Journal of Pathology Informatics Journal of Pathology Informatics
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Technical Note: Remote reporting during a pandemic using digital pathology solution: Experience from a tertiary care cancer center
Veena Ramaswamy, BN Tejaswini, Sowmya B Uthaiah
J Pathol Inform 2021, 12:20 (8 April 2021)
Background: Remote reporting in anatomic pathology is an important advantage of digital pathology that has not been much explored. The COVID-19 pandemic has provided an opportunity to explore this important application of digital pathology system in a tertiary care cancer center to ensure patient care and staff safety. Regulatory guidelines have been described for remote reporting following the pandemic. Herein, we describe our experience of validation of digital pathology workflow for remote reporting to encourage pathologists to utilize this facility which opens door for multiple, multidisciplinary collaborations. Objective: To demonstrate the validation and the operational feasibility of remote reporting using a digital pathology system. Materials and Methods: Our retrospective validation included whole-slide images (WSIs) of 60 cases of histopathology and 20 cases each of frozen sections and a digital image-based breast algorithm after a washout period of 3 months. Three pathologists with different models of consumer-grade laptops reviewed the cases remotely to assess the diagnostic concordance and operational feasibility of the modified workflow. The slides were digitized on a USFDA-approved Philips UFS 300 scanner at ×40 resolution (0.25 μm/pixel) and viewed on the Image Management System through a web browser. All the essential parameters were reported for each case. After successful validation, 886 cases were reported remotely from March 29, 2020, to June 30, 2020, prospectively. Light microscopy formed the gold standard reference in remote reporting. Results: 100% major diagnostic concordance was observed in the validation of remote reporting in the retrospective and prospective studies using consumer-grade laptops. The deferral rate was 0.34%. 97.6% of histopathology and 100% of frozen sections were signed out within the turnaround time. Network speed and a lack of virtual private network did not significantly affect the study. Conclusion: This study of validation and reporting of complete pathology cases remotely, including their operational feasibility during a public health emergency, proves that remote sign-out using a digital pathology system is not inferior to WSIs on medical-grade monitors and light microscopy. Such studies on remote reporting open the door for the use of digital pathology for interinstitutional consultation and collaboration: Its main intended use.
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Technical Note: Use of middleware data to dissect and optimize hematology autoverification
Rachel D Starks, Anna E Merrill, Scott R Davis, Dena R Voss, Pamela J Goldsmith, Bonnie S Brown, Jeff Kulhavy, Matthew D Krasowski
J Pathol Inform 2021, 12:19 (7 April 2021)
Background: Hematology analysis comprises some of the highest volume tests run in clinical laboratories. Autoverification of hematology results using computer-based rules reduces turnaround time for many specimens, while strategically targeting specimen review by technologist or pathologist. Methods: Autoverification rules had been developed over a decade at an 800-bed tertiary/quarternary care academic medical central laboratory serving both adult and pediatric populations. In the process of migrating to newer hematology instruments, we analyzed the rates of the autoverification rules/flags most commonly associated with triggering manual review. We were particularly interested in rules that on their own often led to manual review in the absence of other flags. Prior to the study, autoverification rates were 87.8% (out of 16,073 orders) for complete blood count (CBC) if ordered as a panel and 85.8% (out of 1,940 orders) for CBC components ordered individually (not as the panel). Results: Detailed analysis of rules/flags that frequently triggered indicated that the immature granulocyte (IG) flag (an instrument parameter) and rules that reflexed platelet by impedance method (PLT-I) to platelet by fluorescent method (PLT-F) represented the two biggest opportunities to increase autoverification. The IG flag threshold had previously been validated at 2%, a setting that resulted in this flag alone preventing autoverification in 6.0% of all samples. The IG flag threshold was raised to 5% after detailed chart review; this was also the instrument vendor's default recommendation for the newer hematology analyzers. Analysis also supported switching to PLT-F for all platelet analysis. Autoverification rates increased to 93.5% (out of 91,692 orders) for CBC as a panel and 89.8% (out of 11,982 orders) for individual components after changes in rules and laboratory practice. Conclusions: Detailed analysis of autoverification of hematology testing at an academic medical center clinical laboratory that had been using a set of autoverification rules for over a decade revealed opportunities to optimize the parameters. The data analysis was challenging and time-consuming, highlighting opportunities for improvement in software tools that allow for more rapid and routine evaluation of autoverification parameters.
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Technical Note: Image Analysis Using Machine Learning for Automated Detection of Hemoglobin H Inclusions in Blood Smears – A Method for Morphologic Detection of Rare Cells
Shir Ying Lee, Crystal M E Chen, Elaine Y P Lim, Liang Shen, Aneesh Sathe, Aahan Singh, Jan Sauer, Kaveh Taghipour, Christina Y C Yip
J Pathol Inform 2021, 12:18 (7 April 2021)
Background: Morphologic rare cell detection is a laborious, operator-dependent process which has the potential to be improved by the use of image analysis using artificial intelligence. Detection of rare hemoglobin H (HbH) inclusions in red cells in the peripheral blood is a common screening method for alpha-thalassemia. This study aims to develop a convolutional neural network-based algorithm for the detection of HbH inclusions. Methods: Digital images of HbH-positive and HbH-negative blood smears were used to train and test the software. The software performance was tested on images obtained at various magnifications and on different scanning platforms. Another model was developed for total red cell counting and was used to confirm HbH cell frequency in alpha-thalassemia trait. The threshold minimum red cells to image for analysis was determined by Poisson modeling and validated on image sets. Results: The sensitivity and specificity of the software for HbH+ cells on images obtained at ×100, ×60, and ×40 objectives were close to 91% and 99%, respectively. When an AI-aided diagnostic model was tested on a pilot of 40 whole slide images (WSIs), good inter-rater reliability and high sensitivity and specificity of slide-level classification were obtained. Using the lowest frequency of HbH+ cells (1 in 100,000) observed in our study, we estimated that a minimum of 2.4 × 106 red cells would need to be analyzed to reduce misclassification at the slide level. The minimum required smear size was validated on 78 image sets which confirmed its validity. Conclusions: WSI image analysis can be utilized effectively for morphologic rare cell detection. The software can be further developed on WISs and evaluated in future clinical validation studies comparing AI-aided diagnosis with the routine diagnostic method.
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Original Article: Dissecting the business case for adoption and implementation of digital pathology: A white paper from the digital pathology association
Giovanni Lujan, Jennifer C Quigley, Douglas Hartman, Anil Parwani, Brian Roehmholdt, Bryan Van Meter, Orly Ardon, Matthew G Hanna, Dan Kelly, Chelsea Sowards, Michael Montalto, Marilyn Bui, Mark D Zarella, Gerard Slootweg, Juan Antonio Retamero, Mark C Lloyd, James Madory, Doug Bowman
J Pathol Inform 2021, 12:17 (7 April 2021)
We believe the switch to a digital pathology (DP) workflow is imminent and it is essential to understand the economic implications of conversion. Many aspects of the adoption of DP will be disruptive and have a direct financial impact, both in short term costs, such as investment in equipment and personnel, and long term revenue potential, such as improved productivity and novel tests. The focus of this whitepaper is to educate pathologists, laboratorians and other stakeholders about the business and monetary considerations of converting to a digital pathology workflow. The components of a DP business plan will be thoroughly summarized, and guidance will be provided on how to build a case for adoption and implementation as well as a roadmap for transitioning from an analog to a digital pathology workflow in various laboratory settings. It is important to clarify that this publication is not intended to list prices although some financials will be mentioned as examples. The authors encourage readers who are evaluating conversion to a DP workflow to use this paper as a foundational guide for conducting a thorough and complete assessment while incorporating in current market pricing. Contributors to this paper analyzed peer-reviewed literature and data collected from various institutions, some of which are mentioned. Digital pathology will change the way we practice through facilitating patient access to expert pathology services and enabling image analysis tools and assays to aid in diagnosis, prognosis, risk stratification and therapeutic selection. Together, they will result in the delivery of valuable information from which to make better decisions and improve the health of patients.
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Guidelines: Integrating the health-care enterprise pathology and laboratory medicine guideline for digital pathology interoperability
Rajesh C Dash, Nicholas Jones, Riki Merrick, Gunter Haroske, James Harrison, Craig Sayers, Nick Haarselhorst, Mikael Wintell, Markus D Herrmann, François Macary
J Pathol Inform 2021, 12:16 (24 March 2021)
Integrating the health-care enterprise (IHE) is an international initiative to promote the use of standards to achieve interoperability among health information technology systems. The Pathology and Laboratory Medicine domain within IHE has brought together subject matter experts, electronic health record vendors, and digital imaging vendors, to initiate development of a series of digital pathology interoperability guidelines, called “integration profiles” within IHE. This effort begins with documentation of common use cases, followed by identification of available data and technology standards best utilized to achieve those use cases. An integration profile that describes the information flow and technology interactions is then published for trial use. Real world testing occurs in “connectathon” events, in which multiple vendors attempt to connect their products following the interoperability guidance parameters set forth in the profile. This paper describes the overarching set of integration profiles, one of which has been published, to support key digital pathology use cases.
