Scale Stain: Multi-Resolution Feature Enhancement in Pathology Visualization

Digital whole-slide images of pathological tissue samples have recently become feasible for use within routine diagnostic practice. These gigapixel sized images enable pathologists to perform reviews using computer workstations instead of microscopes. Existing workstations visualize scanned images by providing a zoomable image space that reproduces the capabilities of the microscope. This paper presents a novel visualization approach that enables filtering of the scale-space according to color preference. The visualization method reveals diagnostically important patterns that are otherwise not visible. The paper demonstrates how this approach has been implemented into a fully functional prototype that lets the user navigate the visualization parameter space in real time. The prototype was evaluated for two common clinical tasks with eight pathologists in a within-subjects study. The data reveal that task efficiency increased by 15% using the prototype, with maintained accuracy. By analyzing behavioral strategies, it was possible to conclude that efficiency gain was caused by a reduction of the panning needed to perform systematic search of the images. The prototype system was well received by the pathologists who did not detect any risks that would hinder use in clinical routine

Diagnosis of major cancer resection specimens with virtual slides: Impact of a novel digital pathology workstation

Digital pathology promises a number of benefits in efficiency in surgical pathology, yet the longer time required to review a virtual slide than a glass slide currently represents a significant barrier to the routine use of digital pathology. We aimed to create a novel workstation that enables pathologists to view a case as quickly as on the conventional microscope. The Leeds Virtual Microscope (LVM) was evaluated using a mixed factorial experimental design. Twelve consultant pathologists took part, each viewing one long cancer case (12-25 slides) on the LVM and one on a conventional microscope. Total time taken and diagnostic confidence were similar for the microscope and LVM, as was the mean slide viewing time. On the LVM, participants spent a significantly greater proportion of the total task time viewing slides and revisited slides more often. The unique design of the LVM, enabling real-time rendering of virtual slides while providing users with a quick and intuitive way to navigate within and between slides, makes use of digital pathology in routine practice a realistic possibility. With further practice with the system, diagnostic efficiency on the LVM is likely to increase yet more

Digital pathology access and usage in the UK: results from a national survey on behalf of the National Cancer Research Institute's CM-Path initiative.

Aim To canvass the UK pathology community to ascertain current levels of digital pathology usage in clinical and academic histopathology departments, and prevalent attitudes to digital pathology. Methods A 15-item survey was circulated to National Health Service and academic pathology departments across the UK using the SurveyMonkey online survey tool. Responses were sought at a departmental or institutional level. Where possible, departmental heads were approached and asked to complete the survey, or forward it to the most relevant individual in their department. Data were collected over a 6-month period from February to July 2017. Results 41 institutes from across the UK responded to the survey. 60% (23/39) of institutions had access to a digital pathology scanner, and 60% (24/40) had access to a digital pathology workstation. The most popular applications of digital pathology in current use were undergraduate and postgraduate teaching, research and quality assurance. Investigating the deployment of digital pathology in their department was identified as a high or highest priority by 58.5% of institutions, with improvements in efficiency, turnaround times, reporting times and collaboration in their institution anticipated by the respondents. Access to funding for initial hardware, software and staff outlay, pathologist training and guidance from the Royal College of Pathologists were identified as factors that could enable respondent institutions to increase their digital pathology usage. Conclusion Interest in digital pathology adoption in the UK is high, with usage likely to increase in the coming years. In light of this, pathologists are seeking more guidance on safe usage

Artificial intelligence in digital pathology: a diagnostic test accuracy systematic review and meta-analysis

