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Renal amyloidosis is a rare condition caused by the progressive accumulation of misfolded proteins within glomeruli, vessels, and interstitium, causing functional decline and requiring prompt treatment due to its significant morbidity and mortality. Congo red (CR) stain on renal biopsy samples is the gold standard for diagnosis, but the need for polarized light is limiting the digitization of this nephropathology field. This study explores the feasibility and reliability of CR fluorescence on virtual slides (CRFvs) in evaluating the diagnostic accuracy and proposing an automated digital pipeline for its assessment. Whole-slide images from 154 renal biopsies with CR were scanned through a Texas red fluorescence filter (NanoZoomer S60, Hamamatsu) at the digital Nephropathology Center of the Istituto di Ricovero e Cura a Carattere Scientifico San Gerardo, Monza, Italy, and evaluated double-blinded for the detection and quantification through the amyloid score and a custom ImageJ pipeline was built to automatically detect amyloid-containing regions. Interobserver agreement for CRFvs was optimal (k = 0.90; 95% CI, 0.81-0.98), with even better concordance when consensus-based CRFvs evaluation was compared to the standard CR birefringence (BR) (k = 0.98; 95% CI, 0.93-1). Excellent performance was achieved in the assessment of amyloid score overall by CRFvs (weighted k = 0.70; 95% CI, 0.08-1), especially within the interstitium (weighted k = 0.60; 95% CI, 0.35-0.84), overcoming the misinterpretation of interstitial and capsular collagen BR. The application of an automated digital pathology pipeline (Streamlined Pipeline for Amyloid detection through CR fluorescence Digital Analysis, SPADA) further increased the performance of pathologists, leading to a complete concordance with the standard BR. This study represents an initial step in the validation of CRFvs, demonstrating its general reliability in a digital nephropathology center. The computational method used in this study has the potential to facilitate the integration of spatial omics and artificial intelligence tools for the diagnosis of amyloidosis, streamlining its detection process., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Computational pathology can significantly benefit from ontologies to standardize the employed nomenclature and help with knowledge extraction processes for high-quality annotated image datasets. The end goal is to reach a shared model for digital pathology to overcome data variability and integration problems. Indeed, data annotation in such a specific domain is still an unsolved challenge and datasets cannot be steadily reused in diverse contexts due to heterogeneity issues of the adopted labels, multilingualism, and different clinical practices., Material and Methods: This paper presents the ExaMode ontology, modeling the histopathology process by considering 3 key cancer diseases (colon, cervical, and lung tumors) and celiac disease. The ExaMode ontology has been designed bottom-up in an iterative fashion with continuous feedback and validation from pathologists and clinicians. The ontology is organized into 5 semantic areas that defines an ontological template to model any disease of interest in histopathology., Results: The ExaMode ontology is currently being used as a common semantic layer in: (i) an entity linking tool for the automatic annotation of medical records; (ii) a web-based collaborative annotation tool for histopathology text reports; and (iii) a software platform for building holistic solutions integrating multimodal histopathology data., Discussion: The ontology ExaMode is a key means to store data in a graph database according to the RDF data model. The creation of an RDF dataset can help develop more accurate algorithms for image analysis, especially in the field of digital pathology. This approach allows for seamless data integration and a unified query access point, from which we can extract relevant clinical insights about the considered diseases using SPARQL queries., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Gianmaria Silvello reports financial support was provided by 10.13039/501100000780European Commission. Filippo Fragetta is an author of the paper and a member of the editorial board of JPI., (© 2023 The Authors.)

