Christian A. Kunder

Okyaz Eminaga, Mahmoud Abbas, Christian Kunder et al.

Prostate cancer pathology plays a crucial role in clinical management but is time-consuming. Artificial intelligence (AI) shows promise in detecting prostate cancer and grading patterns. We tested an AI-based digital twin of a pathologist, vPatho, on 2,603 histology images of prostate tissue stained with hematoxylin and eosin. We analyzed various factors influencing tumor-grade disagreement between vPatho and six human pathologists. Our results demonstrated that vPatho achieved comparable performance in prostate cancer detection and tumor volume estimation, as reported in the literature. Concordance levels between vPatho and human pathologists were examined. Notably, moderate to substantial agreement was observed in identifying complementary histological features such as ductal, cribriform, nerve, blood vessels, and lymph cell infiltrations. However, concordance in tumor grading showed a decline when applied to prostatectomy specimens (kappa = 0.44) compared to biopsy cores (kappa = 0.70). Adjusting the decision threshold for the secondary Gleason pattern from 5% to 10% improved the concordance level between pathologists and vPatho for tumor grading on prostatectomy specimens (kappa from 0.44 to 0.64). Potential causes of grade discordance included the vertical extent of tumors toward the prostate boundary and the proportions of slides with prostate cancer. Gleason pattern 4 was particularly associated with discordance. Notably, grade discordance with vPatho was not specific to any of the six pathologists involved in routine clinical grading. In conclusion, our study highlights the potential utility of AI in developing a digital twin of a pathologist. This approach can help uncover limitations in AI adoption and the current grading system for prostate cancer pathology.

Indrani Bhattacharya, David S. Lim, Han Lin Aung et al.

Prostate cancer is the second deadliest cancer for American men. While Magnetic Resonance Imaging (MRI) is increasingly used to guide targeted biopsies for prostate cancer diagnosis, its utility remains limited due to high rates of false positives and false negatives as well as low inter-reader agreements. Machine learning methods to detect and localize cancer on prostate MRI can help standardize radiologist interpretations. However, existing machine learning methods vary not only in model architecture, but also in the ground truth labeling strategies used for model training. In this study, we compare different labeling strategies, namely, pathology-confirmed radiologist labels, pathologist labels on whole-mount histopathology images, and lesion-level and pixel-level digital pathologist labels (previously validated deep learning algorithm on histopathology images to predict pixel-level Gleason patterns) on whole-mount histopathology images. We analyse the effects these labels have on the performance of the trained machine learning models. Our experiments show that (1) radiologist labels and models trained with them can miss cancers, or underestimate cancer extent, (2) digital pathologist labels and models trained with them have high concordance with pathologist labels, and (3) models trained with digital pathologist labels achieve the best performance in prostate cancer detection in two different cohorts with different disease distributions, irrespective of the model architecture used. Digital pathologist labels can reduce challenges associated with human annotations, including labor, time, inter- and intra-reader variability, and can help bridge the gap between prostate radiology and pathology by enabling the training of reliable machine learning models to detect and localize prostate cancer on MRI.

Indrani Bhattacharya, Arun Seetharaman, Wei Shao et al.

Magnetic Resonance Imaging (MRI) is widely used for screening and staging prostate cancer. However, many prostate cancers have subtle features which are not easily identifiable on MRI, resulting in missed diagnoses and alarming variability in radiologist interpretation. Machine learning models have been developed in an effort to improve cancer identification, but current models localize cancer using MRI-derived features, while failing to consider the disease pathology characteristics observed on resected tissue. In this paper, we propose CorrSigNet, an automated two-step model that localizes prostate cancer on MRI by capturing the pathology features of cancer. First, the model learns MRI signatures of cancer that are correlated with corresponding histopathology features using Common Representation Learning. Second, the model uses the learned correlated MRI features to train a Convolutional Neural Network to localize prostate cancer. The histopathology images are used only in the first step to learn the correlated features. Once learned, these correlated features can be extracted from MRI of new patients (without histopathology or surgery) to localize cancer. We trained and validated our framework on a unique dataset of 75 patients with 806 slices who underwent MRI followed by prostatectomy surgery. We tested our method on an independent test set of 20 prostatectomy patients (139 slices, 24 cancerous lesions, 1.12M pixels) and achieved a per-pixel sensitivity of 0.81, specificity of 0.71, AUC of 0.86 and a per-lesion AUC of $0.96 \pm 0.07$, outperforming the current state-of-the-art accuracy in predicting prostate cancer using MRI.