Ensuring diagnostic performance of AI models before clinical use is key to the safe and successful adoption of these technologies. Studies reporting AI applied to digital pathology images for diagnostic purposes have rapidly increased in number in recent years. The aim of this work is to provide an overview of the diagnostic accuracy of AI in digital pathology images from all areas of pathology. This systematic review and meta-analysis included diagnostic accuracy studies using any type of artificial intelligence applied to whole slide images (WSIs) in any disease type. The reference standard was diagnosis through histopathological assessment and / or immunohistochemistry. Searches were conducted in PubMed, EMBASE and CENTRAL in June 2022. We identified 2976 studies, of which 100 were included in the review and 48 in the full meta-analysis. Risk of bias and concerns of applicability were assessed using the QUADAS-2 tool. Data extraction was conducted by two investigators and meta-analysis was performed using a bivariate random effects model. 100 studies were identified for inclusion, equating to over 152,000 whole slide images (WSIs) and representing many disease types. Of these, 48 studies were included in the meta-analysis. These studies reported a mean sensitivity of 96.3% (CI 94.1-97.7) and mean specificity of 93.3% (CI 90.5-95.4) for AI. There was substantial heterogeneity in study design and all 100 studies identified for inclusion had at least one area at high or unclear risk of bias. This review provides a broad overview of AI performance across applications in whole slide imaging. However, there is huge variability in study design and available performance data, with details around the conduct of the study and make up of the datasets frequently missing. Overall, AI offers good accuracy when applied to WSIs but requires more rigorous evaluation of its performance.Comment: 26 pages, 5 figures, 8 tables + Supplementary material

Effect of display resolution on time to diagnosis with virtual pathology slides in a systematic search task

Performing diagnoses using virtual slides can take pathologists significantly longer than with glass slides, presenting a significant barrier to the use of virtual slides in routine practice. Given the benefits in pathology workflow efficiency and safety that virtual slides promise, it is important to understand reasons for this difference and identify opportunities for improvement. The effect of display resolution on time to diagnosis with virtual slides has not previously been explored. The aim of this study was to assess the effect of display resolution on time to diagnosis with virtual slides. Nine pathologists participated in a counterbalanced crossover study, viewing axillary lymph node slides on a microscope, a 23-in 2.3-megapixel single-screen display and a three-screen 11-megapixel display consisting of three 27-in displays. Time to diagnosis and time to first target were faster on the microscope than on the single and three-screen displays. There was no significant difference between the microscope and the three-screen display in time to first target, while the time taken on the single-screen display was significantly higher than that on the microscope. The results suggest that a digital pathology workstation with an increased number of pixels may make it easier to identify where cancer is located in the initial slide overview, enabling quick location of diagnostically relevant regions of interest. However, when a comprehensive, detailed search of a slide has to be made, increased resolution may not offer any additional benefit

Understanding the ethical and legal considerations of Digital Pathology

Digital Pathology (DP) is a platform which has the potential to develop a truly integrated and global pathology community. The generation of DP data at scale creates novel challenges for the histopathology community in managing, processing, and governing the use of these data. The current understanding of, and confidence in, the legal and ethical aspects of DP by pathologists is unknown. We developed an electronic survey (e‐survey) comprising of 22 questions, which was developed with input from the Royal College of Pathologists (RCPath) Digital Pathology Working Group. The e‐survey was circulated via e‐mail and social media (Twitter) through the RCPath Digital Pathology Working Group network, RCPath Trainee Committee network, the Pathology image data Lake for Analytics, Knowledge and Education (PathLAKE) digital pathology consortium, National Pathology Imaging Co‐operative (NPIC), local contacts, and to the membership of both The Pathological Society of Great Britain and Ireland and the British Division of the International Academy of Pathology (BDIAP). Between 14 July 2020 and 6 September 2020, we collected 198 responses representing a cross section of histopathologists, including individuals with experience of DP research. We ascertained that in the UK, DP is being used for diagnosis, research, and teaching, and that the platform is enabling data sharing. Our survey demonstrated that there is often a lack of confidence and understanding of the key issues of consent, legislation, and ethical guidelines. Of 198 respondents, 82 (41%) did not know when the use of digital scanned slide images would fall under the relevant legislation and 93 (47%) were ‘Not confident at all’ in their interpretation of consent for scanned slide images in research. With increasing uptake of DP, a working knowledge of these areas is essential but histopathologists often express a lack of confidence in these topics. The need for specific training in these areas is highlighted by the findings of this study

In-vitro engineering of high modulus cartilage-like constructs.

