Toxicologic Pathology Forum*: Opinion on Integrating Innovative Digital Pathology Tools in the Regulatory Framework.

Digital pathology is defined as the ability to examine digitized microscopic slides and to generate qualitative and quantitative data. The field of digital pathology is rapidly evolving and has the potential to revolutionize toxicologic pathology. Techniques such as automated 2-D image analysis, whole slide imaging, and telepathology are already considered "mature" technologies and have been used for decades in exploratory studies; however, many organizations are reluctant to use digital pathology in regulatory toxicology studies. Innovative technologies using digitized slides including high-content imaging modalities and artificial intelligence are still under development but are increasingly used in toxicologic pathology. While software validation requirements are already described, clear guidance for application of these rules to the digital pathology field are few and the acceptance of these technologies by regulatory authorities remains necessary for successful adoption of digital pathology into the mainstream of toxicologic pathology. This topic was discussed during a roundtable at the 2018 Annual Congress of the French Society of Toxicologic Pathology. This opinion article summarizes the discussion regarding the current questions and challenges on the integration of innovative digital pathology tools within a good laboratory practice framework and is meant to stimulate further discussion among the toxicologic pathology community. *This is an opinion article submitted to the Toxicologic Pathology Forum and does not constitute an official position of the Society of Toxicologic Pathology or the journal Toxicologic Pathology. The views expressed in this article are those of the authors and do not necessarily represent the policies, positions, or opinions of their respective agencies and organizations. The Toxicologic Forum is designed to stimulate broad discussion of topics relevant to regulatory issues in Toxicologic pathology. Readers of Toxicologic Pathology are encouraged to send their thoughts on these articles or ideas for new topics to toxicologicpathologyforum@toxpath.org .

Diabetic Retinopathy Assessment Variability Among Eye Care Providers in an Urban Teleophthalmology Program.

BACKGROUND: Teleophthalmology is an evidence-based method for diabetic eye screening. It is unclear whether the type of eye care provider performing teleophthalmology interpretation produces significant variability. INTRODUCTION: We assessed grading variability between an optometrist, general ophthalmologist, and retinal specialist using images from an urban, diabetic retinopathy teleophthalmology program. METHODS: Three readers evaluated digital retinal images in 100 cases (178 eyes from 90 patients with type 2 diabetes). Fisher's exact test, percent agreement, and the observed proportion of positive (Ppos) or negative agreement (Pneg) were used to assess variability. RESULTS: Among cases deemed gradable by all three readers (n = 65), there was substantial agreement on absence of any retinopathy (88% ± 4.6%, Pneg = 0.91-0.95), presence of moderate nonproliferative or worse retinopathy (87% ± 3.9%, Ppos = 0.67-1.00), and presence of macular edema (99% ± 0.9%, Ppos = 0.67-1.00). There was limited agreement regarding presence of referable nondiabetic eye pathology (61% ± 11%, Ppos = 0.21-0.59) and early, nonroutine referral for a follow-up clinical eye exam (66% ± 8.1%, Ppos = 0.19-0.54). Among all cases (n = 100), there was acceptable agreement regarding which had gradable images (77% ± 5.0%, Ppos = 0.50-0.90). DISCUSSION: Inclusion of multiple types of eye care providers as teleophthalmology readers is unlikely to produce significant variability in the assessment of diabetic retinopathy among high-quality images. Greater variability was found regarding image gradability, nondiabetic eye pathology, and recommended clinical referral times. CONCLUSIONS: Our results suggest that more extensive training and uniform referral standards are needed to improve consensus on image gradability, referable nondiabetic eye pathology, and recommended clinical referral times.

The Influence of Telepathology on Coordination Practices.

