Whole-slide imaging: widening the scope of cytopathology

Whole slide imaging (WSI) is broadening the scope of cytopathology. Whole slide images are being used for telecytology, quality assurance activities (e.g. proficiency testing) and teaching (e.g. digital teaching sets and online virtual atlases). Progress in WSI technology that permits high resolution scanning, z-stacking, and hybrid robotic devices has encouraged the use of this imaging modality for cytology practice, education and research. However, widespread adoption in cytology still depends on overcoming barriers unrelated to cytology and challenges directly related to digitizing cytopathology slides. The aim of this article is to review WSI technology, applications and limitations specific to cytopathology.     

Whole-slide imaging in cytopathology: state of the art and future directions

Whole slide imaging (WSI) has been increasingly adopted for digital evaluation of surgical pathology specimens. Unlike histological slides, cytological preparations frequently display a heterogeneous distribution of cells throughout slides in different focal planes sometimes admixed with obscuring material, therefore requiring multiple scanning planes which significantly lengthens image acquisition and evaluation times. Although examination of digital images can be more advantageous than conventional glass slides, the challenges of focusing, scanning and screening cytological specimens and the associated increase in scan times and data storage needs have limited the routine application of WSI in cytopathology practice. Emerging digital systems designed to overcome image acquisition obstacles coupled with artificial intelligence algorithms augmenting screening of digital cytology slides offer innovative solutions to address these limitations. The aim of this review is to critically address the potential benefits and pitfalls of employing WSI in cytopathology practice and to introduce promising state-of-the-art solutions on the horizon.     

Zytologie im Internet

Computer-based learning (E-learning) is of increasing importance for the education of students and professionals. Various publicly accessible online courses for cytologists now exist and some of these are presented in this paper. For the learning platform Patho-Basiliensis (http://www.unibas.ch/patho/) we have developed several learning materials: a database of 726 cytology images, a cytopathology course to teach the basics of cytopathology, and a game testing histologic-cytologic correlation. Tests on lung and urinary cytology were attended by 383 international participants. The virtual microscopy technology will revolutionize telecytology and cytology education.     

Whole-slide imaging: routine pathologic diagnosis

Digital pathology systems offer pathologists an alternate, emerging mechanism to manage and interpret information. They offer increasingly fast and scalable hardware platforms for slide scanning and software that facilitates remote viewing, slide conferencing, archiving, and image analysis. Deployed initially and validated largely within the research and biopharmaceutical industries, WSI is increasingly being implemented for direct patient care. Improvements in image quality, scan times, and imageviewing browsers will hopefully allow pathologists to more seamlessly convert to digital pathology, much like our radiology colleagues have done before us. However, WSI creates both opportunities and challenges. Although niche applications of WSI technology for clinical, educational, and research purposes are clearly successful, it is evident that several areas still require attention and careful consideration before more widespread clinical adoption of WSI takes place. These include regulatory issues, development of standards of practice and validation guidelines, workflow modifications, as well as defining situations where WSI technology will really improve practice in a cost-effective way. Current progress on these and other issues, along with improving technology, will no doubt pave the way for increased adoption over the next decade, allowing the pathology community as a whole to harness the true potential of WSI for patient care. The digital decade will likely redefine how pathology is practiced and the role of the pathologist.     

Digital pathology: current status and future perspectives

During the last decade pathology has benefited from the rapid progress of image digitizing technology. The improvement in this technology had led to the creation of slide scanners which are able to produce whole slide images (WSI) which can be explored by image viewers in a way comparable to the conventional microscope. The file size of the WSI ranges from a few megabytes to several gigabytes, leading to challenges in the area of image storage and management when they will be used routinely in daily clinical practice. Digital slides are used in pathology for education, diagnostic purposes (clinicopathological meetings, consultations, revisions, slide panels and, increasingly, for upfront clinical diagnostics) and archiving. As an alternative to conventional slides, WSI are generally well accepted, especially in education, where they are available to a large number of students with the full possibilities of annotations without the problem of variation between serial sections. Image processing techniques can also be applied to WSI, providing pathologists with tools assisting in the diagnosis-making process. This paper will highlight the current status of digital pathology applications and its impact on the field of pathology.     

