Automated identification of glomeruli and synchronised review of special stains in renal biopsies by machine learning and slide registration: a cross-institutional study.

AIMS: Machine learning in digital pathology can improve efficiency and accuracy via prescreening with automated feature identification. Studies using uniform histological material have shown promise. Generalised application requires validation on slides from multiple institutions. We used machine learning to identify glomeruli on renal biopsies and compared performance between single and multiple institutions. METHODS AND RESULTS: Randomly selected, adequately sampled renal core biopsy cases (71) consisting of four stains each (haematoxylin and eosin, trichrome, silver, periodic acid Schiff) from three institutions were digitised at ×40. Glomeruli were manually annotated by three renal pathologists using a digital tool. Cases were divided into training/validation (n = 52) and evaluation (n = 19) cohorts. An algorithm was trained to develop three convolutional neural network (CNN) models which tested case cohorts intra- and inter-institutionally. Raw CNN search data from each of the four slides per case were merged into composite regions of interest containing putative glomeruli. The sensitivity and modified specificity of glomerulus detection (versus annotated truth) were calculated for each model/cohort. Intra-institutional (3) sensitivity ranged from 90 to 93%, with modified specificity from 86 to 98%. Interinstitutional (1) sensitivity was 77%, with modified specificity 97%. Combined intra- and inter-institutional (1) sensitivity was 86%, with modified specificity 92%. CONCLUSIONS: Feature detection sensitivity degrades when training and test material originate from different sites. Training using a combined set of digital slides from three institutions improves performance. Differing histology methods probably account for algorithm performance contrasts. Our data highlight the need for diverse training sets for the development of generalisable machine learning histology algorithms.

American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer.

An update to the American Cancer Society (ACS) guideline regarding screening for the early detection of cervical precancerous lesions and cancer is presented. The guidelines are based on a systematic evidence review, contributions from 6 working groups, and a recent symposium cosponsored by the ACS, the American Society for Colposcopy and Cervical Pathology, and the American Society for Clinical Pathology, which was attended by 25 organizations. The new screening recommendations address age-appropriate screening strategies, including the use of cytology and high-risk human papillomavirus (HPV) testing, follow-up (eg, the management of screen positives and screening intervals for screen negatives) of women after screening, the age at which to exit screening, future considerations regarding HPV testing alone as a primary screening approach, and screening strategies for women vaccinated against HPV16 and HPV18 infections.

Test Characteristics of Specific p16 Clones in the Detection of High-grade Squamous Intraepithelial Lesions (HSIL).

p16 immunohistochemistry is recommended by the CAP-ASCCP Lower Anogenital Squamous Terminology (LAST) Standardization Project for human papillomavirus associated Lesions as an adjunct to morphologic assessment in the diagnosis of high-grade squamous intraepithelial lesion. This study evaluates the performance of different p16 clones as compared with E6H4 (CINtec) in detecting high-grade squamous intraepithelial lesion. The 54 high-quality articles addressing the performance of p16 identified by work group 4 of the LAST Project were evaluated for: specific p16 clone, scoring method, number of cases, anatomic site, and histologic diagnoses. Sensitivity, specificity, positive predictive value, and negative predictive value were calculated for each clone. Two-proportion z tests (pooled) were used to evaluate significance. In total, 32 of the 54 studies met the inclusion criteria. The most commonly used clone was E6H4 (17 studies, 3507 cases) with smaller numbers (1-4) of studies evaluating the following: 16P04, JC8, 16P07, G175-405, K5334, K5336, and 7962. p16 clones 16P04 and JC8 performed better than E6H4 with 16P04 exhibiting statistically significant higher sensitivity (94% vs. 87% for E6H4), specificity (94% vs. 81%), and positive predictive value (96% vs. 69%) while JC8 exhibited higher specificity (91% vs. 81%) and positive predictive value (88% vs. 69%). 16P07 performed similarly to E6H4 and the other 4 clones did not perform as well as E6H4. p16 clones 16P04, JC8, and 16P07 clones perform as well or better than the widely used p16 clone E6H4 (CINtec). However, further studies are indicated to determine the reproducibility of these findings and the impact of interlaboratory variation on test performance.

Practical issues related to uterine pathology: in situ and invasive cervical glandular lesions and their benign mimics: emphasis on cytology-histology correlation and interpretive pitfalls.

