Complete digital pathology transition: A large multi-center experience.

INTRODUCTION: Transitioning from glass slide pathology to digital pathology for primary diagnostics requires an appropriate laboratory information system, an image management system, and slide scanners; it also reinforces the need for sophisticated pathology informatics including synoptic reporting. Previous reports have discussed the transition itself and relevant considerations for it, but not the selection criteria and considerations for the infrastructure. OBJECTIVE: To describe the process used to evaluate slide scanners, image management systems, and synoptic reporting systems for a large multisite institution. METHODS: Six network hospitals evaluated six slide scanners, three image management systems, and three synoptic reporting systems. Scanners were evaluated based on the quality of image, speed, ease of operation, and special capabilities (including z-stacking, fluorescence and others). Image management and synoptic reporting systems were evaluated for their ease of use and capacity. RESULTS: Among the scanners evaluated, the Leica GT450 produced the highest quality images, while the 3DHistech Pannoramic provided fluorescence and superior z-stacking. The newest generation of scanners, released relatively recently, performed better than slightly older scanners from major manufacturers Although the Olympus VS200 was not fully vetted due to not meeting all inclusion criteria, it is discussed herein due to its exceptional versatility. For Image Management Software, the authors believe that Sectra is, at the time of writing the best developed option, but this could change in the very near future as other systems improve their capabilities. All synoptic reporting systems performed impressively. CONCLUSIONS: Specifics regarding quality and abilities of different components will change rapidly with time, but large pathology practices considering such a transition should be aware of the issues discussed and evaluate the most current generation to arrive at appropriate conclusions.

Non-invasive scoring of cellular atypia in keratinocyte cancers in 3D LC-OCT images using Deep Learning.

Diagnosis based on histopathology for skin cancer detection is today's gold standard and relies on the presence or absence of biomarkers and cellular atypia. However it suffers drawbacks: it requires a strong expertise and is time-consuming. Moreover the notion of atypia or dysplasia of the visible cells used for diagnosis is very subjective, with poor inter-rater agreement reported in the literature. Lastly, histology requires a biopsy which is an invasive procedure and only captures a small sample of the lesion, which is insufficient in the context of large fields of cancerization. Here we demonstrate that the notion of cellular atypia can be objectively defined and quantified with a non-invasive in-vivo approach in three dimensions (3D). A Deep Learning (DL) algorithm is trained to segment keratinocyte (KC) nuclei from Line-field Confocal Optical Coherence Tomography (LC-OCT) 3D images. Based on these segmentations, a series of quantitative, reproducible and biologically relevant metrics is derived to describe KC nuclei individually. We show that, using those metrics, simple and more complex definitions of atypia can be derived to discriminate between healthy and pathological skins, achieving Area Under the ROC Curve (AUC) scores superior than 0.965, largely outperforming medical experts on the same task with an AUC of 0.766. All together, our approach and findings open the door to a precise quantitative monitoring of skin lesions and treatments, offering a promising non-invasive tool for clinical studies to demonstrate the effects of a treatment and for clinicians to assess the severity of a lesion and follow the evolution of pre-cancerous lesions over time.

Recent technical advances in whole slide imaging instrumentation.

Microscopic observation of biological specimen smears is the mainstay of diagnostic pathology, as defined by the Digital Pathology Association. Though automated systems for this are commercially available, their bulky size and high cost renders them unusable for remote areas. The research community is investing much effort towards building equivalent but portable, low-cost systems. An overview of such research is presented here, including a comparative analysis of recent reports. This paper also reviews recently reported systems for automated staining and smear formation, including microfluidic devices; and optical and computational automated microscopy systems including smartphone-based devices. Image pre-processing and analysis methods for automated diagnosis are also briefly discussed. It concludes with a set of foreseeable research directions that could lead to affordable, integrated and accurate whole slide imaging systems.

Diagnosis of some diseases such as cervical cancer is done using a microscope, and this process still relies heavily on human experts. Since the need for such diagnosis is increasing at a rapid pace, it makes a lot of sense to automate the whole process. This requires automatic microscopes, which should be able to take images of a 'slide' - a glass slab with colorized human cells at its surface. These images should get analyzed by a software, resulting in a fully automated diagnosis. This article reviews recent research into this field, especially the technical advances on the hardware for automated microscopes (also known as slide imagers). It compares research reports and highlights how there's still more effort needed to build low-cost, yet clinically useful systems. It also highlights some of the emerging technologies that can be integrated into slide imagers to enable new kinds of diagnostics.