Molecular techniques in cytopathology practice

In the last decade, new molecular techniques were introduced into pathology laboratories. Cytology also benefited from the innovations emerging from this new era. Molecular cytopathology (MCP) can be defined as molecular studies applied on all types of cytological specimens, namely gynaecology cytology, exfoliative non- gynaecology cytology and fine needle aspirates. The development of many new ancillary techniques has paralleled the emergence of clinical cytology as a major diagnostic specialty. Clinical applications of these techniques have been growing in the last decade. The widespread acceptance of liquid-based systems in gynaecological cytology emphasises the relation between cells and molecules. The increased use of morphology and molecular biology in human papillomavirus-induced lesions for example, showed the potential to optimise, in one single brushed sample, diagnosis and research. Cytology samples from serous effusions, the pulmonary tree, urine, and aspirations, among others, are now likely to be studied by different molecular techniques for diagnosis, prognosis, or even assessment of therapeutic targets. In this review, the main published results concerning the application of molecular techniques in different fields of cytopathology are highlighted, and their applications discussed.     

Recent trends in quality, patient safety, and error reduction in nongyn cytology

This article reviews recent trends in nongyn cytology with an emphasis on error reduction, second opinion, and critical diagnosis. Compared with the surgical pathology literature, there is only a limited number of reports addressing these topics in nongyn cytology. Discussion of the error literature in nongyn cytology is presented with the intent to better identify error-prone cytology cases that could prompt intradepartmental consultation or an outside cytology expert's second opinion. The cytology second-opinion literature is also reviewed with the recommendation that interinstitutional second opinions add value to patient care. Last, the recent concept of critical value (critical diagnosis) in cytopathology is presented. All these initiatives promote patient safety, improve quality, decrease errors, and benefit patients.     

Cytologic-histologic correlation of nongynecologic cytopathology cases: separation of determinate from indeterminate cytologic diagnoses for analysis and monitoring of laboratory performance

Much of the literature on the quality-assurance aspect of cytologic-histologic correlation (CHC) has focused on gynecologic cytology. For nongynecologic cytopathology, the process is complicated by the use of determinate (positive for malignant cells, negative for malignant cells) and indeterminate (atypical, suspicious, or follicular lesion) diagnostic categories. Here, we illustrate our routine methodology for analyzing CHC data on nongynecologic cytopathology cases by separating determinate from indeterminate cases. A focused list of determinate and indeterminate cytopathology cases with surgical pathology correlation is generated each week. The determinate cases are ascertained as true positive (TP), true negative (TN), false positive (FP), or false negative (TN). The discrepant cases (FP and FN) are investigated to determine the cause (sampling, interpretation, or screening). For indeterminate cases, the surgical pathology outcome (benign, malignant) and suitability of the cytopathology category utilized are reviewed. For the focused period of 4 mo, sensitivity was 70% and specificity was 100%. The most common reason for false-negative diagnoses was a sampling problem in the cytologic specimen; there were no false-positive diagnoses. Malignant outcomes for follicular lesion, atypical, and suspicious diagnoses were 29%, 40%, and 76%, respectively. Data derived from regularly performed CHC are useful in reviewing the diagnostic performance of the laboratory.     

Automation in cytology: A survey conducted by the New Technology Task Force,Papanicolaou Society of Cytopathology

Despite the overwhelming interest in the development of several computer based technologies in the last several years, the role of automation in cytology has remained controversial. The potential of these technologies in the reduction of false negative results in pap smears is well recognized. However, there is still remarkable confusion as how to incorporate automation in the routine practice of cytology. This prompted the New Technology Task Force of the George Papanicolaou Society of Cytopathology to design a survey to seek the opinion of those engaged in cervicovaginal cytology screening regarding the value of automation in cytology. In 1996, a ten question survey was sent to 1800 cytopathology laboratories throughout the nation. The response rate was 23% (416/1800). The responders represented laboratories varying from those with less than 5,000 pap smears to those with over 100,000 cases per year. The majority of the responders did not believe that automation is essential for cervicovaginal cytology. This was evidenced by the fact that only 12% of the laboratories were engaged in automated cytology and predominantly used it for quality control measures. The inability of small laboratories to absorb the extra expense involved in the integration of automated cytology in their practice, particularly in the current era of managed care was a major concern. There was also concern about the potential for compromise of patient care by the drive for corporate profits and the dissemination of wrong information to the public and physicians. Suggestions most frequently proposed included appropriate patient and physician education about the merits and pitfalls of the pap smear, and also endorsing an affordable universal fee for pap smears. Rescreening for all pap smears, reassessing the benefits of automation in cytology and development of the standards were other proposals. Partnership with larger cytology laboratories, creation of “cytology consortiums” with shared resources to provide regionalized automated rescreening services were also strongly suggested. This survey clearly indicates the need for further evaluation of automation in cytopathology and a focused attention to various issues surrounding cervicovaginal cytology screening. Diagn. Cytopathol. 1998; 18:47–55. © 1998 Wiley-Liss, Inc.     