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Original Article: Selection of representative histologic slides in interobserver reproducibility studies: Insights from expert review for ovarian carcinoma subtype classification
Marios A Gavrielides, Brigitte M Ronnett, Russell Vang, Fahime Sheikhzadeh, Jeffrey D Seidman
J Pathol Inform 2021, 12:15 (22 March 2021)
Background: Observer studies in pathology often utilize a limited number of representative slides per case, selected and reported in a nonstandardized manner. Reference diagnoses are commonly assumed to be generalizable to all slides of a case. We examined these issues in the context of pathologist concordance for histologic subtype classification of ovarian carcinomas (OCs). Materials and Methods: A cohort of 114 OCs consisting of 72 cases with a single representative slide (Group 1) and 42 cases with multiple representative slides (148 slides, 2-“6 sections per case, Group 2) was independently reviewed by three experts in gynecologic pathology (case-based review). In a follow-up study, each individual slide was independently reviewed in a randomized order by the same pathologists (section-based review). Results: Average interobserver concordance varied from 100% for Group 1 to 64.3% for Group 2 (86.8% across all cases). Across Group 2, 19 cases (45.2%) had at least one slide classified as a different subtype than the subtype assigned from case-based review, demonstrating the impact of intratumoral heterogeneity. Section-based concordance across individual sections from Group 2 was comparable to case-based concordance for those cases indicating diagnostic challenges at the individual section level. Findings demonstrate the increased diagnostic complexity of heterogeneous tumors that require multiple section sampling and its impact on pathologist performance. Conclusions: The proportion of cases with multiple representative slides in cohorts used in validation studies, such as those conducted to evaluate artificial intelligence/machine learning tools, can influence diagnostic performance, and if not accounted for, can cause disparities between research and real-world observations and between research studies. Case selection in validation studies should account for tumor heterogeneity to create balanced datasets in terms of diagnostic complexity.
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Commentary: Commentary: The digital fate of glomeruli in renal biopsy
Ilaria Girolami, Stefano Marletta, Albino Eccher
J Pathol Inform 2021, 12:14 (22 March 2021)
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Review Article: Artificial intelligence in pathology: From prototype to product
André Homeyer, Johannes Lotz, Lars Ole Schwen, Nick Weiss, Daniel Romberg, Henning Höfener, Norman Zerbe, Peter Hufnagl
J Pathol Inform 2021, 12:13 (22 March 2021)
Modern image analysis techniques based on artificial intelligence (AI) have great potential to improve the quality and efficiency of diagnostic procedures in pathology and to detect novel biomarkers. Despite thousands of published research papers on applications of AI in pathology, hardly any research implementations have matured into commercial products for routine use. Bringing an AI solution for pathology to market poses significant technological, business, and regulatory challenges. In this paper, we provide a comprehensive overview and advice on how to meet these challenges. We outline how research prototypes can be turned into a product-ready state and integrated into the IT infrastructure of clinical laboratories. We also discuss business models for profitable AI solutions and reimbursement options for computer assistance in pathology. Moreover, we explain how to obtain regulatory approval so that AI solutions can be launched as in vitro diagnostic medical devices. Thus, this paper offers computer scientists, software companies, and pathologists a road map for transforming prototypes of AI solutions into commercial products.
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Commentary: Commentary: Leveraging edge computing technology for digital pathology
Mustafa Yousif, Ulysses G J Balis, Anil V Parwani, Liron Pantanowitz
J Pathol Inform 2021, 12:12 (22 March 2021)
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Editorial: Virtual mega-meetings: Here to stay?
Lewis A Hassell, Hans J G Hassell
J Pathol Inform 2021, 12:11 (15 March 2021)
Among the paradigms changed by the COVID-19 pandemic is the traditional academic and educational conference. In the vein of turning lemons into lemonade, many organizations and individuals have discovered ways that this public health necessitated change can be transformed into a boon to both participants and organizations. However, the question of whether this shift becomes permanent, or a component of the future of academic and educational meetings remains to be seen, and likely will depend on the solution to some of the challenges that have not been sweetened by the shift. This editorial draws on experience with a limited scope of virtual meetings in two different disciplines to make the case that the Virtual Mega-Conference is likely to continue to be a part of life in the years ahead.
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Editorial: Europe unites for the digital transformation of pathology: The role of the new ESDIP
Catarina Eloy, Norman Zerbe, Filippo Fraggetta
J Pathol Inform 2021, 12:10 (12 March 2021)
The European Society for Digital and Integrative Pathology (ESDIP) was formally founded in 2016 in Berlin. After a well-participated annual general meeting, ESDIP members elected a new active structure for the next term of office. The priority goals of this new and highly motivated team will be to support the digital transformation in the pathology laboratories, to build inter-institutional bridges for cooperation, to establish a solid educational program, and to increase the collaboration with industry partners.
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Original Article: Overcoming an annotation hurdle: Digitizing pen annotations from whole slide images
Peter J. Schüffler, Dig Vijay Kumar Yarlagadda, Chad Vanderbilt, Thomas J Fuchs
J Pathol Inform 2021, 12:9 (23 February 2021)
Background: The development of artificial intelligence (AI) in pathology frequently relies on digitally annotated whole slide images (WSI). The creation of these annotations – manually drawn by pathologists in digital slide viewers – is time consuming and expensive. At the same time, pathologists routinely annotate glass slides with a pen to outline cancerous regions, for example, for molecular assessment of the tissue. These pen annotations are currently considered artifacts and excluded from computational modeling. Methods: We propose a novel method to segment and fill hand-drawn pen annotations and convert them into a digital format to make them accessible for computational models. Our method is implemented in Python as an open source, publicly available software tool. Results: Our method is able to extract pen annotations from WSI and save them as annotation masks. On a data set of 319 WSI with pen markers, we validate our algorithm segmenting the annotations with an overall Dice metric of 0.942, Precision of 0.955, and Recall of 0.943. Processing all images takes 15 min in contrast to 5 h manual digital annotation time. Further, the approach is robust against text annotations. Conclusions: We envision that our method can take advantage of already pen-annotated slides in scenarios in which the annotations would be helpful for training computational models. We conclude that, considering the large archives of many pathology departments that are currently being digitized, our method will help to collect large numbers of training samples from those data.
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Original Article: Examining the relationship between altmetric score and traditional bibliometrics in the pathology literature
Adam R Floyd, Zachary C Wiley, Carter J Boyd, Christine G Roth
J Pathol Inform 2021, 12:8 (23 February 2021)
Background: Recently, research data are increasingly shared through social media and other digital platforms. Traditionally, the influence of a scientific article has been assessed by the publishing journal's impact factor (IF) and its citation count. The Altmetric scoring system, a new bibliometric that integrates research “mentions” over digital media platforms, has emerged as a metric of online research distribution. The aim of this study was to explore the relationship of the Altmetric Score with IF and citation number within the pathology literature. Methods: Citation count and Altmetric scores were obtained from the top 10 most-cited articles from the 15 pathology journals with the highest IF for 2013 and 2016. These variables were analyzed and correlated with each other, as well as the age of the publishing journal's Twitter account. Results: Three hundred articles were examined from the two cohorts. The total citation count of the articles decreased from 21,043 (2013) to 14,679 (2016), while the total Altmetric score increased from 830 (2013) to 4066 (2016). In 2013, Altmetric score weakly correlated with citation number (r = 0.284, P < 0.001) but not with journal IF (r = 0.024, P = 0.771). In 2016, there was strong correlation between citation count and Altmetric Score (r = 0.714, P < 0.0001) but not the IF (r = 0.0442, P = 0.591). Twitter was the single most important contributor to the Altmetric score; however, the age of the Twitter account was not associated with citation number nor Altmetric score. Conclusions: In the pathology literature studied, the Altmetric score correlates with article citation count, suggesting that the Altmetric score and conventional bibliometrics can be treated as complementary metrics. Given the trend towards increasing use of social media, additional investigation is warranted to evaluate the evolving role of social media metrics to assess the dissemination and impact of scientific findings in the field of pathology.