Verification of the ACL Top 50 Family (350, 550, and 750) for Harmonization of Routine Coagulation Assays in a Large Network of 60 Laboratories.

OBJECTIVES: To verify a single platform of hemostasis instrumentation, the ACL TOP 50 Family, comprising 350, 550, and 750 instruments, across a large network of 60 laboratories. METHODS: Comparative evaluations of instrument classes (350 vs 550 and 750) were performed using a large battery of test samples for routine coagulation tests, comprising prothrombin time/international normalized ratio, activated partial thromboplastin time (APTT), thrombin time, fibrinogen and D-dimer, and using HemosIL reagents. Comparisons were also made against existing equipment (Diagnostica Stago Satellite, Compact, and STA-R Evolution) and existing reagents to satisfy national accreditation standards. Verification of manufacturer normal reference ranges (NRRs) and generation of an APTT heparin therapeutic range were undertaken. RESULTS: The three instrument types were verified as a single instrument class, which will permit standardization of methods and NRRs across all instruments (n = 75) to be deployed in 60 laboratories. In particular, ACL TOP 350 test result data were similar to ACL TOP 550 and 750 and showed no to limited bias. All manufacturer NRRs were verified with occasional minor variance. CONCLUSIONS: This ACL TOP 50 Family (350, 550, and 750) verification will enable harmonization of routine coagulation across all laboratories in the largest public pathology network in Australia.

Artificial intelligence in dermatopathology: Diagnosis, education, and research.

Artificial intelligence (AI) utilizes computer algorithms to carry out tasks with human-like intelligence. Convolutional neural networks, a type of deep learning AI, can classify basal cell carcinoma, seborrheic keratosis, and conventional nevi, highlighting the potential for deep learning algorithms to improve diagnostic workflow in dermatopathology of highly routine diagnoses. Additionally, convolutional neural networks can support the diagnosis of melanoma and may help predict disease outcomes. Capabilities of machine learning in dermatopathology can extend beyond clinical diagnosis to education and research. Intelligent tutoring systems can teach visual diagnoses in inflammatory dermatoses, with measurable cognitive effects on learners. Natural language interfaces can instruct dermatopathology trainees to produce diagnostic reports that capture relevant detail for diagnosis in compliance with guidelines. Furthermore, deep learning can power computation- and population-based research. However, there are many limitations of deep learning that need to be addressed before broad incorporation into clinical practice. The current potential of AI in dermatopathology is to supplement diagnosis, and dermatopathologist guidance is essential for the development of useful deep learning algorithms. Herein, the recent progress of AI in dermatopathology is reviewed with emphasis on how deep learning can influence diagnosis, education, and research.

Development of Functional Requirements for Ex Vivo Pathology Applications of In Vivo Microscopy Systems: A Proposal From the In Vivo Microscopy Committee of the College of American Pathologists.

CONTEXT.­: In vivo microscopy (IVM) allows direct, real-time visualization of tissue histology in living patients without the need for tissue removal, processing, or staining. The IVM technologies in clinical use include confocal microscopy and optical coherence tomography. These technologies also show promise for use with pathology specimens (ex vivo microscopy [EVM]). However, few systems designed for EVM are commercially available, at least in part because of the lack of defined minimal functional requirements (FRs). OBJECTIVE.­: To develop minimal FRs for likely high-volume pathology applications of EVM. DESIGN.­: The IVM Committee of the College of American Pathologists identified potential EVM pathology applications based on the published literature. A subcommittee of IVM and EVM early adopters and experts then defined FRs for the most likely EVM applications. RESULTS.­: Potential EVM applications include assessment of margins, adequacy of needle biopsies and aspirates for diagnosis, and transplant tissues; selection of tissue for molecular studies or biorepository; and guidance in block selection from gross specimens. The first 3 applications were selected for development of FRs. The FRs were identified based on existing laboratory practices and guidelines and input from experts in the field and included device footprint and portability, specimen preparation, imaging time, field of view or resolution, morphologic diagnostic capability, yield, accuracy, ease of use, safety, and cost. CONCLUSIONS.­: Consensus was achieved on FRs that would accommodate the selected EVM applications. Publication and dissemination of those FRs will provide guidance to engineers, researchers, and vendors on how to optimally adapt IVM technologies for EVM for widespread adoption by pathologists.