To date, the outcomes of cartilage repair have been inconsistent and have frequently yielded mechanically inferior fibro-cartilage, thereby increasing the chances of damage recurrence. Implantation of constructs with biochemical composition and mechanical properties comparable to natural cartilage could be advantageous for long term repair. This study attempted to create such constructs, in-vitro, using tissue engineering principles. Bovine synoviocytes were seeded on non-woven polyethylene terephthalate fibre scaffolds and cultured in chondrogenic medium for 4 weeks, after which uniaxial compressive loading was applied using an in-house bioreactor for 1 hour per day, at a frequency of 1 Hz, for a further 84 days. The initial loading conditions, determined from the mechanical properties of the immature constructs after 4 weeks in chondrogenic culture, were strains ranging between 13 and 23 %. After 56 days (sustained at 84 days) of loading, the constructs were stained homogenously with Alcian blue and for type-II collagen. Dynamic compressive moduli were comparable to the high end values for native cartilage and proportional to Alcian blue staining intensity. We suggest that these high moduli values were attributable to the bioreactor setup, which caused the loading regime to change as the constructs developed i.e. the applied stress and strain increased with construct thickness and stiffness, providing continued sufficient cell stimulation as further matrix was deposited. Constructs containing cartilage-like matrix with response to load similar to that of native cartilage could produce long-term effective cartilage repair when implanted

Improving tumor budding reporting in colorectal cancer : a Delphi consensus study

Tumor budding is a long-established independent adverse prognostic marker in colorectal cancer, yet methods for its assessment have varied widely. In an effort to standardize its reporting, a group of experts met in Bern, Switzerland, in 2016 to reach consensus on a single, international, evidence-based method for tumor budding assessment and reporting (International Tumor Budding Consensus Conference [ITBCC]). Tumor budding assessment using the ITBCC criteria has been validated in large cohorts of cancer patients and incorporated into several international colorectal cancer pathology and clinical guidelines. With the wider reporting of tumor budding, new issues have emerged that require further clarification. To better inform researchers and health-care professionals on these issues, an international group of experts in gastrointestinal pathology participated in a modified Delphi process to generate consensus and highlight areas requiring further research. This effort serves to re-affirm the importance of tumor budding in colorectal cancer and support its continued use in routine clinical practice.Peer reviewe

Regional differences in prostaglandin E₂ metabolism in human colorectal cancer liver metastases

Background: Prostaglandin (PG) E₂ plays a critical role in colorectal cancer (CRC) progression, including epithelial-mesenchymal transition (EMT). Activity of the rate-limiting enzyme for PGE₂ catabolism (15-hydroxyprostaglandin dehydrogenase [15-PGDH]) is dependent on availability of NAD+. We tested the hypothesis that there is intra-tumoral variability in PGE₂ content, as well as in levels and activity of 15-PGDH, in human CRC liver metastases (CRCLM). To understand possible underlying mechanisms, we investigated the relationship between hypoxia, 15-PGDH and PGE₂ in human CRC cells in vitro. Methods: Tissue from the periphery and centre of 20 human CRCLM was analysed for PGE₂ levels, 15-PGDH and cyclooxygenase (COX)-2 expression, 15-PGDH activity, and NAD+/NADH levels. EMT of LIM1863 human CRC cells was induced by transforming growth factor (TGF) β. Results: PGE₂ levels were significantly higher in the centre of CRCLM compared with peripheral tissue (P = 0.04). There were increased levels of 15-PGDH protein in the centre of CRCLM associated with reduced 15-PGDH activity and low NAD+/NADH levels. There was no significant heterogeneity in COX-2 protein expression. NAD+ availability controlled 15-PGDH activity in human CRC cells in vitro. Hypoxia induced 15-PGDH expression in human CRC cells and promoted EMT, in a similar manner to PGE₂. Combined 15-PGDH expression and loss of membranous E-cadherin (EMT biomarker) were present in the centre of human CRCLM in vivo.Conclusions: There is significant intra-tumoral heterogeneity in PGE₂ content, 15-PGDH activity and NAD+ availability in human CRCLM. Tumour micro-environment (including hypoxia)-driven differences in PGE₂ metabolism should be targeted for novel treatment of advanced CRC