BACKGROUND: Coordination between physicians and allied professionals is essential to the effective delivery of care services and is associated with positive patient outcomes. As information technology can radically transform how professionals collaborate, both researchers and healthcare accreditation bodies are devoting a growing interest to the means of achieving better coordination. INTRODUCTION: The primary aim of this study is to explain the extent to which and how coordination practices between pathologists, technologists, and surgeons are transformed when telepathology is being implemented. MATERIALS AND METHODS: An interpretive case study was conducted. A total of 60 semistructured interviews with key participants were conducted, in addition to several days of direct observation of telepathology-based intraoperative consultations (IOCs). RESULTS: Three major kinds of transformation of coordination practices were observed. First, the telepathology system itself constrains and disrupts coordination routines, such as the presentation of slides. Second, anticipating IOC, proactively performed by the laboratory personnel in traditional settings, requires more formal requests in a telepathology context. Third, local technologists become more autonomous in performing complex macroscopy manipulations and managing the laboratory tasks traditionally performed by pathologists. CONCLUSIONS: Successful coordination of work in a telepathology-based IOC context requires that significant transformations be anticipated and accounted for. Project managers need to formalize new work processes, support the transformations in professional roles, and mitigate the major hindrances that small material changes may have on work routines.

Design and Validation of a Low-Cost Telepathology System.

OBJECTIVE: This work sought to evaluate the precision and repeatability of a telepathology prototype based on open software and hardware. MATERIALS AND METHODS: A prototype was designed with application in telepathology and telemicroscopy. Accuracy and prototype precision were evaluated by calculating the mean absolute error and the intraclass and repeatability correlation coefficients for a series of 190 displacements at 10, 25, 50, 75, and 100 µm. RESULTS AND CONCLUSIONS: This work developed a low-cost prototype that is accessible, easily reproducible, implementable, and scalable; based on the use of technology created under principles of open software and hardware. A pathologist reviewed the obtained images and found them to be of diagnostic quality. Its excellent repeatability, coupled with its good accuracy, allows for its application in telemicroscopy and static, dynamic, and whole-slide imaging pathology systems.

The Use of Telehealth to Reduce Inequalities in Cardiovascular Outcomes in Australia and New Zealand: A Critical Review.

Telehealth, the delivery of health care services at a distance using information and communications technology, is one means of redressing inequalities in cardiovascular outcomes for disadvantaged groups in Australia. This critical review argues that there is sufficient evidence to move to larger-scale implementation of telehealth for acute cardiac, acute stroke, and cardiac rehabilitation services. For cardiovascular chronic disease and risk factor management, telehealth-based services can deliver value but the evidence is less compelling, as the outcomes of these programs are variable and depend upon the context of their implementation.

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.

Telepathology in cytopathology: challenges and opportunities.

OBJECTIVE: Telepathology in cytopathology is becoming more commonly utilized, and newer technologic infrastructures afford the laboratory a variety of options. The options and design of a telepathology system are driven by the clinical needs. This is primarily focused on providing rapid on-site evaluation service for fine needle aspiration. STUDY DESIGN: The clinical requirements and needs of a system are described. Available tools to design and implement a telepathology system are covered, including methods of image capture, network connectivity and remote viewing options. RESULTS: The primary telepathology method currently used and described involves the delivery via a network connection of a live video image to a remote site which is passively viewed by an internet web-based browser. By utilizing live video information and a voice connection to the on-site location, the remote viewer can collect clinical information and direct their view of the slides. CONCLUSIONS: Telepathology systems for use in cytopathology can be designed and implemented with commercially available infrastructure. It is necessary for the laboratory to validate the designed system and adhere to the required regulatory requirements. Telepathology for cytopathology can be reliably utilized by adapting existing technology, and newer advances hold great promise for further applications in the cytopathology laboratory.

[Whole slide imaging technology: from digitization to online applications]. / Technologie des lames virtuelles - De la numérisation à la mise en ligne.

As e-health becomes essential to modern care, whole slide images (virtual slides) are now an important clinical, teaching and research tool in pathology. Virtual microscopy consists of digitizing a glass slide by acquiring hundreds of tiles of regions of interest at different zoom levels and assembling them into a structured file. This gigapixel image can then be remotely viewed over a terminal, exactly the way pathologists use a microscope. In this article, we will first describe the key elements of this technology, from the acquisition, using a scanner or a motorized microscope, to the broadcasting of virtual slides through a local or distant viewer over an intranet or Internet connection. As virtual slides are now commonly used in virtual classrooms, clinical data and research databases, we will highlight the main issues regarding its uses in modern pathology. Emphasis will be made on quality assurance policies, standardization and scaling.

Assessment of static telecytological diagnoses' reproducibility in cervical smears prepared by means of liquid-based cytology.