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Original Article: Experience reviewing digital pap tests using a gallery of images
Liron Pantanowitz, Sarah Harrington
J Pathol Inform 2021, 12:7 (23 February 2021)
Introduction: Hologic is developing a digital cytology platform. An educational website was launched for users to review these digitized Pap test cases. The aim of this study was to analyze data captured from this website. Materials and Methods: ThinPrep® Pap test slides were scanned at ×40 using a volumetric (14 focal plane) technique. Website cases consisted of an image gallery and whole slide image (WSI). Over a 13 month period data were recorded including diagnoses, time participants spent online, and number of clicks on the gallery and WSI. Results: 51,289 cases were reviewed by 918 reviewers. Cytotechnologists spent less time (M [Median] = 65.0 s) than pathologists (M = 82.2 s) reviewing cases (P < 0.001). Longer times were associated with incorrect diagnoses and cases with organisms. Cytotechnologists matched the reference diagnoses in 85% of cases compared to pathologists who matched in 79.8%. While in 62% of cases reviewers only examined the gallery, they attained the correct diagnosis 92.7% of the time. Pathologists made more clicks on the gallery and WSI than cytotechnologists (P < 0.001). Diagnostic accuracy decreased with increasing clicks. Conclusions: Website participation provided feedback about how cytologists interact with a digital platform when reviewing cases. These data suggest that digital Pap test review when comprised of an image gallery displaying diagnostically relevant objects is quick and easy to interpret. The high diagnostic concordance of digital Pap tests with reference diagnoses can be attributed to high image quality with volumetric scanning, image gallery format, and ability for users to freely navigate the entire digital slide.
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Original Article: A comparison of methods for studying the tumor microenvironment's spatial heterogeneity in digital pathology specimens
Ines Panicou Nearchou, Daniel Alexander Soutar, Hideki Ueno, David James Harrison, Ognjen Arandjelovic, Peter David Caie
J Pathol Inform 2021, 12:6 (28 January 2021)
Background: The tumor microenvironment is highly heterogeneous, and it is understood to affect tumor progression and patient outcome. A number of studies have reported the prognostic significance of tumor-infiltrating lymphocytes and tumor budding in colorectal cancer (CRC). However, the significance of the intratumoral heterogeneity present in the spatial distribution of these features within the tumor immune microenvironment (TIME) has not been previously reported. Evaluating this intratumoral heterogeneity may aid the understanding of the TIME's effect on patient prognosis as well as identify novel aggressive phenotypes which can be further investigated as potential targets for new treatment. Methods: In this study, we propose and apply two spatial statistical methodologies for the evaluation of the intratumor heterogeneity present in the distribution of CD3 + and CD8 + lymphocytes and tumor buds (TB) in 232 Stage II CRC cases. Getis-Ord hotspot analysis was applied to quantify the cold and hotspots, defined as regions with a significantly low or high number of each feature of interest, respectively. A novel spatial heatmap methodology for the quantification of the cold and hotspots of each feature of interest, which took into account both the interpatient heterogeneity and the intratumor heterogeneity, was further developed. Results: Resultant data from each analysis, characterizing the spatial intratumor heterogeneity of lymphocytes and TBs were used for the development of two new highly prognostic risk models. Conclusions: Our results highlight the value of applying spatial statistics for the assessment of the intratumor heterogeneity. Both Getis-Ord hotspot and our proposed spatial heatmap analysis are broadly applicable across other tissue types as well as other features of interest. Availability: The code underpinning this publication can be accessed at
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Original Article: Effects of image quantity and image source variation on machine learning histology differential diagnosis models
Elham Vali-Betts, Kevin J Krause, Alanna Dubrovsky, Kristin Olson, John Paul Graff, Anupam Mitra, Ananya Datta-Mitra, Kenneth Beck, Aristotelis Tsirigos, Cynthia Loomis, Antonio Galvao Neto, Esther Adler, Hooman H Rashidi
J Pathol Inform 2021, 12:5 (23 January 2021)
Aims: Histology, the microscopic study of normal tissues, is a crucial element of most medical curricula. Learning tools focused on histology are very important to learners who seek diagnostic competency within this important diagnostic arena. Recent developments in machine learning (ML) suggest that certain ML tools may be able to benefit this histology learning platform. Here, we aim to explore how one such tool based on a convolutional neural network, can be used to build a generalizable multi-classification model capable of classifying microscopic images of human tissue samples with the ultimate goal of providing a differential diagnosis (a list of look-alikes) for each entity. Methods: We obtained three institutional training datasets and one generalizability test dataset, each containing images of histologic tissues in 38 categories. Models were trained on data from single institutions, low quantity combinations of multiple institutions, and high quantity combinations of multiple institutions. Models were tested against withheld validation data, external institutional data, and generalizability test images obtained from Google image search. Performance was measured with macro and micro accuracy, sensitivity, specificity, and f1-score. Results: In this study, we were able to show that such a model's generalizability is dependent on both the training data source variety and the total number of training images used. Models which were trained on 760 images from only a single institution performed well on withheld internal data but poorly on external data (lower generalizability). Increasing data source diversity improved generalizability, even when decreasing data quantity: models trained on 684 images, but from three sources improved generalization accuracy between 4.05' and 18.59'. Maintaining this diversity and increasing the quantity of training images to 2280 further improved generalization accuracy between 16.51' and 32.79'. Conclusions: This pilot study highlights the significance of data diversity within such studies. As expected, optimal models are those that incorporate both diversity and quantity into their platforms.s
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Research Article: Verification and validation of digital pathology (whole slide imaging) for primary histopathological diagnosis: All wales experience
M Babawale, A Gunavardhan, J Walker, T Corfield, P Huey, A Savage, A Bansal, M Atkinson, H Abdelsalam, E Raweily, A Christian, I Evangelou, D Thomas, J Shannon, E Youd, P Brumwell, J Harrison, I Thompson, M Rashid, G Leopold, A Finall, S Roberts, D Housa, P Nedeva, A Davies, D Fletcher, Muhammad Aslam
J Pathol Inform 2021, 12:4 (23 January 2021)
Aims: The study is aimed to verify Aperio AT2 scanner for reporting on the digital pathology platform (DP) and to validate the cohort of pathologists in the interpretation of DP for routine diagnostic histopathological services in Wales, United Kingdom. Materials, Methods and Results: This was a large multicenter study involving seven hospitals across Wales and unique with 22 (largest number) pathologists participating. 7491 slides from 3001 cases were scanned on Leica Aperio AT2 scanner and reported on digital workstations with Leica software of e-slide manager. A senior pathology fellow compared DP reports with authorized reports on glass slide (GS). A panel of expert pathologists reviewed the discrepant cases under multiheader microscope to establish ground truth. 2745 out of 3001 (91%) cases showed complete concordance between DP and GS reports. Two hundred and fifty-six cases showed discrepancies in diagnosis, of which 170 (5.6%) were deemed of no clinical significance by the review panel. There were 86 (2.9%) clinically significant discrepancies in the diagnosis between DP and GS. The concordance was raised to 97.1% after discounting clinically insignificant discrepancies. Ground truth lay with DP in 28 out of 86 clinically significant discrepancies and with GS in 58 cases. Sensitivity of DP was 98.07% (confidence interval [CI] 97.57–98.56%); for GS was 99.07% (CI 98.72–99.41%). Conclusions: We concluded that Leica Aperio AT2 scanner produces adequate quality of images for routine histopathologic diagnosis. Pathologists were able to diagnose in DP with good concordance as with GS. Strengths and Limitations of this Study: Strengths of this study – This was a prospective blind study. Different pathologists reported digital and glass arms at different times giving an ambience of real-time reporting. There was standardized use of software and hardware across Wales. A strong managerial support from efficiency through the technology group was a key factor for the implementation of the study. Limitations: This study did not include Cytopathology and in situ hybridization slides. Difficulty in achieving surgical pathology practise standardization across the whole country contributed to intra-observer variations.