In situ and invasive neoplastic glandular lesions of the uterine have cytologic correlates that must be distinguished from a variety of benign and reactive conditions. Careful study of the cytologic features allows discrimination in the majority of cases; however, the designation of 'atypical glandular cells' is reserved for equivocal cases that cannot be readily resolved. In this article, the cytologic features of endocervical adenocarcinoma in situ and invasive endocervical adenocarcinoma will be presented, highlighting their correlation to the well-known histologic features. Variants of the usual type of endocervical neoplasms that have important clinical and differential diagnostic features, including mucinous adenocarcinoma and clear-cell carcinoma, will be discussed. There are a number of common cytologic mimics of endocervical neoplasms, including tubal metaplasia, directly sampled (abraded) endometrium, and high-grade squamous intraepithelial lesion involving endocervical glands. The cytologic features of these entities and their differentiation from endocervical neoplasia will be explored. Finally, the role of ancillary studies such as human papillomavirus testing in the management of glandular lesions of the cervix will be integrated into the discussion.

The Pap Test and Bethesda 2014. "The reports of my demise have been greatly exaggerated." (after a quotation from Mark Twain).

The history of 'The Bethesda System' for reporting cervical cytology goes back almost 3 decades. This terminology and the process that created it have had a profound impact on the practice of cervical cytology for laboratorians and clinicians alike. The Bethesda conferences and their ensuing output have also set the stage for standardization of terminology across multiple organ systems, including both cytology and histology, have initiated significant research in the biology and cost-effective management for human papillomavirus-associated anogenital lesions, and, finally, have fostered worldwide unification of clinical management for these lesions. Herein, we summarize the process and rationale by which updates were made to the terminology in 2014 and outline the contents of the new, third edition of the Bethesda atlas and corresponding website.

The Pap Test and Bethesda 2014: "The reports of my demise have been greatly exaggerated. (after a quotation from Mark Twain)".

The Bethesda System for gynecologic cytopathology has standardized reporting terminology over the past quarter of a century. In doing so, it has allowed for improved communication among practitioners around the world, facilitated large research projects and clinical trials, and has provided the basis from which uniformly accepted risk-based management strategies have been developed. Over time, changes in terminology and the underlying science require revisions, and the third edition of the Bethesda "Atlas" is the result of a yearlong effort to provide such an update. New material was developed and proposed via an Internet bulletin board, allowing for wide commentary that was compiled and incorporated. New images were collected, which comprised many new examples of equivocal presentations and mimics. New background material on the scientific basis supporting the terminology categories, the most current management algorithms, and comprehensive references were included. The effort completely refurbishes this standard reference that forms an inexpensive and, therefore, widely available resource for the world's cytology community.

The Lower Anogenital Squamous Terminology Standardization project for HPV-associated lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology.

The terminology for human papillomavirus (HPV)-associated squamous lesions of the lower anogenital tract has a long history marked by disparate diagnostic terms derived from multiple specialties. It often does not reflect current knowledge of HPV biology and pathogenesis. A consensus process was convened to recommend terminology unified across lower anogenital sites. The goal was to create a histopathologic nomenclature system that reflects current knowledge of HPV biology, optimally uses available biomarkers, and facilitates clear communication across different medical specialties. The Lower Anogenital Squamous Terminology (LAST) project was co-sponsored by the College of American Pathologists (CAP) and the American Society for Colposcopy and Cervical Pathology (ASCCP) and included 5 working groups; three work groups performed comprehensive literature reviews and developed draft recommendations. Another work group provided the historical background and the fifth will continue to foster implementation of the LAST recommendations. After an open comment period, the draft recommendations were presented at a consensus conference attended by LAST work group members, advisors and representatives from 35 stakeholder organizations including professional societies and government agencies. Recommendations were finalized and voted upon at the consensus meeting. The final approved recommendations standardize biologically-relevant histopathologic terminology for HPV-associated squamous intraepithelial lesions and superficially invasive squamous carcinomas across all lower anogenital tract sites and detail appropriate use of specific biomarkers to clarify histologic interpretations and enhance diagnostic accuracy. A plan for disseminating and monitoring recommendation implementation in the practicing community was also developed. The implemented recommendations will facilitate communication between pathologists and their clinical colleagues and improve accuracy of histologic diagnosis with the ultimate goal of providing optimal patient care.

Effects on cervical cytology screening productivity associated with implementation of the BD FocalPoint™ Guided Screener Imaging System.

