Automated Detection and Scoring of Tumor-Infiltrating Lymphocytes in Breast Cancer Histopathology Slides

Simple Summary Tumor-infiltrating lymphocytes have gained a critical role in the newly developed cancer immunotherapy methods. Traditionally, pathologists and researchers count and score these lymphocytes to evaluate the patient's response to the treatments. However, scoring the lymphocytes is conducted microscopically and highly depends on the pathologist and researcher's experiences. In this manuscript, we have proposed and developed an automated method, using a two-stage deep learning model to score the lymphocytes in breast cancer histopathology slides. We further verified the accuracy of our method by statistically comparing results from expert pathologists to the output from our developed model. Detection of tumor-infiltrating lymphocytes (TILs) in cancer images has gained significant importance as these lymphocytes can be used as a biomarker in cancer detection and treatment procedures. Our goal was to develop and apply a TILs detection tool that utilizes deep learning models, following two sequential steps. First, based on the guidelines from the International Immuno-Oncology Biomarker Working Group (IIOBWG) on Breast Cancer, we labeled 63 large pathology imaging slides and annotated the TILs in the stroma area to create the dataset required for model development. In the second step, various machine learning models were employed and trained to detect the stroma where U-Net deep learning structure was able to achieve 98% accuracy. After detecting the stroma area, a Mask R-CNN model was employed for the TILs detection task. The R-CNN model detected the TILs in various images and was used as the backbone analysis network for the GUI development of the TILs detection tool. This is the first study to combine two deep learning models for TILs detection at the cellular level in breast tumor histopathology slides. Our novel approach can be applied to scoring TILs in large cancer slides. Statistical analysis showed that the output of the implemented approach had 95% concordance with the scores assigned by the pathologists, with a p-value of 0.045 (n = 63). This demonstrated that the results from the developed software were statistically meaningful and highly accurate. The implemented approach in analyzing whole tumor histology slides and the newly developed TILs detection tool can be used for research purposes in biomedical and pathology applications and it can provide researchers and clinicians with the TIL score for various input images. Future research using additional breast cancer slides from various sources for further training and validation of the developed models is necessary for more inclusive, rigorous, and robust clinical applications.