Okyaz Eminaga, Mahmood Abbas, Yuri Tolkach et al.

Histopathology is a reflection of the molecular changes and provides prognostic phenotypes representing the disease progression. In this study, we introduced feature scores generated from hematoxylin and eosin histology images based on deep learning (DL) models developed for prostate pathology. We demonstrated that these feature scores were significantly prognostic for time to event endpoints (biochemical recurrence and cancer-specific survival) and had simultaneously molecular biologic associations to relevant genomic alterations and molecular subtypes using already trained DL models that were not previously exposed to the datasets of the current study. Further, we discussed the potential of such feature scores to improve the current tumor grading system and the challenges that are associated with tumor heterogeneity and the development of prognostic models from histology images. Our findings uncover the potential of feature scores from histology images as digital biomarkers in precision medicine and as an expanding utility for digital pathology.

Okyaz Eminaga, Yuri Tolkach, Christian Kunder et al.

The current study detects different morphologies related to prostate pathology using deep learning models; these models were evaluated on 2,121 hematoxylin and eosin (H&E) stain histology images captured using bright field microscopy, which spanned a variety of image qualities, origins (whole slide, tissue micro array, whole mount, Internet), scanning machines, timestamps, H&E staining protocols, and institutions. For case usage, these models were applied for the annotation tasks in clinician-oriented pathology reports for prostatectomy specimens. The true positive rate (TPR) for slides with prostate cancer was 99.7% by a false positive rate of 0.785%. The F1-scores of Gleason patterns reported in pathology reports ranged from 0.795 to 1.0 at the case level. TPR was 93.6% for the cribriform morphology and 72.6% for the ductal morphology. The correlation between the ground truth and the prediction for the relative tumor volume was 0.987 n. Our models cover the major components of prostate pathology and successfully accomplish the annotation tasks.

Okyaz Eminaga, Mahmoud Abbas, Christian Kunder et al.

Different convolutional neural network (CNN) models have been tested for their application in histological image analyses. However, these models are prone to overfitting due to their large parameter capacity, requiring more data or valuable computational resources for model training. Given these limitations, we introduced a novel architecture (termed PlexusNet). We utilized 310 Hematoxylin and Eosin stained (H&E) annotated histological images of prostate cancer cases from TCGA-PRAD and Stanford University and 398 H&E whole slides images from the Camelyon 2016 challenge. PlexusNet-architecture -derived models were compared to models derived from several existing "state of the art" architectures. We measured discrimination accuracy, calibration, and clinical utility. An ablation study was conducted to study the effect of each component of PlexusNet on model performance. A well-fitted PlexusNet-based model delivered comparable classification performance (AUC: 0.963) in distinguishing prostate cancer from healthy tissues, although it was at least 23 times smaller, had a better model calibration and clinical utility than the comparison models. A separate smaller PlexusNet model accurately detected slides with breast cancer metastases (AUC: 0.978); it helped reduce the slide number to examine by 43.8% without consequences, although its parameter capacity was 200 times smaller than ResNet18. We found that the partitioning of the development set influences the model calibration for all models. However, with PlexusNet architecture, we could achieve comparable well-calibrated models trained on different partitions. In conclusion, PlexusNet represents a novel model architecture for histological image analysis that achieves classification performance comparable to other models while providing orders-of-magnitude parameter reduction.