Molecular testing in cytology

In the era of personalized medicine, molecular testing plays a critical role in patient care. The rapid advance of molecular techniques, especially next-generation sequencing, makes molecular diagnosis feasible in daily practice. Molecular testing can be used as a valuable ancillary test to increase diagnostic sensitivity and specificity, especially in small biopsy or cytology samples. In addition, molecular testing plays an important role in selecting patients for appropriate treatment by detecting therapeutic and predictive biomarkers in tissue or cytology samples. Molecular studies can be applied in all cytology samples, sometimes with better results than histology. As molecular testing has become essential for patient care and is often requested to be performed in cytology samples, it is critical for cytopathologists to understand the basics of molecular diagnostic methods, indications for molecular testing, and how to best utilize different cytologic samples for this purpose. In this special issue, experts in various areas of cytopathology and molecular pathology review the literature and discuss the basics of molecular techniques and the application of molecular testing in various types of cytology samples. It is our hope that after reading the articles in this special issue, the readers can know better about the possibilities of molecular cytology, a very exciting field of pathology.     

Application and performance of artificial intelligence technology in cytopathology

Deep learning algorithms and artificial intelligence (AI) are making great progress in their capacity to evaluate and interpret image data recent advancements in computer vision and machine learning. The first use of AI in a pathology lab was in cytopathology, when a computer-assisted Pap test screening was created. Initially designed to diagnose rather than screen, there was a lot of disagreement concerning their wide use to clinical specimens. However, whole-slide imaging of both gynaecological and non-gynaecological histopathology have been the subject of recent AI work. An overview of the literature on AI in cytopathology is provided in this brief review. To be more precise, it intends to emphasize the relevance of applications of AI algorithms to gynaecological and non-gynaecologic cytology. Between January 2000 and December 2021, a search on artificial intelligence in cytopathology was conducted in several well-known databases, including PubMed, Web of Science, Scopus, Embase, and Google Scholar. Only full-text papers that could be accessed online were evaluated.     

The minefield of indeterminate thyroid nodules: could artificial intelligence be a suitable diagnostic tool?

Artificial intelligence (AI) is assuming a central role in anatomic pathology for ancillary diagnosis in histology and cytology. AI techniques can analyse large amounts of data and identify patterns that may not be visible to the human eye.Several studies have explored the potential of such techniques to improve the accuracy and efficiency of thyroid nodule diagnosis and to increase the sensitivity and specificity of thyroid cytopathology. Specifically, the indeterminate categories of ‘the Bethesda system for reporting thyroid cytopathology’ (TBSRTC) represent a major diagnostic challenge, and articles reported in this review highlight the potential of new AI technologies in improving the accuracy and standardisation of the cytological diagnosis of indeterminate thyroid nodules.Although a large amount of data supports AI's utility in thyroid cytopathology, further research is needed to integrate and standardise AI-based diagnostic systems in clinical workflows.     

Adaptive eLearning modules for cytopathology education: A review and approach

Clinical training imposes time and resource constraints on educators and learners, making it difficult to provide and absorb meaningful instruction. Additionally, innovative and personalized education has become an expectation of adult learners. Fortunately, the development of web‐based educational tools provides a possible solution to these challenges. Within this review, we introduce the utility of adaptive eLearning platforms in pathology education. In addition to a review of the current literature, we provide the reader with a suggested approach for module creation, as well as a critical assessment of an available platform, based on our experience in creating adaptive eLearning modules for teaching basic concepts in gynecologic cytopathology. Diagn. Cytopathol. 2016;44:944–951. © 2016 Wiley Periodicals, Inc.     