OBJECTIVES: Automated screening will become important due to an aging workforce, declining numbers of new cytotechnologists, and the need for increased screening sensitivity in the vaccine era, where high-grade abnormalities will decline. This study documents workload in gynecologic cytology throughput before and after the implementation of the BD FocalPoint™ Guided Screener (GS) System. STUDY DESIGN: We collected daily screening data from 3 time periods: the 12 months prior to GS implementation, the 6 months immediately after implementation, and the ensuing 7-18 months after implementation. Data was tabulated at the individual and total laboratory levels. RESULTS: In the 6-month period immediately following implementation, productivity increased in 3 of 5 cytotechnologists, as compared to the figures 12 months before implementation. The laboratory increased productivity slightly (+2.4%), with individual changes ranging from -6.9 to +14.7%. In the 7- to 18-month 'mature' period after implementation, productivity increased in all 5 cytotechnologists with an average of +15.4%. Individual increases ranged from +6.1 to +26.9%. CONCLUSIONS: Overall productivity increased in the period beyond 6 months, and this increase was eventually noted in all personnel. Increased productivity was associated with a short period of learning in which the magnitude of the effect was less than in the mature period.

The Lower Anogenital Squamous Terminology Standardization Project for HPV-Associated Lesions: background and consensus recommendations from the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology.

The terminology for human papillomavirus (HPV)-associated squamous lesions of the lower anogenital tract has a long history marked by disparate diagnostic terms derived from multiple specialties. It often does not reflect current knowledge of HPV biology and pathogenesis. A consensus process was convened to recommend terminology unified across lower anogenital sites. The goal was to create a histopathologic nomenclature system that reflects current knowledge of HPV biology, optimally uses available biomarkers, and facilitates clear communication across different medical specialties. The Lower Anogenital Squamous Terminology (LAST) Project was cosponsored by the College of American Pathologists and the American Society for Colposcopy and Cervical Pathology and included 5 working groups; 3 work groups performed comprehensive literature reviews and developed draft recommendations. Another work group provided the historical background and the fifth will continue to foster implementation of the LAST recommendations. After an open comment period, the draft recommendations were presented at a consensus conference attended by LAST work group members, advisors, and representatives from 35 stakeholder organizations including professional societies and government agencies. Recommendations were finalized and voted on at the consensus meeting. The final, approved recommendations standardize biologically relevant histopathologic terminology for HPV-associated squamous intraepithelial lesions and superficially invasive squamous carcinomas across all lower anogenital tract sites and detail the appropriate use of specific biomarkers to clarify histologic interpretations and enhance diagnostic accuracy. A plan for disseminating and monitoring recommendation implementation in the practicing community was also developed. The implemented recommendations will facilitate communication between pathologists and their clinical colleagues and improve accuracy of histologic diagnosis with the ultimate goal of providing optimal patient care.

American Cancer Society, American Society for Colposcopy and Cervical Pathology, and American Society for Clinical Pathology screening guidelines for the prevention and early detection of cervical cancer.

An update to the American Cancer Society (ACS) guideline regarding screening for the early detection of cervical precancerous lesions and cancer is presented. The guidelines are based on a systematic evidence review, contributions from six working groups, and a recent symposium co-sponsored by the ACS, American Society for Colposcopy and Cervical Pathology (ASCCP), and American Society for Clinical Pathology (ASCP), which was attended by 25 organizations. The new screening recommendations address age-appropriate screening strategies, including the use of cytology and high-risk human papillomavirus (HPV) testing, follow-up (e.g., management of screen positives and screening interval for screen negatives) of women after screening, age at which to exit screening, future considerations regarding HPV testing alone as a primary screening approach, and screening strategies for women vaccinated against HPV16/18 infections.

Digital cytology: current state of the art and prospects for the future.

The growth of digital methods in pathology is accelerating. Digital images can be used for a variety of applications in cytology, including rapid interpretations, primary diagnosis and second opinions, continuing education and proficiency testing. All of these functions can be performed using small static digital images, real-time dynamic digital microscopy, or whole-slide images. This review will discuss the general principles of digital pathology, its methods and applications to cytologic specimens. As cytologic specimens have unique features compared to histopathology specimens, the key differences will be discussed. Technical and administrative issues in digital pathology applications and the outlook for the future of the field will be presented.

Computational Cytology: Lessons Learned from Pap Test Computer-Assisted Screening.

