Deep learning enables spatial mapping of the mosaic microenvironment of myeloma bone marrow trephine biopsies

Bone marrow trephine biopsy is crucial for the diagnosis of multiple myeloma. However, the complexity of bone marrow cellular, morphological, and spatial architecture preserved in trephine samples hinders comprehensive evaluation. To dissect the diverse cellular communities and mosaic tissue habitats, we developed a superpixel-inspired deep learning method (MoSaicNet) that adapts to complex tissue architectures and a cell imbalance aware deep learning pipeline (AwareNet) to enable accurate detection and classification of rare cell types in multiplex immunohistochemistry images. MoSaicNet and AwareNet achieved an area under the curve of >0.98 for tissue and cellular classification on separate test datasets. Application of MoSaicNet and AwareNet enabled investigation of bone heterogeneity and thickness as well as spatial histology analysis of bone marrow trephine samples from monoclonal gammopathies of undetermined significance (MGUS) and from paired newly diagnosed and post-treatment multiple myeloma. The most significant difference between MGUS and newly diagnosed multiple myeloma (NDMM) samples was not related to cell density but to spatial heterogeneity, with reduced spatial proximity of BLIMP1+ tumor cells to CD8+ cells in MGUS compared with NDMM samples. Following treatment of multiple myeloma patients, there was a reduction in the density of BLIMP1+ tumor cells, effector CD8+ T cells, and T regulatory cells, indicative of an altered immune microenvironment. Finally, bone heterogeneity decreased following treatment of MM patients. In summary, deep-learning based spatial mapping of bone marrow trephine biopsies can provide insights into the cellular topography of the myeloma marrow microenvironment and complement aspirate-based techniques

Cell abundance aware deep learning for cell detection on highly imbalanced pathological data

Automated analysis of tissue sections allows a better understanding of disease biology and may reveal biomarkers that could guide prognosis or treatment selection. In digital pathology, less abundant cell types can be of biological significance, but their scarcity can result in biased and sub-optimal cell detection model. To minimize the effect of cell imbalance on cell detection, we proposed a deep learning pipeline that considers the abundance of cell types during model training. Cell weight images were generated, which assign larger weights to less abundant cells and used the weights to regularize Dice overlap loss function. The model was trained and evaluated on myeloma bone marrow trephine samples. Our model obtained a cell detection F1-score of 0.78, a 2% increase compared to baseline models, and it outperformed baseline models at detecting rare cell types. We found that scaling deep learning loss function by the abundance of cells improves cell detection performance. Our results demonstrate the importance of incorporating domain knowledge on deep learning methods for pathological data with class imbalance.Comment: Accepted at The IEEE International Symposium on Biomedical Imaging (ISBI) 2021, 5 pages, 5 figure