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Original Article: Remote reporting from home for primary diagnosis in surgical pathology: A tertiary oncology center experience during the COVID-19 pandemic Highly accessed article
Vidya Rao, Rajiv Kumar, Sathyanarayanan Rajaganesan, Swapnil Rane, Gauri Deshpande, Subhash Yadav, Asawari Patil, Trupti Pai, Santosh Menon, Aekta Shah, Katha Rabade, Mukta Ramadwar, Poonam Panjwani, Neha Mittal, Ayushi Sahay, Bharat Rekhi, Munita Bal, Uma Sakhadeo, Sumeet Gujral, Sangeeta Desai
J Pathol Inform 2021, 12:3 (8 January 2021)
Background: The COVID-19 pandemic accelerated the widespread adoption of digital pathology (DP) for primary diagnosis in surgical pathology. This paradigm shift is likely to influence how we function routinely in the postpandemic era. We present learnings from early adoption of DP for a live digital sign-out from home in a risk-mitigated environment. Materials and Methods: We aimed to validate DP for remote reporting from home in a real-time environment and evaluate the parameters influencing the efficiency of a digital workflow. Eighteen pathologists prospectively validated DP for remote use on 567 biopsy cases including 616 individual parts from 7 subspecialties over a duration from March 21, 2020, to June 30, 2020. The slides were digitized using Roche Ventana DP200 whole-slide scanner and reported from respective homes in a risk-mitigated environment. Results: Following re-review of glass slides, there was no major discordance and 1.2% (n = 7/567) minor discordance. The deferral rate was 4.5%. All pathologists reported from their respective homes from laptops with an average network speed of 20 megabits per second. Conclusion: We successfully validated and adopted a digital workflow for remote reporting with available resources and were able to provide our patients, an undisrupted access to subspecialty expertise during these unprecedented times.
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Technical Note: Implementation of collodion bag protocol to improve whole-slide imaging of scant gynecologic curettage specimens
Iny Jhun, David Levy, Harumi Lim, Quintina Herrera, Erika Dobo, Dominique Burns, William Hetherington, Ronald Macasaet, April J Young, Christina S Kong, Ann K Folkins, Eric Joon Yang
J Pathol Inform 2021, 12:2 (8 January 2021)
Background: Digital pathology has been increasingly implemented for primary surgical pathology diagnosis. In our institution, digital pathology was recently deployed in the gynecologic (GYN) pathology practice. A notable challenge encountered in the digital evaluation of GYN specimens was high rates of scanning failure of specimens with fragmented as well as scant tissue. To improve tissue detection failure rates, we implemented a novel use of the collodion bag cell block preparation method. Materials and Methods: In this study, we reviewed 108 endocervical curettage (ECC) specimens, representing specimens processed with and without the collodion bag cell block method (n = 56 without collodion bag, n = 52 with collodion bag). Results: Tissue detection failure rates were reduced from 77% (43/56) in noncollodion bag cases to 23/52 (44%) of collodion bag cases, representing a 42% reduction. The median total area of tissue detection failure per level was 0.35 mm2 (interquartile range [IQR]: 0.14, 0.70 mm2) for noncollodion bag cases and 0.08 mm2 (IQR: 0.03, 0.20 mm2) for collodion bag cases. This represents a greater than fourfold reduction in the total area of tissue detection failure per level (P < 0.001). In addition, there were no out-of-focus levels among collodion bag cases, compared to 6/56 (11%) of noncollodion bag cases (median total area = 4.9 mm2). Conclusions: The collodion bag method significantly improved the digital image quality of fragmented/scant GYN curettage specimens, increased efficiency and accuracy of diagnostic evaluation, and enhanced identification of tissue contamination during processing. The logistical challenges and labor cost of deploying the collodion bag protocol are important considerations for feasibility assessment at an institutional level.
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Letters: Digital slides as an effective tool for programmed death ligand 1 combined positive score assessment and training: Lessons learned from the “Programmed death ligand 1 key learning program in Head-and-Neck squamous cell carcinoma”
Albino Eccher, Gabriella Fontanini, Nicola Fusco, Ilaria Girolami, Paolo Graziano, Elena Guerini Rocco, Maurizio Martini, Patrizia Morbini, Liron Pantanowitz, Anil Parwani, Anna Maria Pisano, Giancarlo Troncone, Elena Vigliar
J Pathol Inform 2021, 12:1 (8 January 2021)
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Original Article: DeepCIN: Attention-based cervical histology image classification with sequential feature modeling for pathologist-level accuracy
Sudhir Sornapudi, R Joe Stanley, William V Stoecker, Rodney Long, Zhiyun Xue, Rosemary Zuna, Shellaine R Frazier, Sameer Antani
J Pathol Inform 2020, 11:40 (24 December 2020)
Background: Cervical cancer is one of the deadliest cancers affecting women globally. Cervical intraepithelial neoplasia (CIN) assessment using histopathological examination of cervical biopsy slides is subject to interobserver variability. Automated processing of digitized histopathology slides has the potential for more accurate classification for CIN grades from normal to increasing grades of pre-malignancy: CIN1, CIN2, and CIN3. Methodology: Cervix disease is generally understood to progress from the bottom (basement membrane) to the top of the epithelium. To model this relationship of disease severity to spatial distribution of abnormalities, we propose a network pipeline, DeepCIN, to analyze high-resolution epithelium images (manually extracted from whole-slide images) hierarchically by focusing on localized vertical regions and fusing this local information for determining Normal/CIN classification. The pipeline contains two classifier networks: (1) a cross-sectional, vertical segment-level sequence generator is trained using weak supervision to generate feature sequences from the vertical segments to preserve the bottom-to-top feature relationships in the epithelium image data and (2) an attention-based fusion network image-level classifier predicting the final CIN grade by merging vertical segment sequences. Results: The model produces the CIN classification results and also determines the vertical segment contributions to CIN grade prediction. Conclusion: Experiments show that DeepCIN achieves pathologist-level CIN classification accuracy.
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Technical Note: A novel web application for rapidly searching the diagnostic case archive
Scott Robertson
J Pathol Inform 2020, 11:39 (24 December 2020)
Academic pathologists must have the ability to search their institution's archive of diagnostic case data. This ability is foundational for research, education, and other academic activities. However, the built-in search functions of commercial laboratory information systems are not always optimized for this activity, leading to delays between an initial search request, and eventual results delivery. To solve this problem, a novel web-based search platform was developed, named Pathtools, which allows our staff and trainees to directly and rapidly search our diagnostic case archive. Pathtools was built with open-source components and features a web-based user-interface. Pathtools uses an SQL database which was populated with anatomic pathology case data going back to 1980, and contains 4.2 million cases (as of July 31, 2020). Pathtools has two major modes of operation, “Preview Mode” and “Research Mode.” Since deployment in February of 2019, Pathtools carried out 33,817 searches in Preview Mode, averaging 0.72 s (standard deviation = 1.7) between search submission, and on-screen display of search results. In Research Mode, Pathtools has also been used to produce data sets for research activity, providing the data used in many abstracts and manuscripts our investigators submitted recently. Interestingly, 75% of search activity is from trainees during their preview time. In a survey of residents and fellows, 83% used Pathtools during the majority of their preview sessions, demonstrating an important role for this resource in trainee education. In conclusion, a web-based search tool can rapidly and securely provide search capability directly to end-users, which has augmented trainee education and research activity in our department.
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Research Article: Constellation loss: Improving the efficiency of deep metric learning loss functions for the optimal embedding of histopathological images
Alfonso Medela, Artzai Picon
J Pathol Inform 2020, 11:38 (26 November 2020)
Background: Deep learning diagnostic algorithms are proving comparable results with human experts in a wide variety of tasks, and they still require a huge amount of well-annotated data for training, which is often non affordable. Metric learning techniques have allowed a reduction in the required annotated data allowing few-shot learning over deep learning architectures. Aims and Objectives: In this work, we analyze the state-of-the-art loss functions such as triplet loss, contrastive loss, and multi-class N-pair loss for the visual embedding extraction of hematoxylin and eosin (H&E) microscopy images and we propose a novel constellation loss function that takes advantage of the visual distances of the embeddings of the negative samples and thus, performing a regularization that increases the quality of the extracted embeddings. Materials and Methods: To this end, we employed the public H&E imaging dataset from the University Medical Center Mannheim (Germany) that contains tissue samples from low-grade and high-grade primary tumors of digitalized colorectal cancer tissue slides. These samples are divided into eight different textures (1. tumour epithelium, 2. simple stroma, 3. complex stroma, 4. immune cells, 5. debris and mucus, 6. mucosal glands, 7. adipose tissue and 8. background,). The dataset was divided randomly into train and test splits and the training split was used to train a classifier to distinguish among the different textures with just 20 training images. The process was repeated 10 times for each loss function. Performance was compared both for cluster compactness and for classification accuracy on separating the aforementioned textures. Results: Our results show that the proposed loss function outperforms the other methods by obtaining more compact clusters (Davis-Boulding: 1.41 ± 0.08, Silhouette: 0.37 ± 0.02) and better classification capabilities (accuracy: 85.0 ± 0.6) over H and E microscopy images. We demonstrate that the proposed constellation loss can be successfully used in the medical domain in situations of data scarcity.
