
                                                                                                               (TP + TN)
                                                                                            Accuracy =                        ,
                                                                                                          (TP + TN + FP + FN)
                                           where TP represents the true positive rate (i.e., diseased images are correctly predicted as diseased images), FP
                                           represents the false positive rate (i.e., normal images are wrongly predicted as diseased images), FN represents
                                           the false negative rate (i.e., diseased images are wrongly predicted as normal images) and TN represents the true
                                           negative rate (i.e., normal images are correctly predicted as normal images)48,49.
                                            Layer            Filter size   No. of filters     Stride   Input dimension   Output dimension   Activation function
                                            Convolution 1    11 × 11       96                 4        227 × 227 × 3     55 × 55 × 96       ReLU
                                            Maxpooling       3×3           –                  2        55 × 55 × 96      27 × 27 × 96       –
                                            Convolution 2    5×5           256                1        27 × 27 × 96      27 × 27 × 256      ReLU
                                            Maxpooling       3×3           –                  2        27 × 27 × 256     13 × 13 × 256      –
                                            Convolution 3    3×3           384                1        13 × 13 × 256     13 × 13 × 384      ReLU
                                            Convolution 4    3×3           384                1        13 × 13 × 384     13 × 13 × 384      ReLU
                                            Convolution 5    3×3           256                1        13 × 13 × 384     13 × 13 × 256      ReLU
                                            Maxpooling       3×3           –                  2        13 × 13 × 256     6 × 6 × 256        –
                                            Flatten          –             –                  –        6 × 6 × 256       9216               –
                                            Dense            –             –                  –        9216              4096               ReLU
                                            Dense            –             –                  –        4096              4096               ReLU
                                            Dense (output)   –             –                  –        4096              2                  Softmax
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                                 Figure 3.  Original CT images: (a) lateral CT of parosteal osteosarcoma, (b) coronal CT of Osteochondroma,
                                 and (c) lateral CT of Enchondroma.
                                 Figure 4.  Effect of the median filter: (a) lateral CT of parosteal osteosarcoma, (b) coronal CT of
                                 Osteochondroma, and (c) lateral CT of enchondroma.
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                                           Figure 5.  Effect of K-means clustering: (a) lateral CT of Parosteal osteosarcoma, (b) coronal CT of
                                           osteochondroma, and (c) lateral CT of enchondroma.
                                           Figure 6.  Canny edge detection: (a) lateral CT of parosteal osteosarcoma, (b) coronal CT of osteochondroma,
                                           and (c) lateral CT of enchondroma.
0.6
0.4
0.2
                                                                        0
                                                                             0   4        8            12      16          20
                                                                                              Epochs
Figure 7. Total weighted loss of AlexNet model during training and validation stages.
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0.9
0.8
Accuracy 0.7
                                            0.6
                                                                                           Training
                                                                                           Validaon
                                            0.5
                                                  0   4            8            12         16           20
                                                                       Epochs
                                                                                                             Computational processing
Classification model       Training accuracy (%)      Validation accuracy (%)        Testing accuracy (%)    time (min)                 Number of epochs
AlexNet                    98                         98                             100                     29                         20
ResNet50                   84                         83                             81                      50                         20
ResNet101                  88                         92                             89                      71                         20
VGG16                      83                         77                             74                      120                        20
VGG19                      86                         87                             80                      150                        20
 DenseNet121               64                         64                             68                       33                        20
 EfficientNet B0           86                         94                             89                       17                        20
 EfficientNet B2           87                         91                             91                       48                        20
 Xception                  65                         58                             68                      105                        20
 InceptionV3               59                         59                             69                       51                        20
                                  Conclusion
                                  Bone cancer is one of the hazardous disease and hence early detection is utmost important for better diagnosis.
                                  This can be diagnosed based on three elements: symptoms, histopathological and imaging. The symptoms are
                                  mostly nonspecific during the initial stages whereas histopathology examination is an invasive method that
                                  detects the cancer mostly at the final stage but not during initial stage. In such cases, imaging has the ability to
                                  differentiate the normal and cancerous image during the early stage. The goal of this current study is to detect
                                  and classify bone cancer present in the CT images using various image processing techniques along with the vari-
                                  ous CNN models. The image processing techniques were used to detect the cancer region using pre-processing
                                  (median filter) to remove the noise in the image, K- means clustering to segment the cancer region, canny edge
                                  detection segmentation to extract the cancer edges. When compared with other CNN models, the AlexNet model
                                  showed the best performance, with training accuracy of 98%, validation accuracy of 98%, testing accuracy of
                                  100% and lowest computational processing time. Thus, AlexNet could be a useful tool to predict the bone cancer
                                  at the early stage from CT images using DNN. As a future work, the low, medium, and high level features from
                                  the CT images can also be extracted prior to classification using DNNs (e.g., ResNet, VGGNet and DenseNet) to
                                  achieve automated AI based model to detect the stages of bone cancer and classification of normal and subtypes
                                  of bone cancer.
                                  Data availability
                                  The dataset generated and/or analyzed during the current study are available in the [radiopeadia and cancerim-
                                  agingarchive] repositories, [www.radiopeadia.org and www.cancerimagingarchive.net].
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                                 Acknowledgements
                                 This work was supported by the third author’s Seed Grant (SG20220094) awarded by the Vellore Institute of
                                 Technology.
                                 Author contributions
                                 S.K.—Concept and writing—original draft. R.S.—Supervision and reviewing. A.K.C.—Supervision and
                                 validation.
                                 Competing interests
                                 The authors declare no competing interests.
                                 Additional information
                                 Correspondence and requests for materials should be addressed to S.R.
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