OBJECTIVE: This study evaluated the accuracy and reproducibility of telecytological diagnoses proffered on the basis of digitized images from cervical smears prepared by means of liquid-based cytology. MATERIALS AND METHODS: Representative digital cytological images from a total of 404 cervical smears (benign, 135; atypical squamous cells of undetermined significance, 92; low-grade squamous intraepithelial lesion, 62; high-grade squamous intraepithelial lesion, 87; squamous cell carcinoma, 26; and adenocarcinoma, 2) were uploaded to the CytoTrainer e-learning telecytology platform (developed in the Department of Cytopathology, "ATTIKON" University General Hospital, Athens, Greece) with specific password-protected accounts and were reviewed remotely by four independent board-certified cytopathologists (checking round). Their reports were recorded and classified. After 12 and 24 months, the same representative digital images were transferred in random order to the same cytopathologists and were reviewed again (first and second review rounds, respectively). The cytopathologists' first and second round diagnoses were recorded and compared with their initial ones. RESULTS: Statistical evaluation of cytological diagnoses detected no significant difference in diagnostic accuracy among checking and review diagnoses. The overall interobserver agreement was almost perfect with κ values of 0.79-0.97, whereas intraobserver agreement ranged from almost perfect to perfect with κ values of 0.76-1 in all diagnostic rounds. CONCLUSIONS: Digital images of cervical smears can be used for rapid and accurate diagnosis, by diminishing turnaround times and improving small cytology departments' quality indices. Diagnoses made by using static telecytological systems can be as reliable as those made by using conventional microscopy, under the conditions that representative images are taken and that standard cytological diagnostic criteria are applied. Telecytology can be used as an alternative method for the cytologic diagnosis of cervical smears, particularly in quality assurance programs.

Standards and specifications in pathology: image management, report management and terminology.

For making medical decisions, healthcare professionals require that all necessary information is both correct and easily available. Collaborative Digital Anatomic Pathology refers to the use of information technology that supports the creation and sharing or exchange of information, including data and images, during the complex workflow performed in an Anatomic Pathology department from specimen reception to report transmission and exploitation. Collaborative Digital Anatomic Pathology is supported by standardization efforts toward knowledge representation for sharable and computable clinical information. The goal of the international integrating the Healthcare Enterprise (IHE) initiative is precisely specifying how medical informatics standards should be implemented to meet specific health care needs and making systems integration more efficient and less expensive. The IHE Anatomic Pathology initiative was launched to implement the best use of medical informatics standards in order to produce, share and exchange machine-readable structured reports and their evidences (including whole slide images) within hospitals and across healthcare facilities. DICOM supplements 122 and 145 provide flexible object information definitions dedicated respectively to specimen description and WSI acquisition, storage and display. The profiles "Anatomic Pathology Reporting for Public Health" (ARPH) and "Anatomic Pathology Structured Report" (APSR) provide standard templates and transactions for sharing or exchanging structured reports in which textual observations - encoded using PathLex, an international controlled vocabulary currently being mapped to SNOMED CT concepts - may be bound to digital images or regions of interest in images. Current implementations of IHE Anatomic Pathology profiles in North America, France and Spain demonstrate the applicability of recent advances in standards for Collaborative Digital Anatomic Pathology. The use of machine-readable format of Anatomic Pathology information supports the development of computer-based decision support as well as secondary use of Anatomic Pathology information for research or public health.

The COST Action IC0604 "Telepathology Network in Europe" (EURO-TELEPATH).

The COST Action IC0604 "Telepathology Network in Europe" (EURO-TELEPATH) is a European COST Action that has been running from 2007 to 2011. COST Actions are funded by the COST (European Cooperation in the field of Scientific and Technical Research) Agency, supported by the Seventh Framework Programme for Research and Technological Development (FP7), of the European Union. EURO-TELEPATH's main objectives were evaluating and validating the common technological framework and communication standards required to access, transmit and manage digital medical records by pathologists and other medical professionals in a networked environment. The project was organized in four working groups. orking Group 1 "Business modeling in pathology" has designed main pathology processes - Frozen Study, Formalin Fixed Specimen Study, Telepathology, Cytology, and Autopsy -using Business Process Modeling Notation (BPMN). orking Group 2 "Informatics standards in pathology" has been dedicated to promoting the development and application of informatics standards in pathology, collaborating with Integrating the Healthcare Enterprise (IHE), Digital Imaging and Communications in Medicine (DICOM), Health Level Seven (HL7), and other standardization bodies. Working Group 3 "Images: Analysis, Processing, Retrieval and Management" worked on the use of virtual or digital slides that are fostering the use of image processing and analysis in pathology not only for research purposes, but also in daily practice. Working Group 4 "Technology and Automation in Pathology" was focused on studying the adequacy of current existing technical solutions, including, e.g., the quality of images obtained by slide scanners, or the efficiency of image analysis applications. Major outcome of this action are the collaboration with international health informatics standardization bodies to foster the development of standards for digital pathology, offering a new approach for workflow analysis, based in business process modeling. Health terminology standardization research has become a topic of high interest. Future research work should focus on standardization of automatic image analysis and tissue microarrays imaging.