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Original Article: Using image registration and machine learning to develop a workstation tool for rapid analysis of glomeruli in medical renal biopsies
David C Wilbur, Jason R Pettus, Maxwell L Smith, Lynn D Cornell, Alexander Andryushkin, Richard Wingard, Eric Wirch
J Pathol Inform 2020, 11:37 (7 November 2020)
Background: Prescreening of biopsies has the potential to improve pathologists' workflow. Tools that identify features and display results in a visually thoughtful manner can enhance efficiency, accuracy, and reproducibility. Machine learning for detection of glomeruli ensures comprehensive assessment and registration of four different stains allows for simultaneous navigation and viewing. Methods: Medical renal core biopsies (4 stains each) were digitized using a Leica SCN400 at ×40 and loaded into the Corista Quantum research platform. Glomeruli were manually annotated by pathologists. The tissue on the 4 stains was registered using a combination of keypoint- and intensity-based algorithms, and a 4-panel simultaneous viewing display was created. Using a training cohort, machine learning convolutional neural net (CNN) models were created to identify glomeruli in all stains, and merged into composite fields of views (FOVs). The sensitivity and specificity of glomerulus detection, and FOV area for each detection were calculated. Results: Forty-one biopsies were used for training (28) and same-batch evaluation (6). Seven additional biopsies from a temporally different batch were also evaluated. A variant of AlexNet CNN, used for object recognition, showed the best result for the detection of glomeruli with same-batch and different-batch evaluation: Same-batch sensitivity 92%, “modified” specificity 89%, average FOV size represented 0.8% of the total slide area; different-batch sensitivity 90%, “modified” specificity 98% and average FOV size 1.6% of the total slide area. Conclusions: Glomerulus detection in the best CNN model shows that machine learning algorithms may be accurate for this task. The added benefit of biopsy registration with simultaneous display and navigation allows reviewers to move from one machine-generated FOV to the next in all 4 stains. Together these features could increase both efficiency and accuracy in the review process.
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Research Article: Reproducible color gamut of hematoxylin and eosin stained images in standard color spaces
Wei- Chung Cheng
J Pathol Inform 2020, 11:36 (6 November 2020)
A whole-slide imaging (WSI) system is a digital color imaging system used in digital pathology with the potential to substitute the conventional light microscope. A WSI system digitalizes a glass slide by converting the optical image to digital data with a scanner and then converting the digital data back to the optical image with a display. During the digital-to-optical or optical-to-digital conversion, a color space is required to define the mapping between the digital domain and the optical domain so that the numerical data of each color pixel can be interpreted meaningfully. Unfortunately, many current WSI products do not specify the designated color space clearly, which leaves the user using the universally default color space, sRGB. sRGB is a legacy color space that has a limited color gamut, which is known to be unable to reproduce all color shades present in histology slides. In this work, experiments were conducted to quantitatively investigate the limitation of the sRGB color space used in WSI systems. Eight hematoxylin and eosin (H and E)-stained tissue samples, including human bladder, brain, breast, colon, kidney, liver, lung, and uterus, were measured with a multispectral imaging system to obtain the true colors at the pixel level. The measured color truth of each pixel was converted into the standard CIELAB color space to test whether it was within the color gamut of the sRGB color space. Experiment results show that all the eight images have a portion of pixels outside the sRGB color gamut. In the worst-case scenario, the bladder sample, about 35% of the image exceeded the sRGB color gamut. The results suggest that the sRGB color space is inadequate for WSI scanners to encode H and E-stained whole-slide images, and an sRGB display may have insufficient color gamut for displaying H and E-stained histology images.
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Research Article: Computerized image analysis of tumor cell nuclear morphology can improve patient selection for clinical trials in localized clear cell renal cell carcinoma
In Hwa Um, Lindesay Scott-Hayward, Monique Mackenzie, Puay Hoon Tan, Ravindran Kanesvaran, Yukti Choudhury, Peter D Caie, Min-Han Tan, Marie O’Donnell, Steve Leung, Grant D Stewart, David J Harrison
J Pathol Inform 2020, 11:35 (6 November 2020)
Background: Clinicopathological scores are used to predict the likelihood of recurrence-free survival for patients with clear cell renal cell carcinoma (ccRCC) after surgery. These are fallible, particularly in the middle range. This inevitably means that a significant proportion of ccRCC patients who will not develop recurrent disease enroll into clinical trials. As an exemplar of using digital pathology, we sought to improve the predictive power of “recurrence free” designation in localized ccRCC patients, by precise measurement of ccRCC nuclear morphological features using computational image analysis, thereby replacing manual nuclear grade assessment. Materials and Methods: TNM 8 UICC pathological stage pT1-pT3 ccRCC cases were recruited in Scotland and in Singapore. A Leibovich score (LS) was calculated. Definiens Tissue studio® (Definiens GmbH, Munich) image analysis platform was used to measure tumor nuclear morphological features in digitized hematoxylin and eosin (H&E) images. Results: Replacing human-defined nuclear grade with computer-defined mean perimeter generated a modified Leibovich algorithm, improved overall specificity 0.86 from 0.76 in the training cohort. The greatest increase in specificity was seen in LS 5 and 6, which went from 0 to 0.57 and 0.40, respectively. The modified Leibovich algorithm increased the specificity from 0.84 to 0.94 in the validation cohort. Conclusions: CcRCC nuclear mean perimeter, measured by computational image analysis, together with tumor stage and size, node status and necrosis improved the accuracy of predicting recurrence-free in the localized ccRCC patients. This finding was validated in an ethnically different Singaporean cohort, despite the different H and E staining protocol and scanner used. This may be a useful patient selection tool for recruitment to multicenter studies, preventing some patients from receiving unnecessary additional treatment while reducing the number of patients required to achieve adequate power within neoadjuvant and adjuvant clinical studies.
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Book Review: Review of “artificial intelligence and deep learning in pathology” by Stanley Cohen
Jerome Cheng
J Pathol Inform 2020, 11:34 (6 November 2020)
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Technical Note: (Re) Defining the high-power field for digital pathology
David Kim, Liron Pantanowitz, Peter Schüffler, Dig Vijay Kumar Yarlagadda, Orly Ardon, Victor E Reuter, Meera Hameed, David S Klimstra, Matthew G Hanna
J Pathol Inform 2020, 11:33 (9 October 2020)
Background: The microscope high-power field (HPF) is the cornerstone for histopathology diagnostic evaluation such as the quantification of mitotic figures, lymphocytes, and tumor grading. With traditional light microscopy, HPFs are typically evaluated by quantifying histologic events in 10 fields of view at × 400 magnification. In the era of digital pathology, new variables are introduced that may affect HPF evaluation. The aim of this study was to determine the parameters that influence HPF in whole slide images (WSIs). Materials and Methods: Glass slides scanned on various devices (Leica's Aperio GT450, AT2, and ScanScope XT; Philips UltraFast Scanner; Hamamatsu's Nanozoomer 2.0HT; and 3DHistech's P1000) were compared to acquired digital slides reviewed on each vendor's respective WSI viewer software (e.g., Aperio ImageScope, ImageScope DX, Philips IMS, 3DHistech CaseViewer, and Hamamatsu NDP.view) and an in-house developed vendor-agnostic viewer. WSIs were reviewed at “×40” equivalent HPF on different sized monitors with varying display resolutions (1900 × 1080–4500 × 3000) and aspect ratios (e.g., Food and Drug Administration [FDA]-cleared 27” Philips PS27QHDCR, FDA-cleared 24” Dell MR2416, 24” Hewlett Packard Z24n G2, and 28” Microsoft Surface Studio). Digital and microscopic HPF areas were calculated and compared. Results: A significant variation of HPF area occurred between differing monitor size and display resolutions with minor differences between WSI viewers. No differences were identified by scanner or WSIs scanned at different resolutions (e.g., 0.5, 0.25, 0.24, and 0.12 μm/pixel). Conclusion: Glass slide HPF at × 400 magnification with conventional light microscopy was not equivalent to “×40” digital HPF areas. Digital HPF quantification may vary due to differences in the tissue area displayed by monitor sizes, display resolutions, and WSI viewers but not by scanner or scanning resolution. These findings will need to be further clinically validated with potentially new digital metrics for evaluation.