Exa-scale volumes of medical data have been produced for decades. In most cases, the diagnosis is reported in free text, encoding medical knowledge that is still largely unexploited. In order to allow decoding medical knowledge included in reports, we propose an unsupervised knowledge extraction system combining a rule-based expert system with pre-trained Machine Learning (ML) models, namely the Semantic Knowledge Extractor Tool (SKET). Combining rule-based techniques and pre-trained ML models provides high accuracy results for knowledge extraction. This work demonstrates the viability of unsupervised Natural Language Processing (NLP) techniques to extract critical information from cancer reports, opening opportunities such as data mining for knowledge extraction purposes, precision medicine applications, structured report creation, and multimodal learning. SKET is a practical and unsupervised approach to extracting knowledge from pathology reports, which opens up unprecedented opportunities to exploit textual and multimodal medical information in clinical practice. We also propose SKET eXplained (SKET X), a web-based system providing visual explanations about the algorithmic decisions taken by SKET. SKET X is designed/developed to support pathologists and domain experts in understanding SKET predictions, possibly driving further improvements to the system., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Filippo Fraggetta is an author of this work and a member of the editorial board., (© 2022 The Authors.)

Background: The implementation of a fully digital workflow in any anatomic pathology department requires a complete conversion to a tracked system. Ensuring the strict correspondence of the material submitted for the analysis, from the accessioning to the reporting phase, is mandatory in the anatomic pathology laboratory, especially when implementing the digital pathology for primary histological diagnosis. The proposed solutions, up to now, rely on the verification that all the materials present in the glass slide are also present in the whole slide images (WSIs). Although different methods have already been implemented for this purpose (e.g., the "macroimage" of the digital slide, representing the overview of the glass slide), the recent introduction of a device to capture the cut surface of paraffin blocks put the quality control of the digital workflow a step forward, allowing to match the digitized slide with the corresponding block. This system may represent a reliable, easy-to-use alternative to further reduce tissue inconsistencies between material sent to the lab and the final glass slides or WSIs., Methods: The Anatomic Pathology of the Gravina Hospital in Caltagirone, Sicily, Italy, has implemented the application of the BlocDoc devices (SPOT Imaging, Sterling Heights, USA) in its digital workflow. The instruments were positioned next to every microtome/sectioning station, with the possibility to capture the "normal" and the polarized image of the cut surface of the blocks directly by the technician. The presence of a monitor in the BlocDoc device allowed the technician to check the concordance between the cut surface of the block and the material on the corresponding slide. The link between BlocDoc and the laboratory information system, through the presence of the 2D barcode, allowed the pathologists to access the captured image of the cut surface of the block at the pathologist workstation, thus enabling the direct comparison between this image and the WSI (thumbnail and "macroimage")., Results: During the implementation period, more than 10.000 (11.248) blocks were routinely captured using the BlocDoc. The employment of this approach allowed a drastic reduction of the discordances and tissue inconsistencies. The implementation of the BlocDoc in the routine allowed the detection of two different types of "errors," the so-called "systematic" and "occasional" ones. The first type was intrinsic of some specific specimens (e.g., transurethral resection of the prostate, nasal polypectomies, and piecemeal uterine myomectomies) characterized by the three-dimensional nature of the fragments and affected almost 100% of these samples. On the other hand, the "occasional" errors, mainly due to inexperience or extreme caution of the technicians in handling tiny specimens, affected 98 blocks (0.9%) of these samples and progressively reduced with the rising confidence with the BlocDoc. One of these cases was clinically relevant. No problems in the recognition of the 2D barcodes were encountered using a laser cassette printer. Finally, rare failures have been recorded during the period, accounting for <0.1% of all the cases, mainly due to network connection issues., Conclusions: The implementation of BlocDoc can further improve the effectiveness of the digital workflow, demonstrating its safety and robustness as a valid alternative to the traditional, nontracked analogic workflow., Competing Interests: Fraggetta F is one of the inventors of “Sample imaging and imagery archiving for imagery comparison Merlo PT et al. US patent 16/688/613 2020.”, (Copyright: © 2021 Journal of Pathology Informatics.)