The Emergence of Microphysiological Systems (Organs-on-chips) as Paradigm-changing Tools for Toxicologic Pathology.

Microphysiological systems (MPS), commonly known as organs-on-chips, are a rapidly advancing technology that promises to impact many areas of medical and toxicological pathology. In this minireview, the history of MPS and its potential utility in safety assessment are described with the toxicologic pathologist in mind. Several MPS development focus areas are defined, and recent progress in the area is highlighted. MPS will likely become an important tool for the toxicologic pathologist as part of our role in the safety assessment process within the pharmaceutical, biotechnology, medical device, and cosmetic and agrichemical industries.

Nasal cytology as a screening tool in formaldehyde-exposed workers.

Background: Workers in pathology and anatomy laboratories may be exposed to formaldehyde. An evaluation of the early effects of this substance is, therefore, paramount. This preliminary study was conducted to evaluate if nasal cytology could be used as a tool to detect changes in nasal mucosa in workers exposed to formaldehyde. Aims: To assess whether nasal cytology was able to reveal any alteration of nasal mucosa in workers exposed to formaldehyde compared to unexposed subjects, and to ascertain whether a specific pattern of alterations correlated with years of exposure in order to evaluate long-term occupational exposure effects. Methods: The study included a group of workers exposed to formaldehyde and a group of non-exposed workers. All subjects underwent clinical examination, followed by nasal cytology. Pathological indices from each rhinocytograms were compared between the two groups. Results: Nasal cytology revealed a chronic inflammatory non-allergic condition in the exposed group. Qualitative analysis of data distribution of neutrophils and mucous-secreting/ciliated cells ratio showed data clustering with a cut-off set at 15 years of exposure. The mean formaldehyde concentrations ranged from <0.04 to 0.15 parts per million (ppm). The maximum levels of formaldehyde concentrations ranged from 0.2 to 0.67 ppm. Conclusions: Our data indicate that nasal cytology may be a promising tool for the health surveillance of workers exposed to formaldehyde and may also represent a useful research tool for the study of the health effects of other chemicals irritants for the upper airways.

Augmented Reality Technology Using Microsoft HoloLens in Anatomic Pathology.

Context Augmented reality (AR) devices such as the Microsoft HoloLens have not been well used in the medical field. Objective To test the HoloLens for clinical and nonclinical applications in pathology. Design A Microsoft HoloLens was tested for virtual annotation during autopsy, viewing 3D gross and microscopic pathology specimens, navigating whole slide images, telepathology, as well as real-time pathology-radiology correlation. Results Pathology residents performing an autopsy wearing the HoloLens were remotely instructed with real-time diagrams, annotations, and voice instruction. 3D-scanned gross pathology specimens could be viewed as holograms and easily manipulated. Telepathology was supported during gross examination and at the time of intraoperative consultation, allowing users to remotely access a pathologist for guidance and to virtually annotate areas of interest on specimens in real-time. The HoloLens permitted radiographs to be coregistered on gross specimens and thereby enhanced locating important pathologic findings. The HoloLens also allowed easy viewing and navigation of whole slide images, using an AR workstation, including multiple coregistered tissue sections facilitating volumetric pathology evaluation. Conclusions The HoloLens is a novel AR tool with multiple clinical and nonclinical applications in pathology. The device was comfortable to wear, easy to use, provided sufficient computing power, and supported high-resolution imaging. It was useful for autopsy, gross and microscopic examination, and ideally suited for digital pathology. Unique applications include remote supervision and annotation, 3D image viewing and manipulation, telepathology in a mixed-reality environment, and real-time pathology-radiology correlation.

Medical Devices; Hematology and Pathology Devices; Classification of the Whole Slide Imaging System. Final order.

The Food and Drug Administration (FDA or we) is classifying the whole slide imaging system into class II (special controls). The special controls that apply to the device type are identified in this order and will be part of the codified language for the whole slide imaging system's classification. We are taking this action because we have determined that classifying the device into class II (special controls) will provide a reasonable assurance of safety and effectiveness of the device. We believe this action will also enhance patients' access to beneficial innovative devices, in part by reducing regulatory burdens.

Medical Devices; Hematology and Pathology Devices; Classification of a Cervical Intraepithelial Neoplasia Test System. Final order.