BACKGROUND: In the face of rapid technological advances in computational cytology including artificial intelligence (AI), optimization of its application to clinical practice would benefit from reflection on the lessons learned from the decades-long journey in the development of computer-assisted Pap test screening. SUMMARY: The initial driving force for automated screening in cytology was the overwhelming number of Pap tests requiring manual screening, leading to workflow backlogs and incorrect diagnoses. Several companies invested resources to address these concerns utilizing different specimen processing techniques and imaging systems. However, not all companies were commercially prosperous. Successful implementation of this new technology required viable use cases, improved clinical outcomes, and an acceptable means of integration into the daily workflow of cytopathology laboratories. Several factors including supply and demand, Food and Drug Administration (FDA) oversight, reimbursement, overcoming learning curves and workflow changes associated with the adoption of new technology, and cytologist apprehension, played a significant role in either promoting or preventing the widespread adoption of automated screening technologies. Key Messages: Any change in health care, particularly those involving new technology that impacts clinical workflow, is bound to have its successes and failures. However, perseverance through learning curves, optimizing workflow processes, improvements in diagnostic accuracy, and regulatory and financial approval can facilitate widespread adoption of these technologies. Given their history with successfully implementing automated Pap test screening, cytologists are uniquely positioned to not only help with the development of AI technology for other areas of pathology, but also to guide how they are utilized, regulated, and managed.

Using Image Registration and Machine Learning to Develop a Workstation Tool for Rapid Analysis of Glomeruli in Medical Renal Biopsies.

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.

Advanced imaging technology applications in cytology.

Novel techniques have been developed to image cells at cellular and subcellular levels. They allow images to be analyzed with ultra-high resolution, in 2D and/or 3D. Several of these tools have been tested on cytology specimens demonstrating emerging applications that are likely to change the field of cytopathology. This review covers several of these advanced imaging methods. The use of optical coherence tomography to perform optical biopsies during endoscopic ultrasound procedures or visualize cells within effusion samples is discussed. The potential for quantitative phase microscopy to accurately screen Pap test slides or resolve indeterminate diagnoses in urine cytology is reviewed. The article also examines the application of 3D cytology using LuCED for lung cancer detection in sputum samples and the feasibility of imaging flow and mass cytometry to measure multiple biomarkers at the single cell level. Although these novel technologies have great potential, further research is necessary to validate their routine use in cytopathology practice.

Internet-based gynecologic telecytology with remote automated image selection: results of a first-phase developmental trial.

A retrospective set of 191 gynecologic cytology slides with reference interpretations was run on an automated screening device that selects fields of view (FOVs) based on a hierarchical probability of abnormality being present. An interface was developed between the device and a remote server using customized image review software. FOVs were reviewed by 3 cytotechnologists and 3 cytopathologists, and binary triage (unsatisfactory for evaluation/negative for intraepithelial lesion or malignancy [NILM] vs "abnormal" [neither unsatisfactory nor NILM]) and specific interpretations were done. No morphologic training before FOV review was provided. Three or more reviewers agreed on the correct categorization of NILM/unsatisfactory in 89% (85/96) and abnormal in 83% (79/95). Three or more reviewers triaged cases to abnormal as follows: atypical squamous cells of uncertain significance, 83% (5/6); atypical squamous cells, cannot exclude high-grade lesion, 100% (3/3); low-grade squamous intraepithelial lesion (SIL), 83% (52/63); high-grade SIL, 94% (17/18); and atypical glandular cells, 40% (2/5). This procedure may have comparable sensitivity and specificity and possibly could provide effective initial triage to further evaluation. A review of individual cases suggests that further accuracy can be achieved with additional training and experience.

Cytologic features of endocervical glandular lesions: comparison of SurePath, ThinPrep, and conventional smear specimen preparations.

The cytologic features of endocervical neoplasia have been well-described for conventional and ThinPrep, but not for SurePath, methods. This study is designed to ascertain if cytological features are similar in SurePath specimens. Conventional, ThinPrep and SurePath specimens with either endocervical adenocarcinoma in situ or invasive endocervical adenocarcinoma were evaluated for architectural and cytological features previously described for endocervical neoplasia. A generalized linear model was used to assess the differences of ordinal multinomial data. Of 18 evaluated, the only features showing statistical differences were architectural: large groups of cells and single cells were more frequent in SurePath preparations and conventional smears. Feathering was more frequently noted in conventional smears. Individual cytological features were identical across all groups. Mitoses and apoptotic debris were seen with equal frequency in all preparations. The architectural and cytologic features of endocervical glandular neoplasia in liquid-based specimens show only subtle architectural differences when compared with conventional smears. Keeping these differences in mind, virtually the same criteria can be used to identify endocervical glandular lesions in all three specimen types.