We report a case of giant retrovesical adenoma originating from ectopic prostatic tissue. A 73-year-old man presented with progressive dysuria, increasing PSA values, and acute urinary retention. One year before presentation, the patient had undergone retropubic prostatic adenomectomy for benign prostate hyperplasia. At last admission, PSA value was 23 ng/ml; mpMRI demonstrated a dysomogeneus retrovesical mass of 8 cm in diameter. Biopsy histology demonstrated acute prostatitis of the residual parenchyma and a prostatic adenoma in the retrovesical mass. After antibiotics and restored spontaneous urination, the patient was discharged and refused surgical lesion removal. After three months, the patient remains asymptomatic., Competing Interests: The authors declare that they have no conflicts of interest. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (© 2020 The Authors.)

Introduction: A whole slide image (WSI) is typically comprised of a macro image (low-power snapshot of the entire glass slide) and stacked tiles in a pyramid structure (with the lowest resolution thumbnail at the top). The macro image shows the label and all pieces of tissue on the slide. Many whole slide scanner vendors do not readily show the macro overview to pathologists. We demonstrate that failure to do so may result in a serious misdiagnosis., Materials and Methods: Various examples of errors were accumulated that occurred during the digitization of glass slides where the virtual slide differed from the macro image of the original glass slide. Such examples were retrieved from pathology laboratories using different types of scanners in the USA, Canada, Europe, and Asia., Results: The reasons for image errors were categorized into technical problems (e.g., automatic tissue finder failure, image mismatches, and poor scan coverage) and human operator mistakes (e.g., improper manual region of interest selection). These errors were all detected because they were highlighted in the macro image., Conclusion: Our experience indicates that WSI can be subject to inadvertent errors related to glitches in scanning slides, corrupt images, or mistakes made by humans when scanning slides. Displaying the macro image that accompanies WSIs is critical from a quality control perspective in digital pathology practice as this can help detect these serious image-related problems and avoid compromised diagnoses., Competing Interests: There are no conflicts of interest.

Introduction: Whole-slide imaging (WSI) technology can be used for primary diagnosis and consultation, including intraoperative (IO) frozen section (FS). We aimed to implement and validate a digital system for the FS evaluation of cancer and transplant specimens following recommendations of the College of American Pathologists., Materials and Methods: FS cases were routinely scanned at ×20 employing the "Navigo" scanner system. IO diagnoses using glass versus digital slides after a 3-week washout period were recorded. Intraobserver concordance was evaluated using accuracy rate and kappa statistics. Feasibility of WSI diagnoses was assessed by the way of sensitivity, specificity, as well as positive and negative predictive values. Participants also completed a survey denoting scan time, time spent viewing cases, preference for glass versus WSI, image quality, interface experience, and any problems encountered., Results: Of the 125 cases submitted, 121 (436 slides) were successfully scanned including 93 oncological and 28 donor-organ FS biopsies. Four cases were excluded because of failed digitalization due to scanning problems or sample preparation artifacts. Full agreement between glass and digital-slide diagnosis was obtained in 90 of 93 (97%, κ = 0.96) oncology and in 24 of 28 (86%, κ = 0.91) transplant cases. There were two major and one minor discrepancy for cancer cases (sensitivity 100%, specificity 96%) and two major and two minor disagreements for transplant cases (sensitivity 96%, specificity 75%). Average scan and viewing/reporting time were 12 and 3 min for cancer cases, compared to 18 and 5 min for transplant cases. A high diagnostic comfort level among pathologists emerged from the survey., Conclusions: These data demonstrate that the "Navigo" digital WSI system can reliably support an IO FS service involving complicated cancer and transplant cases., Competing Interests: There are no conflicts of interest.

