Contributed Commentary by Jenny Ross, ICON
September 22, 2023 | Digital anatomic pathology allows for several potential benefits in clinical research, from speedier and traceable processes to improved consistency in visualisations and assessment outcomes. Currently, much of digital pathology consists of whole slide imaging where slides are stained and scanned to generate high-quality digital images. However, digital pathology is continuously expanding as innovations increase capabilities and provide valuable efficiencies.
Novel technologies utilizing whole slide images provide the potential to improve detection and quantitation of specific morphological traits. The following article details practical uses of such technologies and illustrates considerations for their use in global clinical trials.
Time is a critical component in clinical trials; subject status must be accurately assessed as soon as possible to determine their suitability for inclusion in the study. Sites are often racing against the clock to recruit, randomize and treat subjects. One of the most immediate benefits of digital pathology is its speed.
Once a slide is digitized and a histotechnologist has reviewed for quality control, the whole slide images and associated data are available to the pathologist in a manner of minutes. Reviewing whole slide images avoids shipping—immediately recovering 1-2 days in the process—and eliminates the associated courier risks and fees, regulatory and customs preparations for physical shipping, and frees personnel to dedicate their time to more important tasks.
Unlike glass slides, pathologists and key opinion leaders can more easily document detailed questions and comments related to each image. When the images are accessed by others, the complete notes are automatically available, saving additional time.
In addition to whole slide imaging, telepathology is a hybrid approach within digital pathology that allows the concurrent review of a glass slide between two geographically dispersed pathologists: one localized with the glass slide and a microscope enabled to project in real-time to the screen of the other, with a conversation happening real-time either via telephone or meeting software. Telepathology allows for timely collaboration on a slide assessment without having to ship the glass back and forth, putting it at risk and using up valuable time. In instances where there are multiple readers, or consensus reads are required with an adjudicator, digital pathology has the potential to significantly expedite the assessment process.
Decentralized Digital Reads
Although only a very small percentage of glass slides are lost or damaged in transit due to abundant precaution, there is still inherent risk in shipping original glass slides. Digital pathology decentralizes the assessment process, reducing the need to ship slides, be it to pathologists or downstream testing labs. This decentralization is key for global trials, allowing information to be shared faster. It also allows for the inclusion and management of pathology needs of sites in locations which otherwise would have been excluded due to strict import/export restrictions. In addition, it allows inclusion and coordination of a larger group of global pathology experts and enables them to collectively review specimens in real time, in a manner that would be impossible via use of only glass slides.
Digital pathology essentially creates a digital backup of the glass slide in case of loss, damage, or degradation. In the past, digital slide images would be similarly vulnerable to deletion or file corruption, but technology has advanced rapidly, and new platforms and modalities offer capabilities for improved storage and access that increase fidelity and improve user experience and throughput.
These technologies allow digital pathology to be incorporated into fully auditable systems that provide transparency and traceability throughout the process. This increases the efficiency of inspections and queries for both regulators and sponsors.
Artificial intelligence (AI) is opening a new realm of possibilities within clinical research, and digital pathology produces samples that are amenable to AI analysis. There are multiple potential applications for AI in digital pathology including automatic detection of various morphological traits. AI can also reduce placebo observation effect and inter-observer variability to improve efficiency and consistency in slide assessment.
Algorithm-assisted assessments are not replacements for human reads, however, as there is still much learning and training required for these systems. Instead, they can serve as important benchmarks to harmonise reads across multiple observers. In the future, AI could assist in directly linking clinical data with the images or provide other valuable efficiencies or insights that drive progress in histopathology.
To date, most histopathology has utilized stain. Depending on the stain, the staining processes have the potential for variability resulting from differences in preanalytical handling, which requires additional considerations for dye type, regulatory compliance, and availability across all sites within a trial footprint. Innovative new technology has enabled a new method of visualization for assessment via second harmonic generation / two-photon excited fluorescence (SHG/TPE).