Rapid Validation of Whole-Slide Imaging for Primary Histopathology Diagnosis.

OBJECTIVES: The ongoing global severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic necessitates adaptations in the practice of surgical pathology at scale. Primary diagnosis by whole-slide imaging (WSI) is a key component that would aid departments in providing uninterrupted histopathology diagnosis and maintaining revenue streams from disruption. We sought to perform rapid validation of the use of WSI in primary diagnosis meeting recommendations of the College of American Pathologists guidelines. METHODS: Glass slides from clinically reported cases from 5 participating pathologists with a preset washout period were digitally scanned and reviewed in settings identical to typical reporting. Cases were classified as concordant or with minor or major disagreement with the original diagnosis. Randomized subsampling was performed, and mean concordance rates were calculated. RESULTS: In total, 171 cases were included and distributed equally among participants. For the group as a whole, the mean concordance rate in sampled cases (n = 90) was 83.6% counting all discrepancies and 94.6% counting only major disagreements. The mean pathologist concordance rate in sampled cases (n = 18) ranged from 90.49% to 97%. CONCLUSIONS: We describe a novel double-blinded method for rapid validation of WSI for primary diagnosis. Our findings highlight the occurrence of a range of diagnostic reproducibility when deploying digital methods.

Experience with telepathology in combination with diagnostic assistance systems in countries with restricted resources.

INTRODUCTION: We describe the use of telepathology in countries with restricted resources using two diagnosis assistance systems (Isabel and Memem7) in addition to the diagnoses made by experts in pathology via the iPath-Network. METHODS: A total of 156 cases, largely from Afghanistan, were analysed; 18 cases had to be excluded because of poor image quality. RESULTS: Of the remaining 138 cases (100%), a responsible physician provided a tentative diagnosis for 61.6% of them. With a diagnosis from a consultant pathologist, it was then possible to make a definite diagnosis in 84.8% of cases on the basis of images taken from hematoxylin and eosin staining sections alone. The use of the diagnosis assistance systems resulted in an ordered list of differential diagnoses in 82.6% (IsabelHealth) and in 74.6% (Memem7) of cases, respectively. Adding morphological terminology reduced the list of possible diagnoses to 52.2% (72 cases, Memem7), but improved their quality. DISCUSSION: In summary, diagnosis assistance systems are promising approaches to provide physicians in countries with restricted resources with lists of probable differential diagnoses, thus increasing the plausibility of the diagnosis of the consultant pathologist.

Telepathology: An update on applications, latest advances, and current status in Indian scenario.

Pathologists have been using their tool of trade, "the microscope," since the early 17th century, but now diagnostic pathology or tissue-based diagnosis is characterized by its high specificity and sensitivity. Technological telecommunication advances have revolutionized the face of medicine, and in pursuit of better health-care delivery, telepathology has emerged. Telepathology is the practice of diagnostic pathology performed at a distance, with images viewed on a video monitor rather than directly through the (light) microscope. This article aims to provide an overview of the field, including specific applications, practice, benefits, limitations, regulatory issues, latest advances, and a perspective on the current status of telepathology in Indian scenario based on literature review.

Quantitative Assessment of the Effects of Compression on Deep Learning in Digital Pathology Image Analysis.

