Histopathological image analysis is an essential process for the discovery of diseases such as cancer. However, it is challenging to train CNN on whole slide images (WSIs) of gigapixel resolution considering the available memory capacity. Most of the previous works divide high resolution WSIs into small image patches and separately input them into the model to classify it as a tumor or a normal tissue. However, patch-based classification uses only patch-scale local information but ignores the relationship between neighboring patches. If we consider the relationship of neighboring patches and global features, we can improve the classification performance. In this paper, we propose a new model structure combining the patch-based classification model and whole slide-scale segmentation model in order to improve the prediction performance of automatic pathological diagnosis. We extract patch features from the classification model and input them into the segmentation model to obtain a whole slide tumor probability heatmap. The classification model considers patch-scale local features, and the segmentation model can take global information into account. We also propose a new optimization method that retains gradient information and trains the model partially for end-to-end learning with limited GPU memory capacity. We apply our method to the tumor/normal prediction on WSIs and the classification performance is improved compared with the conventional patch-based method.

BACKGROUND: The recent success of immunotherapy in treating tumors has attracted increasing interest in research related to the adaptive immune system in the tumor microenvironment. Recent advances in next-generation sequencing technology enabled the sequencing of whole T-cell receptors (TCRs) and B-cell receptors (BCRs)/immunoglobulins (Igs) in the tumor microenvironment. Since BCRs/Igs in tumor tissues have high affinities for tumor-specific antigens, the patterns of their amino acid sequences and other sequence-independent features such as the number of somatic hypermutations (SHMs) may differ between the normal and tumor microenvironments. However, given the high diversity of BCRs/Igs and the rarity of recurrent sequences among individuals, it is far more difficult to capture such differences in BCR/Ig sequences than in TCR sequences. The aim of this study was to explore the possibility of discriminating BCRs/Igs in tumor and in normal tissues, by capturing these differences using supervised machine learning methods applied to RNA sequences of BCRs/Igs. RESULTS: RNA sequences of BCRs/Igs were obtained from matched normal and tumor specimens from 90 gastric cancer patients. BCR/Ig-features obtained in Rep-Seq were used to classify individual BCR/Ig sequences into normal or tumor classes. Different machine learning models using various features were constructed as well as gradient boosting machine (GBM) classifier combining these models. The results demonstrated that BCR/Ig sequences between normal and tumor microenvironments exhibit their differences. Next, by using a GBM trained to classify individual BCR/Ig sequences, we tried to classify sets of BCR/Ig sequences into normal or tumor classes. As a result, an area under the curve (AUC) value of 0.826 was achieved, suggesting that BCR/Ig repertoires have distinct sequence-level features in normal and tumor tissues. CONCLUSIONS: To the best of our knowledge, this is the first study to show that BCR/Ig sequences derived from tumor and normal tissues have globally distinct patterns, and that these tissues can be effectively differentiated using BCR/Ig repertoires.