SHG/TPE is different from typical microscopy modalities (brightfield, darkfield, phase contrast). It was designed expressly for use in preclinical studies and clinical trials in fibrotic diseases such as non-alcoholic steatohepatitis (NASH). This method analyzes unstained biopsy slides by quantifying the morphological and architectural features of collagen fibres and other relevant disease characteristics that would indicate fibrosis. By reading unstained slides, the original sample can, in effect, remain unaltered until a stain may be required or requested. By minimizing handling and staining requirements, this will minimize the risk of adulterating or potentially damaging the sample.
The key features in the sample are precisely visualized in high-quality images in red and green on black background without staining them. The high contrast differentiated images—in combination with their independence from staining variability present in other methods—are claimed to allow for easier identification and assessments by an observer as well as offering a new modality for AI examination.
The SHG/TPE images can help reduce eye strain, an issue that plagues pathologists, and can facilitate consistency: whereas dyes can vary significantly, the high-contrast SHG/TPE are expected to produce consistent saturation and hue. This consistency should reduce inter-and intra-observer discrepancies and has significant potential to enhance evaluation of therapeutic efficacy.
Reducing Pre-Analytical Variability
Although imaging technology continues to advance, the overall quality of any digital pathology output is far more dependent on pre-analytical variables than the digitisation process itself when done on high-quality scanners. Before a sample is ready for assessment, it must pass unmarred through fixation, grossing, embedding, sectioning, mounting, and staining which all hold possibilities for damage or other impact on quality. These are all important steps that will affect analysis. For example, one bad stain can lead to fibrosis being under-staged, significantly impacting the assessment.
With new modalities like SHG/TPE, some of the technical problems resulting from the pre-analytical stage may become irrelevant and others may be harder to compensate for, such as tissue folds or debris on the slides. The variability in staining methodology has allowed for some workarounds that would help pathologists in making their assessment. As SHG/TPE is a high-contrast laser-assisted image, there is no way to make those same adjustments and the quality of the original slide is critical.
A global CRO is in a unique position to harmonize processes, workflows and quality across global labs, increasing consistency across histopathology sample preparation and enabling these advanced technologies. Consistency and reproducibility provide a solid foundation for digital pathology’s innovations, ensuring high-quality images for assessment.
Data And Regulatory Considerations
Transmitting digital images outside of the secure central system comes with numerous significant risks. Therefore, the digital pathology system that the CRO uses should be a central database for the collection, processing, management, and storage of the digital images and should allow for remote viewing. Digital pathology is only as effective to the extent that it is utilized, meaning that an intuitive host platform should be easy for pathologists to navigate and use to make the most of the benefits available. The digital pathology system should also integrate with the laboratory information management system (LIMS) to reduce timelines and streamline review processes. While these new technologies and software packages create a new way of working that brings change and adjustment of processes, it is to be expected that new users will require time to adapt. However, it is without doubt that the usability and breadth of application of these packages will improve significantly over time in a manner that was not previously possible using glass slides and microscopes.
Many regulators approve the use of WSI scanners, including the FDA, however it is important to consider the current state of technology on offer as it pertains to either a research or diagnostic capacity. The technologies will be subject to different regulation and approval processes depending on the intended application and geographical region in question. For example, various regions limit export of all modalities of visualizations of their subjects, thus requiring an export permit. In such regions, digital pathology reduces the time that samples spend in transit as compared to slides, allowing faster processing, assessment and clinical action (if appropriate).
Better Methods For Better Results
Advancements in digital pathology and imaging solutions are important opportunities to bring efficiencies to clinical research and into broader healthcare applications, which ultimately benefit patients. As digital pathology continues to evolve, it becomes more accessible and more widely adopted, bringing opportunities for cost-savings and efficiencies at multiple levels that facilitate global clinical research.
Jenny Ross, MD, FASCP, FCAP is a Pathologist and Medical Director at ICON Central Laboratories. Dr. Ross is an anatomic/clinical pathology board-certified pathologist, licensed in New York and Pennsylvania. She studied at Northwestern University, where she did her second fellowship in genitourinary pathology, preceded by a general surgical pathology fellowship at the University of Texas Health Sciences Center at San Antonio. Her interests include thoracic and transplant pathology, as well as head-and-neck. She can be reached at Jenny.firstname.lastname@example.org.