Papillary thyroid carcinoma with nodular fasciitis-like stroma. Pitfalls in fine-needle aspiration cytology.

Papillary thyroid carcinoma with nodular fasciitis-like stroma is one of the rare variants of papillary thyroid carcinoma. The problems posed by the exuberant nodular fasciitis-like stroma, which obscures the neoplastic nature of the tumor, are recognized in surgical pathology but have received little attention in the cytopathology literature. We report a rare case of papillary thyroid carcinoma in which nodular fasciitis-like stroma posed difficulty on fine-needle aspiration cytology. The differential diagnosis of fibroproliferative processes in thyroid fine-needle aspirations is also discussed.     

The Paris system of Reporting Urinary Cytology: Strengths and opportunities

The Paris system for reporting urinary cytopathology (TPS) was created to address inherent weaknesses inherent in the practice of urinary cytopathology. While urothelial cytology has always performed well at finding high grade, genetically unstable urothelial carcinoma, it performs poorly when it comes to detecting low‐grade urothelial neoplasia. TPS intends to improve the utility of urothelial cytology by focusing on what is important, high‐grade urothelial carcinoma. This article is a snapshot of the current state of TPS as it heads into its second edition. Successes are described and further developments are considered.     

Reconciliation of diverse telepathology system designs. Historic issues and implications for emerging markets and new applications

Telepathology, the distant service component of digital pathology, is a growth industry. The word "telepathology" was introduced into the English Language in 1986. Initially, two different, competing imaging modalities were used for telepathology. These were dynamic (real time) robotic telepathology and static image (store-and-forward) telepathology. In 1989, a hybrid dynamic robotic/static image telepathology system was developed in Norway. This hybrid imaging system bundled these two primary pathology imaging modalities into a single multi-modality pathology imaging system. Similar hybrid systems were subsequently developed and marketed in other countries as well. It is noteworthy that hybrid dynamic robotic/static image telepathology systems provided the infrastructure for the first truly sustainable telepathology services. Since then, impressive progress has been made in developing another telepathology technology, so-called "virtual microscopy" telepathology (also called "whole slide image" telepathology or "WSI" telepathology). Over the past decade, WSI has appeared to be emerging as the preferred digital telepathology digital imaging modality. However, recently, there has been a re-emergence of interest in dynamic-robotic telepathology driven, in part, by concerns over the lack of a means for up-and-down focusing (i.e., Z-axis focusing) using early WSI processors. In 2010, the initial two U.S. patents for robotic telepathology (issued in 1993 and 1994) expired enabling many digital pathology equipment companies to incorporate dynamic-robotic telepathology modules into their WSI products for the first time. The dynamic-robotic telepathology module provided a solution to the up-and-down focusing issue. WSI and dynamic robotic telepathology are now, rapidly, being bundled into a new class of telepathology/digital pathology imaging system, the "WSI-enhanced dynamic robotic telepathology system". To date, six major WSI processor equipment companies have embraced the approach and developed WSI-enhanced dynamic-robotic digital telepathology systems, marketed under a variety of labels. Successful commercialization of such systems could help overcome the current resistance of some pathologists to incorporate digital pathology, and telepathology, into their routine and esoteric laboratory services. Also, WSI-enhanced dynamic robotic telepathology could be useful for providing general pathology and subspecialty pathology services to many of the world's underserved populations in the decades ahead. This could become an important enabler for the delivery of patient-centered healthcare in the future.     

Use of whole slide imaging in surgical pathology quality assurance: design and pilot validation studies

By imaging large numbers of slides automatically at high resolution, modem automated whole slide imaging (WSI) systems have the potential to become useful tools in pathology practice. This article describes a pilot validation study for use of automated high-speed WSI systems for surgical pathology quality assurance (QA). This was a retrospective comparative study in which 24 full genitourinary cases (including 47 surgical parts and 391 slides) were independently reviewed with traditional microscopy and whole slide digital images. Approximately half the cases had neoplasia in the diagnostic line. At the end of the study, diagnostic discrepancies were evaluated by a pathology consensus committee. The study pathologists felt that the traditional and WSI methods were comparable for case review. They reported no difference in perceived case complexity or diagnostic confidence between the methods. There were 4 clinically insignificant discrepancies with the signed-out cases: 2 from glass slide and 2 with WSI review. Of the 2 discrepancies reported by the WSI method, the committee agreed with the reviewer once and the original report once. At the end of the study, the participants agreed that automated WSI is a viable potential modality for surgical pathology QA, especially in multifacility health systems that would like to establish interfacility QA. The participants felt that major issues limiting the implementation of WSI-based QA did not involve image acquisition or quality but rather image management issues such as the pathologist's interface, the hospital's network, and integration with the laboratory information system.     