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Original Article: Comparing deep learning and immunohistochemistry in determining the site of origin for well-differentiated neuroendocrine tumors
Jordan Redemann, Fred A Schultz, Cathy Martinez, Michael Harrell, Douglas P Clark, David R Martin, Joshua A Hanson
J Pathol Inform 2020, 11:32 (9 October 2020)
Background: Determining the site of origin for metastatic well-differentiated neuroendocrine tumors (WDNETs) is challenging, and immunohistochemical (IHC) profiles do not always lead to a definitive diagnosis. We sought to determine if a deep-learning convolutional neural network (CNN) could improve upon established IHC profiles in predicting the site of origin in a cohort of WDNETs from the common primary sites. Materials and Methods: Hematoxylin and eosin (H&E)-stained tissue microarrays (TMAs) were created using 215 WDNETs arising from the known primary sites. A CNN trained and tested on 60% (n = 130) and 40% (n = 85) of these cases, respectively. One hundred and seventy-nine cases had TMA tissue remaining for the IHC analysis. These cases were stained with IHC markers pPAX8, CDX2, SATB2, and thyroid transcription factor-1 (markers of pancreas/duodenum, ileum/jejunum/duodenum, colorectum/appendix, and lung WDNET sites of origin, respectively). The CNN diagnosis was deemed correct if it designated a majority or plurality of the tumor area as the known site of origin. The IHC diagnosis was deemed correct if the most specific marker for a particular site of origin met an H-score threshold determined by two pathologists. Results: When all cases were considered, the CNN correctly identified the site of origin at a lower rate compared to IHC (72% vs. 82%, respectively). Of the 85 cases in the CNN test set, 66 had sufficient TMA material for IHC stains, thus 66 cases were available for a direct case-by-case comparison of IHC versus CNN. The CNN correctly identified 70% of these cases, while IHC correctly identified 76%, a finding that was not statistically significant (P = 0.56). Conclusion: A CNN can identify WDNET site of origin at an accuracy rate close to the current gold standard IHC methods.
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Original Article: UniTwain: A cost-effective solution for lean gross imaging
Hansen Lam, Ricky Kwan, Mark Tuthill, Mehrvash Haghighi
J Pathol Inform 2020, 11:31 (5 October 2020)
Background: Gross imaging of surgical specimens is paramount for the accurate gross examination and diagnosis of disease. Optimized imaging workflow can facilitate consistently high-quality gross photographs, especially in high-volume, metropolitan hospitals such as ours. Most commercial medical gross imaging technology provides ergonomically well-designed hardware, remotely operated cameras, intuitive software interfaces, and automation of workflow. However, these solutions are usually cost-prohibitive and require a large sum of capital budget. Materials and Methods: We applied lean techniques such as value stream mapping (VSM) to design a streamlined and error-free workflow for gross imaging process. We implemented a cost-effective technology, UniTwain, combined with high-resolution webcam to achieve the ideal results. Results: We reduced the mean process time from 600 min to 4.0 min (99.3% decrease in duration); the median process time was reduced from 580 min to 3.0 min. The process efficiency increased from 20% to 100%. The implemented solution has a comparable durability, scalability, and archiving feasibility to commercial medical imaging systems and costs four times less. The only limitations are manual operation of the webcam and lower resolution. The webcam sensors have 8.2 megapixel (MP) resolution, approximately 12 MP less than medical imaging devices. However, we believe that this difference is not visually significant and the effect on gross diagnosis with the naked eye is minimal. Conclusions: To our knowledge, this is the first study that utilized UniTwain as a viable, low-cost solution to streamline the gross imaging workflow. The UniTwain combined with high-resolution webcam could be a suitable alternative for our institution that does not plan to heavily invest in medical imaging.
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ABSTRACTS: What did we expect from Porto's ECDP2020

J Pathol Inform 2020, 11:30 (18 September 2020)
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Original Article: ImageBox 2 – Efficient and rapid access of image tiles from whole-slide images using serverless HTTP range requests
Erich Bremer, Joel Saltz, Jonas S Almeida
J Pathol Inform 2020, 11:29 (10 September 2020)
Background: Whole-slide images (WSI) are produced by a high-resolution scanning of pathology glass slides. There are a large number of whole-slide imaging scanners, and the resulting images are frequently larger than 100,000 × 100,000 pixels which typically image 100,000 to one million cells, ranging from several hundred megabytes to many gigabytes in size. Aims and Objectives: Provide HTTP access over the web to Whole Slide Image tiles that do not have localized tiling servers but only basic HTTP access. Move all image decode and tiling functions to calling agent (ImageBox). Methods: Current software systems require tiling image servers to be installed on systems providing local disk access to these images. ImageBox2 breaks this requirement by accessing tiles from remote HTTP source via byte-level HTTP range requests. This method does not require changing the client software as the operation is relegated to the ImageBox2 server which is local (or remote) to the client and can access tiles from remote images that have no server of their own such as Amazon S3 hosted images. That is, it provides a data service [on a server that does not need to be managed], the definition of serverless execution model increasingly favored by cloud computing infrastructure. Conclusions: The specific methodology described and assessed in this report preserves normal client connection semantics by enabling cloud-friendly tiling, promoting a web of http connected whole-slide images from a wide-ranging number of sources, and providing tiling where local tiling servers would have been otherwise unavailable.
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Original Article: Colorectal cancer detection based on deep learning
Lin Xu, Blair Walker, Peir-In Liang, Yi Tong, Cheng Xu, Yu Chun Su, Aly Karsan
J Pathol Inform 2020, 11:28 (21 August 2020)
Introduction: The initial point in the diagnostic workup of solid tumors remains manual, with the assessment of hematoxylin and eosin (H&E)-stained tissue sections by microscopy. This is a labor-intensive step that requires attention to detail. In addition, diagnoses are influenced by an individual pathologist's knowledge and experience and may not always be reproducible between pathologists. Methods: We introduce a deep learning-based method in colorectal cancer detection and segmentation from digitized H&E-stained histology slides. Results: In this study, we demonstrate that this neural network approach produces median accuracy of 99.9% for normal slides and 94.8% for cancer slides compared to pathologist-based diagnosis on H&E-stained slides digitized from clinical samples. Conclusion: Given that our approach has very high accuracy on normal slides, use of neural network algorithms may provide a screening approach to save pathologist time in identifying tumor regions. We suggest that this new method may be a powerful assistant for colorectal cancer diagnostics.
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Research Article: TissueWand, a rapid histopathology annotation tool
Martin Lindvall, Alexander Sanner, Fredrik Petré, Karin Lindman, Darren Treanor, Claes Lundström, Jonas Löwgren
J Pathol Inform 2020, 11:27 (21 August 2020)
Background: Recent advancements in machine learning (ML) bring great possibilities for the development of tools to assist with diagnostic tasks within histopathology. However, these approaches typically require a large amount of ground truth training data in the form of image annotations made by human experts. As such annotation work is a very time-consuming task, there is a great need for tools that can assist in this process, saving time while not sacrificing annotation quality. Methods: In an iterative design process, we developed TissueWand – an interactive tool designed for efficient annotation of gigapixel-sized histopathological images, not being constrained to a predefined annotation task. Results: Several findings regarding appropriate interaction concepts were made, where a key design component was semi-automation based on rapid interaction feedback in a local region. In a user study, the resulting tool was shown to cause substantial speed-up compared to manual work while maintaining quality. Conclusions: The TissueWand tool shows promise to replace manual methods for early stages of dataset curation where no task-specific ML model yet exists to aid the effort.
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Original Article: LibMI: An open source library for efficient histopathological image processing
Yuxin Dong, Pargorn Puttapirat, Jingyi Deng, Xiangrong Zhang, Chen Li
J Pathol Inform 2020, 11:26 (21 August 2020)
Background: Whole-slide images (WSIs) as a kind of image data are rapidly growing in the digital pathology domain. With unusual high resolution, these images make them hard to be supported by conventional tools or file formats. Thus, it obstructs data sharing and automated analysis. Here, we propose a library, LibMI, along with its open and standardized image file format. They can be used together to efficiently read, write, modify, and annotate large images. Materials and Methods: LibMI utilizes the concept of pyramid image structure and lazy propagation from a segment tree algorithm to support reading and modifying and to guarantee that both operations have linear time complexity. Further, a cache mechanism was introduced to speed up the program. Results: LibMI is an open and efficient library for histopathological image processing. To demonstrate its functions, we applied it to several tasks including image thresholding, microscopic color correction, and storing pixel-wise information on WSIs. The result shows that libMI is particularly suitable for modifying large images. Furthermore, compared with congeneric libraries and file formats, libMI and modifiable multiscale image (MMSI) run 18.237 times faster on read-only tasks. Conclusions: The combination of libMI library and MMSI file format enables developers to efficiently read and modify WSIs, thus can assist in pixel-wise image processing on extremely large images to promote building image processing pipeline. The library together with the data schema is freely available on GitLab:
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Editorial: A synoptic electronic order set for placental pathology: A framework extensible to nonneoplastic pathology
Adela Cimic, Maria Mironova, Scarlett Karakash, Sahussapont Joseph Sirintrapun
J Pathol Inform 2020, 11:25 (21 August 2020)
Accurate pathologic assessment in placental pathology is mostly dependent on a complete clinical history provided by a clinical team. However, often, the necessary clinical information is lacking, and electronic order sets (EOSs), if implemented correctly, create an opportunity for entering consistent and accurate clinical data. In this viewpoint piece, we describe a framework for synoptic EOS in placental pathology. We outline the necessary data and create optional clinical data that get entered as a dropdown menu of free text. While EOSs are the best way to approach and diagnose placenta and other nonneoplastic pathologic specimens, the barriers for implementation include paper requisitions and a cultural mindset resistance. The aspiration for our synoptic EOS is to become an effective tool for communication between proceduralists and pathologists for proper diagnosis of placental specimens. Through our EOS, the appropriate and complete clinical context is conveyed from the clinical teams to the pathologist. The pathologist can easily and rapidly extract the necessary information to render an accurate and precise diagnosis. The captured data likewise become a valuable research resource.
