Nondestructive Volumetric Pathology of Prostate Biopsies for Accurate Prognostication and Treatment Stratification
Abstract
The majority of prostate cancers progress slowly. The overtreatment of patients with such indolent prostate cancers creates more harm (e.g., impotence and incontinence) than benefits. However, correctly identifying and treating patients with aggressive prostate cancers is critical for their survival. In a patient with suspected prostate cancer, the standard diagnostic technique involves the microscopic analysis of core needle biopsy specimens by pathologists. These results are the most valuable data that oncologists have for patient prognostication (distinguishing between indolent and deadly cancer) and for deciding between different treatment options, such as active surveillance, surgery, radiation, and/or chemotherapy—each with dramatically different risks and side effects. Unfortunately, many studies have shown that current pathology techniques are neither accurate nor reproducible, with high levels of disagreement between pathologists regarding critical elements such as carcinoma grade. A primary reason for this problem is that pathology laboratories process biopsy cores via a tedious and destructive centuries-old process that introduces a variety of artifacts and only samples a small fraction (~1%) of the biopsy specimens. Furthermore, the thin slide-mounted tissue sections that are currently viewed by pathologists provide a limited and often misleading two-dimensional (2D) view of tissue structures and molecular targets that can only be fully appreciated and quantified in three dimensions. This is especially true for prostate cancers, for which the 3D architecture of cancer glands is a basis for Gleason grading. To address the need for more accurate and standardized analyses of prostate biopsies, we will develop a novel “open-top light-sheet microscope” technology, along with optical-clearing and labeling methods, to enable rapid 3D pathology of prostate core needle biopsies. Our hypothesis is that the ability to visualize tissue microstructures and molecular biomarkers (protein targets that are diagnostically informative) in three dimensions, throughout entire biopsy specimens that are optically cleared (a chemical process to render the tissues transparent to light), will greatly improve the accuracy of prognostication and treatment stratification. Key advantages of our technology include: (1) improved sampling of large volumes of tissue rather than the sparse sampling of thin slide-mounted sections; (2) volumetric imaging of 3D structures that are critical for diagnostic grading (e.g., glandular architecture); (3) nondestructive imaging, which allows valuable biopsy specimens to be used for downstream assays such as next-generation genetic sequencing; and (4) slide-free imaging, which has the potential to conserve healthcare resources (time and cost). Our approach will be clinically validated by demonstrating improved interobserver concordance (precision) for the diagnosis and grading of prostate biopsies in comparison to traditional 2D slide-based histology, as well as through outcomes-based studies (accuracy) to show that our molecular 3D pathology techniques can provide superior tumor grading and prediction of tumor aggressiveness. These early-stage studies will pave the way for larger-scale prospective clinical trials in the future (following this 3-year technology development project) to show that our approaches can improve the outcomes and quality of life for individuals with prostate cancer. Furthermore, these technologies and our comprehensive 3D imaging datasets (tied to outcomes) will lead naturally to efforts in image processing (data science and analytics) for computer-aided diagnosis, prognostication, and treatment decision-making. In terms of clinical translation, we are currently in discussions with potential licensing partners to commercialize our refined light-sheet microscopy technologies and will engage with the Food and Drug Administration for regulatory approval, with the ultima
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810359
Entities
People
- Lawrence D. True
Organizations
- United States Army
- University of Washington