Introduction: Successful implementation of whole slide imaging (WSI) for routine clinical practice has been accomplished in only a few pathology laboratories worldwide. We report the transition to an effective and complete digital surgical pathology workflow in the pathology laboratory at Cannizzaro Hospital in Catania, Italy., Methods: All (100%) permanent histopathology glass slides were digitized at ×20 using Aperio AT2 scanners. Compatible stain and scanning slide racks were employed to streamline operations. eSlide Manager software was bidirectionally interfaced with the anatomic pathology laboratory information system. Virtual slide trays connected to the two-dimensional (2D) barcode tracking system allowed pathologists to confirm that they were correctly assigned slides and that all tissues on these glass slides were scanned., Results: Over 115,000 glass slides were digitized with a scan fail rate of around 1%. Drying glass slides before scanning minimized them sticking to scanner racks. Implementation required introduction of a 2D barcode tracking system and modification of histology workflow processes., Conclusion: Our experience indicates that effective adoption of WSI for primary diagnostic use was more dependent on optimizing preimaging variables and integration with the laboratory information system than on information technology infrastructure and ensuring pathologist buy-in. Implementation of digital pathology for routine practice not only leveraged the benefits of digital imaging but also creates an opportunity for establishing standardization of workflow processes in the pathology laboratory., Competing Interests: There are no conflicts of interest.

CD117, a trans-membrane tyrosine kinase receptor, has been immunolocalized in a large variety of human neoplasms. Little, however, is known about the prevalence and clinical implications of CD117 in stage I adenocarcinoma and squamous cell carcinoma of the lung. We evaluated 201 consecutive stage I adenocarcinoma and squamous cell carcinoma of the lung for CD117 immunoreactivity (dichotomized as negative or positive if containing less than 5% or >/=5% immunoreactive neoplastic cells, respectively), also taking into account the pattern (either membranous or cytoplasmic), and the intensity of immunostaining in comparison with intratumoral mast cells. The immunostaining results were then correlated with tumor biopathological characteristics and patients' survival. Membranous CD117 immunoreactivity was documented in 19 (22%) of 88 adenocarcinomas and 15 (13%) of 113 squamous cell carcinomas, whereas cytoplasmic labelling was seen in 28 (32%) adenocarcinomas and eight (7%) squamous cell carcinomas. In both tumor types, membranous or cytoplasmic CD117 immunoreactivity was associated with higher proliferative fraction and with features of more aggressive tumor behavior, including higher stage, size and grade, occurrence of clinical symptoms, high microvessel density and neuroendocrine differentiation. Furthermore, immunoreactive tumors exhibited increased levels of bcl-2, cyclin-E, Her-2, p27(Kip1) and fascin, the latter being a marker of tumor cell metastatization in lung cancer. Membranous but not cytoplasmic labelling emerged as an independent risk factor for death and reduced time to progression in adenocarcinoma but not in squamous cell carcinoma patients, when singly adjusted for confounding factors. CD117 immunoreactivity identifies a peculiar subset of stage I adenocarcinoma and squamous cell carcinoma of the lung with highly proliferative tumors and may have prognostic relevance in adenocarcinoma patients. Targeting the CD117 pathway could be a novel therapeutic strategy in a subset of pulmonary carcinomas.

We investigated 27 pleomorphic carcinomas of the lung for exon 1 K-ras gene mutations using polymerase chain reaction-single-strand conformation polymophism analysis and direct sequencing. All pleomorphic carcinomas were biphasic, that is, composed of an adeno-, squamous- or large-cell-carcinomatous component associated with a spindle- and/or giant-cell component. Of 27 cases, six (22%) showed K-ras codon 12 mutations, which is a figure higher than that previously reported on in pure sarcoma-like pleomorphic carcinomas. Five tumors displayed the same mutation in both the epithelial and the sarcomatoid components, whereas in one tumor the mutation was restricted to the epithelial component. All mutations occurred in smokers, and were transversions, including GGT (glycine) to TGT (cysteine) change in two cases, to GCT (alanine) in two and to GTT (valine) in two. No significant relationships were found between the occurrence and type of mutations and patients' survival or any other clinicopathological variable, suggesting that K-ras mutations are early events in the development of these tumors. Our results indicate that most, though not all, biphasic pleomorphic carcinomas of the lung are monoclonal in origin, and that cigarette smoking may have a causative role in the development of K-ras alterations in these tumors, as all mutations are transversions.