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Letters: Digital pathology during a pandemic
Aleksandar Vodovnik, Tonje Bøyum Riste, Bjørn Ståle Sund
J Pathol Inform 2020, 11:24 (11 August 2020)
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Review Article: Display characteristics and their impact on digital pathology: A current review of pathologists' future “microscope” Highly accessed article
Jacob T Abel, Peter Ouillette, Christopher L Williams, John Blau, Jerome Cheng, Keluo Yao, Winston Y Lee, Toby C Cornish, Ulysses G J Balis, David S McClintock
J Pathol Inform 2020, 11:23 (10 August 2020)
Digital displays (monitors) are an indispensable component of a pathologists' daily workflow, from writing reports, viewing whole-slide images, or browsing the Internet. Due to a paucity of literature and experience surrounding display use and standardization in pathology, the Food and Drug Administration's (FDA) has currently restricted FDA-cleared whole-slide imaging systems to a specific model of display for each system, which at this time consists of only medical-grade (MG) displays. Further, given that a pathologists' display will essentially become their new surrogate “microscope,” it becomes exceedingly important that all pathologists have a basic understanding of fundamental display properties and their functional consequences. This review seeks to: (a) define and summarize the current and emerging display technology, terminology, features, and regulation as they pertain to pathologists and review the current literature on the impact of different display types (e.g. MG vs. consumer off the shelf vs. professional grade) on pathologists' diagnostic performance and (b) discuss the impact of the recent digital pathology device componentization and the coronavirus disease 2019 public emergency on the pixel pathway and display use for remote digital pathology. Display technology has changed dramatically over the past 20 years and continues to change at a rapid rate. There is a paucity of published studies to date that investigate how display type affects pathologist performance, with more research necessary in order to develop standards and minimum specifications for displays in digital pathology. Given the complexity of modern displays, pathologists must become better informed regarding display technology if they wish to have more choice over their future “microscopes.”
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Original Article: A regulatory science initiative to harmonize and standardize digital pathology and machine learning processes to speed up clinical innovation to patients Highly accessed article
Hetal Desai Marble, Richard Huang, Sarah Nixon Dudgeon, Amanda Lowe, Markus D Herrmann, Scott Blakely, Matthew O Leavitt, Mike Isaacs, Matthew G Hanna, Ashish Sharma, Jithesh Veetil, Pamela Goldberg, Joachim H Schmid, Laura Lasiter, Brandon D Gallas, Esther Abels, Jochen K Lennerz
J Pathol Inform 2020, 11:22 (6 August 2020)
Unlocking the full potential of pathology data by gaining computational access to histological pixel data and metadata (digital pathology) is one of the key promises of computational pathology. Despite scientific progress and several regulatory approvals for primary diagnosis using whole-slide imaging, true clinical adoption at scale is slower than anticipated. In the U.S., advances in digital pathology are often siloed pursuits by individual stakeholders, and to our knowledge, there has not been a systematic approach to advance the field through a regulatory science initiative. The Alliance for Digital Pathology ( the Alliance) is a recently established, volunteer, collaborative, regulatory science initiative to standardize digital pathology processes to speed up innovation to patients. The purpose is: (1) to account for the patient perspective by including patient advocacy; (2) to investigate and develop methods and tools for the evaluation of effectiveness, safety, and quality to specify risks and benefits in the precompetitive phase; (3) to help strategize the sequence of clinically meaningful deliverables; (4) to encourage and streamline the development of ground-truth data sets for machine learning model development and validation; and (5) to clarify regulatory pathways by investigating relevant regulatory science questions. The Alliance accepts participation from all stakeholders, and we solicit clinically relevant proposals that will benefit the field at large. The initiative will dissolve once a clinical, interoperable, modularized, integrated solution (from tissue acquisition to diagnostic algorithm) has been implemented. In times of rapidly evolving discoveries, scientific input from subject-matter experts is one essential element to inform regulatory guidance and decision-making. The Alliance aims to establish and promote synergistic regulatory science efforts that will leverage diverse inputs to move digital pathology forward and ultimately improve patient care.
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Original Article: Improving critical value notification through secure text messaging
Terrance James Lynn, Jordan Erik Olson
J Pathol Inform 2020, 11:21 (6 August 2020)
Background: To improve communication between clinical providers and the laboratory, we recently implemented secure text messaging for our critical value notifications. This was done to communicate laboratory critical values (CV) to providers faster so changes to patient care could be done faster. Our previous method of communicating CV to providers was paging and relied on a call back to receive the critical value. Methods: We implemented delivery of CV through a secure texting application in which the CV was directly communicated to the provider on their smart phone device. Results: The mean pre-implementation turnaround time (TAT) was 11.3 minutes (median: 7 minutes, range: 0 - 210 minutes). The mean post- secure text messaging implementation TAT was 3.03 minutes (median: 0.89 minutes, range: < 1 - 95 minutes).When comparing pre- and post-implementation, there was a significant reduction in the TAT from using secure text messaging (p < 0.001). Of the 234 surveys sent out, 81 providers responded (35%). Of these responses, 85% reported that critical value notification by secure text messaging has increased their efficiency and 95% reported that critical value notification is more effective than a pager-phone-call based system. 83% of providers reported that they were able to provide better, faster care to their patients. Conclusions: Using secure text messaging (STM) to deliver critical values significantly reduces the CV TAT. Furthermore, providers noted they preferred to receive CV notifications through STM and reported that they were able to provide more effective care to their patients.
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Original Article: Whole-slide imaging allows pathologists to work remotely in regions with severe logistical constraints due to Covid-19 pandemic
Daniel S Liscia, Donata Bellis, Elena Biletta, Mariangela D’Andrea, Giorgio A Croci, Umberto Dianzani
J Pathol Inform 2020, 11:20 (28 July 2020)
Introduction: In this study, we report on our experience using digital pathology to overcome the severe limitations imposed on health care by the Covid-19 outbreak in Northern Italy. Social distancing had a major impact on public transportation, causing it to run with reduced timetables. This resulted in a major challenge for hospital commuters. To limit the presence in our hospital of no more than two pathologists at a time out of four, a web-based digital pathology system (DPS) was employed to work remotely. Subjects and Methods: We used a DPS in which a scanner, a laboratory information system, a storage device, and a web server were interfaced so that tissue slides could be viewed over the Internet by whole-slide imaging (WSI). After a brief internal verification test, the activity on the DPS was recorded, taking track of a set of performance and efficiency indicators. At the end of the study, 405 cases were signed out remotely. Results: Of 693 cases, 58.4% were signed out remotely by WSI, while 8.4% needed to be kept on hold to return to the original microscope slide. In three cases, at least one slide had to be rescanned. In eight cases, one slide was recut. Panel discussion by WSI was necessary in 34 cases, a condition in which all pathologists were asked for their opinion. A consultation with a more experienced colleague was necessary in 17 cases. Conclusions: We show that WSI easily allows pathologists to overcome the problems caused by the severe social distancing measures imposed by the Covid-19 pandemic. Our experience shows that soon there will not be alternatives to digital pathology, given that there is no assurance that other similar outbreaks will not occur.