The Food and Drug Administration (FDA or we) is classifying the cervical intraepithelial neoplasia (CIN) test system into class II (special controls). The special controls that apply to the device type are identified in this order and will be part of the codified language for the CIN test system's classification. We are taking this action because we have determined that classifying the device into class II (special controls) will provide a reasonable assurance of safety and effectiveness of the device. We believe this action will also enhance patients' access to beneficial innovative devices, in part by reducing regulatory burdens.

Super-resolution structured illumination in optically thick specimens without fluorescent tagging.

This research extends the work of Hoffman et al. to provide both sectioning and super-resolution using random patterns within thick specimens. Two methods of processing structured illumination in reflectance have been developed without the need for a priori knowledge of either the optical system or the modulation patterns. We explore the use of two deconvolution algorithms that assume either Gaussian or sparse priors. This paper will show that while both methods accomplish their intended objective, the sparse priors method provides superior resolution and contrast against all tested targets, providing anywhere from ∼1.6× to ∼2× resolution enhancement. The methods developed here can reasonably be implemented to work without a priori knowledge about the patterns or point spread function. Further, all experiments are run using an incoherent light source, unknown random modulation patterns, and without the use of fluorescent tagging. These additional modifications are challenging, but the generalization of these methods makes them prime candidates for clinical application, providing super-resolved noninvasive sectioning in vivo.

El patólogo intervencionista. Punción aspiración con aguja fina «ecoguiada» realizada por citopatólogo. Una realidad en España / The interventional pathologist. Ultrasound guided fine needle aspiration performed by cytopathologists. Now a reality in Spain

Introducción. El desarrollo y perfeccionamiento de la ecografía a partir de los setenta supuso un gran avance en el ámbito de la punción aspiración con aguja fina (PAAF), posibilitando localizar lesiones no palpables y minimizar complicaciones. El uso de PAAF ecoguiada trajo como consecuencia que dicha técnica se desplazara por motivos logísticos de los servicios de anatomía patológica a los servicios de radiología. El «alejamiento del patólogo» trajo como consecuencia numerosos inconvenientes. Con la finalidad de recuperar el territorio perdido y optimizar el procedimiento se inició una experiencia pionera —y hasta donde sabemos única España— en el Servicio de Anatomía Patológica del Hospital Universitario Central de Asturias (HUCA) con la PAAF ecoguiada realizada por citopatólogo. Método. Se cuantificaron todas las PAAF realizadas en el HUCA desde el 1 de julio de 2015 hasta el 30 de junio de 2016. Se procedió a clasificarlas dependiendo de si fueron PAAF ecoguiadas realizadas por patólogo o PAAF no realizada por patólogo, teniendo como principal criterio si fueron valorables o insuficientes. Resultados. Casi la mitad de las PAAF efectuadas fueron realizadas por citopatólogo (923). Las PAAF ecoguiadas realizadas por patólogo superaron en rendimiento diagnóstico a las PAAF no realizadas por patólogo. En todas las localizaciones anatómicas comprables, la PAAF ecoguiada realizada por patólogo tuvo un menor porcentaje de muestras insuficientes (4,33%) en comparación con la PAAF no realizada por patólogo (12,05%). Conclusión. El citopatólogo adecuadamente adiestrado es capaz de realiza PAAF ecoguiada con excelentes resultados. Los buenos resultados obtenidos han traído como consecuencia el aumento progresivo del número de PAAF solicitadas para llevar a cabo en el Servicio de Anatomía Patológica (AU)

Introduction. The development and improvement of ultrasound from the seventies has caused a breakthrough in fine needle aspiration (FNA), allowing the location of non-palpable lesions and minimizing complications. For logistic reasons, ultrasound-guided-FNA (US-FNA) is carried out in the department of radiology. However, the distance from the pathologist has many disadvantages. In order to correct this and thus optimize the procedure, the Department of Pathology at the University Hospital of Asturias (Hospital Universitario Central de Asturias [HUCA]) has initiated, for the first time in Spain, the Ultrasound-Guided-FNA Performed by Cytopathologists programme. We present our experience so far. Method. FNA performed at HUCA were quantified from July 1st 2015 to June 30th 2016. FNA were classified as US-FNA-cytopathologists or US-FNA-without cytopathologists. Criteria of sufficient and insufficient samples were taken into account. Results. Almost half of the FNA were made by cytopathologists (923). The performance of US-FNA-cytopathologists was better than US-FNA-without cytopathologists. US-FNA-cytopathologists had a lower percentage of inadequate samples (4.33%) compared to FNA carried out by non cytopathologists (12.05%). Conclusion. Adequately trained cytopathologists can perform US-FNA with excellent results. Our positive experience has resulted in an increase in the number of requests for FNA to be carried out in the Department of Pathology (AU)

Acceptability of the Cytosponge procedure for detecting Barrett's oesophagus: a qualitative study.