PURPOSE: Deep learning (DL), a class of approaches involving self-learned discriminative features, is increasingly being applied to digital pathology (DP) images for tasks such as disease identification and segmentation of tissue primitives (eg, nuclei, glands, lymphocytes). One application of DP is in telepathology, which involves digitally transmitting DP slides over the Internet for secondary diagnosis by an expert at a remote location. Unfortunately, the places benefiting most from telepathology often have poor Internet quality, resulting in prohibitive transmission times of DP images. Image compression may help, but the degree to which image compression affects performance of DL algorithms has been largely unexplored. METHODS: We investigated the effects of image compression on the performance of DL strategies in the context of 3 representative use cases involving segmentation of nuclei (n = 137), segmentation of lymph node metastasis (n = 380), and lymphocyte detection (n = 100). For each use case, test images at various levels of compression (JPEG compression quality score ranging from 1-100 and JPEG2000 compression peak signal-to-noise ratio ranging from 18-100 dB) were evaluated by a DL classifier. Performance metrics including F1 score and area under the receiver operating characteristic curve were computed at the various compression levels. RESULTS: Our results suggest that DP images can be compressed by 85% while still maintaining the performance of the DL algorithms at 95% of what is achievable without any compression. Interestingly, the maximum compression level sustainable by DL algorithms is similar to where pathologists also reported difficulties in providing accurate interpretations. CONCLUSION: Our findings seem to suggest that in low-resource settings, DP images can be significantly compressed before transmission for DL-based telepathology applications.

Digital pathology for intraoperative frozen section diagnosis of thoracic specimens: an evaluation of a system using remote sampling and whole slide imaging diagnosis.

BACKGROUND: Digital pathology is now used for primary diagnostic work as well as teaching, research and consultation. In our multisite institution service reorganisation led to histopathology being located in a separate hospital from some surgical specialities. We implemented remotely supervised specimen sampling and frozen section diagnosis using digital pathology. In this study we assessed the concordance of glass and digital slide diagnosis using this system. METHODS: We reviewed cases from the first 2 years of digital frozen section reporting at our institution. Cases with potential digital to glass slide discordance were reviewed by three experienced thoracic histopathologists. The reasons for discordance were determined and common themes identified. We also reviewed critical incidents relating to digital pathology during the study period. RESULTS: The study population comprised 211 cases. Frozen section to final diagnosis concordance between digital and glass slide diagnosis was found in 196 (92.6%) cases. The 15 potentially discordant cases were reviewed. Intraobserver concordance between glass and digital slide review ranged from 9/15 to 12/15 cases across the three pathologists. Glass slide review diagnosis showed better concordance with ground truth in two cases; digital slide review was more accurate in two cases. One relevant critical incident was identified during the study period. DISCUSSION: This is the largest study to examine digital pathology for thoracic frozen section diagnosis and shows that this is a safe and feasible alternative to glass slide diagnosis. Discordance between digital and glass slide diagnoses were unrelated to the processes of whole slide imaging and digital microscopy.

Assessment of diagnostic accuracy and feasibility of dynamic telepathology in China.

To assess the feasibility, including diagnostic accuracy and time cost, of a real-time telepathology system with pathologic slides, 600 cases covering a wide spectrum of lesions from 16 organ systems were tested. The "correct" diagnosis (gold standard) was established as a consensus by 2 experienced pathologists. The cases were first examined by 4 pathologists at different levels of experience with dynamic telepathology. Cases were then reviewed by the same pathologists using light microscopy in a blinded fashion 3 weeks to 2 months later. A diagnosis, together with reading times for telepathology and light microscopy, was recorded for each case. Diagnostic accuracy by telepathology was 94.8% (569/600), 93.3% (560/600), 91.6% (550/600), and 97% (388/400) for pathologists A, B, C, and D, respectively. Telepathologic diagnosis was concordant with the gold standard and with direct microscopy, with a mean of 94.2% and 99.26%, respectively. Most cases (510 or 85%) were diagnosed in 15 to 40 minutes by telepathology, with a mean of 17.0 minutes. The time needed to review a slide by telepathology was 3 to 4 times longer than that of standard light microscopy. All 4 pathologists were able to render a diagnosis in all cases. Our results showed that robotic telepathology is sufficiently accurate for primary diagnosis in surgical pathology, but modifications in laboratory protocols, telepathology hardware, and internet speed are needed to reduce the time necessary for diagnosis by telepathology before this method may be deemed suitable for use in a busy practice.