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Research Article: Deep learning to estimate human epidermal growth factor receptor 2 status from hematoxylin and eosin-stained breast tissue images
Deepak Anand, Nikhil Cherian Kurian, Shubham Dhage, Neeraj Kumar, Swapnil Rane, Peter H Gann, Amit Sethi
J Pathol Inform 2020, 11:19 (24 July 2020)
Context: Several therapeutically important mutations in cancers are economically detected using immunohistochemistry (IHC), which highlights the overexpression of specific antigens associated with the mutation. However, IHC panels can be imprecise and relatively expensive in low-income settings. On the other hand, although hematoxylin and eosin (H&E) staining used to visualize the general tissue morphology is a routine and low cost, it does not highlight any specific antigen or mutation. Aims: Using the human epidermal growth factor receptor 2 (HER2) mutation in breast cancer as an example, we strengthen the case for cost-effective detection and screening of overexpression of HER2 protein in H&E-stained tissue. Settings and Design: We use computational methods that reliably detect subtle morphological changes associated with the over-expression of mutation-specific proteins directly from H&E images. Subjects and Methods: We trained a classification pipeline to determine HER2 overexpression status of H&E stained whole slide images. Our training dataset was derived from a single hospital containing 26 (11 HER2+ and 15 HER2–) cases. We tested the classification pipeline on 26 (8 HER2+ and 18 HER2–) held-out cases from the same hospital and 45 independent cases (23 HER2+ and 22 HER2–) from the TCGA-BRCA cohort. The pipeline was composed of a stain separation module and three deep neural network modules in tandem for robustness and interpretability. Statistical Analysis Used: We evaluate our trained model through area under the curve (AUC)-receiver operating characteristic. Results: Our pipeline achieved an AUC of 0.82 (confidence interval [CI]: 0. 65–0. 98) on held-out cases and an AUC of 0.76 (CI: 0. 61–0. 89) on the independent dataset from TCGA. We also demonstrate the region-level correspondence of HER2 overexpression between a patient's IHC and H&E serial sections. Conclusions: Our work strengthens the case for automatically quantifying the overexpression of mutation-specific proteins in H&E-stained digital pathology, and it highlights the importance of multi-stage machine learning pipelines for added robustness and interpretability.
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Commentary: Commentary: Impact of digital pathology in the field of intraoperative neuropathology: Master the tool
Albino Eccher, Ilaria Girolami
J Pathol Inform 2020, 11:18 (16 July 2020)
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Technical Note: A point-of-use quality assurance tool for digital pathology remote working
Alexander I Wright, Emily L Clarke, Catriona M Dunn, Bethany J Williams, Darren E Treanor, David S Brettle
J Pathol Inform 2020, 11:17 (16 July 2020)
Pathology services are facing pressures due to the COVID-19 pandemic. Digital pathology has the capability to meet some of these unprecedented challenges by allowing remote diagnoses to be made at home, during periods of social distancing or self-isolation. However, while digital pathology allows diagnoses to be made on standard computer screens, unregulated home environments may not be conducive for optimal viewing conditions. There is also a paucity of experimental evidence available to support the minimum display requirements for digital pathology. This study presents a Point-of-Use Quality Assurance (POUQA) tool for remote assessment of viewing conditions for reporting digital pathology slides. The tool is a psychophysical test combining previous work from successfully implemented quality assurance tools in both pathology and radiology to provide a minimally intrusive display screen validation task, before viewing digital slides. The test is specific to pathology assessment in that it requires visual discrimination between colors derived from hematoxylin and eosin staining, with a perceptual difference of ±1 delta E (dE). This tool evaluates the transfer of a 1 dE signal through the digital image display chain, including the observers' contrast and color responses within the test color range. The web-based system has been rapidly developed and deployed as a response to the COVID-19 pandemic and may be used by anyone in the world to help optimize flexible working conditions at: earch/systems/pouqa/.
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Editorial: Is the time right to start using digital pathology and artificial intelligence for the diagnosis of lymphoma?
Mohamed E Salama, William R Macon, Liron Pantanowitz
J Pathol Inform 2020, 11:16 (26 June 2020)
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Editorial: The future of pathology: What can we learn from the COVID-19 pandemic?
Bethany J Williams, Filippo Fraggetta, Matthew G Hanna, Richard Huang, Jochen Lennerz, Roberto Salgado, S Joseph Sirintrapun, Liron Pantanowitz, Anil Parwani, Mark Zarella, Darren E Treanor
J Pathol Inform 2020, 11:15 (9 June 2020)
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Research Article: Bridging the collaboration gap: Real-time identification of clinical specimens for biomedical research
Thomas J S Durant, Guannan Gong, Nathan Price, Wade L Schulz
J Pathol Inform 2020, 11:14 (20 May 2020)
Introduction: Biomedical and translational research often relies on the evaluation of patients or specimens that meet specific clinical or laboratory criteria. The typical approach used to identify biospecimens is a manual, retrospective process that exists outside the clinical workflow. This often makes biospecimen collection cost prohibitive and prevents the collection of analytes with short stability times. Emerging data architectures offer novel approaches to enhance specimen-identification practices. To this end, we present a new tool that can be deployed in a real-time environment to automate the identification and notification of available biospecimens for biomedical research. Methods: Real-time clinical and laboratory data from Cloverleaf (Infor, NY, NY) were acquired within our computational health platform, which is built on open-source applications. Study-specific filters were developed in NiFi (Apache Software Foundation, Wakefield, MA, USA) to identify the study-appropriate specimens in real time. Specimen metadata were stored in Elasticsearch (Elastic N. V., Mountain View, CA, USA) for visualization and automated alerting. Results: Between June 2018 and December 2018, we identified 2992 unique specimens belonging to 2815 unique patients, split between two different use cases. Based on laboratory policy for specimen retention and study-specific stability requirements, secure E-mail notifications were sent to investigators to automatically notify of availability. The assessment of throughput on commodity hardware demonstrates the ability to scale to approximately 2000 results per second. Conclusion: This work demonstrates that real-world clinical data can be analyzed in real time to increase the efficiency of biospecimen identification with minimal overhead for the clinical laboratory. Future work will integrate additional data types, including the analysis of unstructured data, to enable more complex cases and biospecimen identification.
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Original Article: The next generation robotic microscopy for intraoperative teleneuropathology consultation
Swikrity Upadhyay Baskota, Clayton Wiley, Liron Pantanowitz
J Pathol Inform 2020, 11:13 (23 April 2020)
Introduction: Teleneuropathology at our institution evolved over the last 17 years from using static to dynamic robotic microscopy. Historically (2003–2007), using older technology, the deferral rate was 19.7%, and the concordance was 81% with the final diagnosis. Two years ago, we switched to use hybrid robotic devices to perform these intraoperative (IO) consultations because our older devices were obsolete. The aim of this study was to evaluate the impact this change had on our deferral and concordance rates with teleneuropathology using this newer instrument. Materials and Methods: Aperio LV1 4-slide capacity hybrid robotic scanners with an attached desktop console (Leica Biosystems, Vista, CA, USA) and GoToAssist (v4.5.0.1620, Boston, MA, USA) were used for IO telepathology cases. A cross-sectional comparative study was conducted comparing teleneuropathology from three remote hospitals (193 cases) to IO neuropathology consultation performed by conventional glass slide examination at a light microscope (310 cases) from the host hospital. Deferral and concordance rates were compared to final histopathological diagnoses. Results: The deferral rate for IO teleneuropathology was 26% and conventional glass slide 24.24% (P = 0.58). The concordance rate for teleneuropathology was 93.94%, which was slightly higher than 89.09% for conventional glass slides (P = 0.047). Conclusion: The new hybrid robotic device for performing IO teleneuropathology interpretations at our institution was as effective as conventional glass slide interpretation. While we did observe a noticeable change in the deferral rate compared to prior years, we did appreciate the marked improvement of the concordance rate using this new hybrid scanner.
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Guidelines: Guidance for remote reporting of digital pathology slides during periods of exceptional service pressure: An emergency response from the UK royal college of pathologists Highly accessed article
Bethany Jill Williams, David Brettle, Muhammad Aslam, Paul Barrett, Gareth Bryson, Simon Cross, David Snead, Clare Verrill, Emily Clarke, Alexander Wright, Darren Treanor
J Pathol Inform 2020, 11:12 (17 April 2020)
Pathology departments must rise to new staffing challenges caused by the coronavirus disease-19 pandemic and may need to work more flexibly for the foreseeable future. In light of this, many pathologists and departments are considering the merits of remote or home reporting of digital cases. While some individuals have experience of this, little work has been done to determine optimum conditions for home reporting, including technical and training considerations. In this publication produced in response to the pandemic, we provide information regarding risk assessment of home reporting of digital slides, summarize available information on specifications for home reporting computing equipment, and share access to a novel point-of-use quality assurance tool for assessing the suitability of home reporting screens for digital slide diagnosis. We hope this study provides a useful starting point and some practical guidance in a difficult time. This study forms the basis of the guidance issued by the Royal College of Pathologists, available at:
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Erratum: Erratum: Guidelines from the Canadian Association of Pathologists for Establishing a Telepathology Service for Anatomic Pathology Using Whole-slide Imaging

J Pathol Inform 2020, 11:11 (10 April 2020)
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