OBJECTIVE: To investigate the acceptability of the Cytosponge, a novel sampling device to detect Barrett's oesophagus (BE), a precursor to oesophageal adenocarcinoma (EAC), among people with risk factors for this condition. DESIGN: A qualitative study using semistructured interviews and focus group discussions. Data were explored by three researchers using thematic analysis. SETTING: Community setting in London, UK. PARTICIPANTS: A recruitment company identified 33 adults (17 men, 16 women) aged 50-69 years with gastro-oesophageal reflux disease (GERD), a risk factor for BE. The majority of participants were white British (73%). The focus groups were stratified by gender and education. 10 individuals were interviewed and 23 participated in four focus groups. RESULTS: 3 key themes emerged from the data: the anticipated physical experience, preferences for the content of information materials and comparisons with the current gold-standard test. Overall acceptability was high, but there was initial concern about the physical experience of taking the test, including swallowing and extracting the Cytosponge. These worries were reduced after handling the device and a video demonstration of the procedure. Knowledge of the relationship between GERD, BE and EAC was poor, and some suggested they would prefer not to know about the link when being offered the Cytosponge. Participants perceived the Cytosponge to be more comfortable, practical and economical than endoscopy. CONCLUSIONS: These qualitative data suggest the Cytosponge was acceptable to the majority of participants with risk factors for BE, and could be used as a first-line test to investigate GERD symptoms. Concerns about the physical experience of the test were alleviated through multimedia resources. The development of patient information materials is an important next step to ensuring patients are adequately informed and reassured about the procedure. Patient stakeholders should be involved in this process to ensure their concerns and preferences are considered. TRIAL REGISTRATION NUMBER: ISRCTN68382401; pre-results.

Assisting the examination of large histopathological slides with adaptive forests.

The examination of biopsy samples plays a central role in the diagnosis and staging of numerous diseases, including most cancer types. However, because of the large size of the acquired images, the localization and quantification of diseased portions of a tissue is usually time-consuming, as pathologists must scroll through the whole slide to look for objects of interest which are often only scarcely distributed. In this work, we introduce an approach to facilitate the visual inspection of large digital histopathological slides. Our method builds on a random forest classifier trained to segment the structures sought by the pathologist. However, moving beyond the pixelwise segmentation task, our main contribution is an interactive exploration framework including: (i) a region scoring function which is used to rank and sequentially display regions of interest to the user, and (ii) a relevance feedback capability which leverages human annotations collected on each suggested region. Thereby, an online domain adaptation of the learned pixelwise segmentation model is performed, so that the region scores adapt on-the-fly to possible discrepancies between the original training data and the slide at hand. Three real-time update strategies are compared, including a novel approach based on online gradient descent which supports faster user interaction than an accurate delineation of objects. Our method is evaluated on the task of extramedullary hematopoiesis quantification within mouse liver slides. We assess quantitatively the retrieval abilities of our approach and the benefit of the interactive adaptation scheme. Moreover, we demonstrate the possibility of extrapolating, after a partial exploration of the slide, the surface covered by hematopoietic cells within the whole tissue.

Microscopy with ultraviolet surface excitation for rapid slide-free histology.

Histological examination of tissues is central to the diagnosis and management of neoplasms and many other diseases and is a foundational technique for preclinical and basic research. However, commonly used bright-field microscopy requires prior preparation of micrometre-thick tissue sections mounted on glass slides-a process that can require hours or days, contributes to cost and delays access to critical information. Here, we introduce a simple, non-destructive slide-free technique that, within minutes, provides high-resolution diagnostic histological images resembling those obtained from conventional haematoxylin and eosin histology. The approach, which we named microscopy with ultraviolet surface excitation (MUSE), can also generate shape and colour-contrast information. MUSE relies on ~280 nm ultraviolet light to restrict the excitation of conventional fluorescent stains to tissue surfaces and it has no significant effects on downstream molecular assays (including fluorescence in situ hybridization and RNA sequencing). MUSE promises to improve the speed and efficiency of patient care in both state-of-the-art and low-resource settings and to provide opportunities for rapid histology in research.