The use of electron microscopy to refine diagnoses in the daily practice of cytopathology

Conceived as a screening tool, cytology is a field that since the 1980s has become more diagnostic in its scope. The advent of the fine-needle aspiration biopsy (FNAB) is responsible for cytology's new place in pathology. In the everyday practice of cytopathology, about 85-90% of the nongynecologic cases can be diagnosed with the use of routine stains (i.e., Papanicolaou and Diff Quik). The other 10-15% of the cases require the use of ancillary diagnostic techniques for a precise diagnosis. Immunohistochemistry helps solve approximately 50% of these cases, and the other half of these challenging cases are best approached and diagnosed by using electron microscopy (EM). In their practice, the authors obtain cytologic samples for EM routinely in difficult cases. Unfortunately, a percentage of these cases collected for ultrastructural evaluation do not have enough cells after processing, and others only have a few diagnostic cells available. In the cases in which at least a handful of cells are available, EM is almost invariably helpful in one way or another, either making a definitive diagnosis or refining the diagnosis. A sampling of FNAB cases from the authors' everyday practice is prevented to illustrate the use of EM in the practice of cytopathology. The cases have been selected from among the most common diagnostic challenges to highlight the important role that ultrastructural evaluation plays in a busy cytology practice. In our practice ultrastructural evaluation is a piece of the puzzle, which, along with the clinical history, clinical impression, light microscopic/cytologic features, and other ancillary techniques (IHC, flow cytometry, and molecular pathology), help compile an accurate diagnosis. Many times EM is the most important component of the diagnostic algorithm.     

Significance of incidental detection of filariasis on aspiration smears: A case series

Filariasis is a major public health problem in tropical and subtropical countries including India. Although there are reports of incidentally diagnosed cases of lymphatic filariasis in the existing literature, the significance of this finding needs to be summarised in one place. The association of filariasis with neoplasms is still debatable. For this series, cases diagnosed as filariasis on aspiration cytology (with or without coexistent pathology) over a period of 1 year were retrieved. The cases with a clinical suspicion of filariasis were excluded. Hence, five cases with incidental diagnosis of filariasis on aspiration cytology were included. The site of aspiration included one case each of thyroid, breast, bone marrow, cervical lymph node, and subcutaneous nodule. Of these, three cases showed microfilariae, one showed only adult female worm while one showed both microfilariae and adult worm. Two cases did not show any inflammatory response while three cases showed a variable inflammatory reaction. Only one case (thyroid aspirate) had a coexistent pathology (colloid goitre). Filariasis may be detected in a clinically unsuspected case, especially in an endemic zone. The spectrum of host response may vary from no reaction to a marked inflammatory response. The entire spectrum of changes should be kept in mind while practicing cytopathology in an endemic area. In such situations, a high index of suspicion and careful screening of cytology smears are keys to a correct diagnosis. At the same time, keen search for a coexisting pathology, benign or malignant, is also mandatory. Diagn. Cytopathol. 2010. © 2009 Wiley‐Liss, Inc.     

Teaching interventional cytopathology

Interventional cytopathology is a unique area of pathology, where cytopathologists play a primary role in obtaining fine needle aspiration biopsies and/or making determinations through rapid on-site evaluations to guide sample procurement in real-time. Unsurprisingly, experience and skill are directly related to success in these endeavors, and both can be fostered with formal instruction. There is a wealth of resources available to aid in teaching interventional cytopathology, including instructional videos, courses, and model phantoms which can help to build familiarity and confidence. These tools can provide a basic framework upon which skills can be developed through in-person guidance, real-time feedback and practice. This article reviews the tools available to enhance training, details the authors’ institutional experience in teaching interventional cytopathology at a tertiary care center, and provides recommendations and pearls for success in this endeavor.