Wilms tumor (WT) is the most frequent pediatric tumor in children and shows highly variable histology, leading to variation in classification. Artificial intelligence-based automatic recognition holds the promise that this may be done in a more consistent way than human observers can. We have therefore studied digital microscopic slides, stained with standard hematoxylin and eosin, of 72 WT patients and used a deep learning (DL) system for the recognition of 15 different normal and tumor components. We show that such DL system can do this task with high accuracy, as exemplified by a Dice score of 0.85 for the 15 components. This approach may allow future automated WT classification.(1) Background: Histopathological assessment of Wilms tumors (WT) is crucial for risk group classification to guide postoperative stratification in chemotherapy pre-treated WT cases. However, due to the heterogeneous nature of the tumor, significant interobserver variation between pathologists in WT diagnosis has been observed, potentially leading to misclassification and suboptimal treatment. We investigated whether artificial intelligence (AI) can contribute to accurate and reproducible histopathological assessment of WT through recognition of individual histopathological tumor components. (2) Methods: We assessed the performance of a deep learning-based AI system in quantifying WT components in hematoxylin and eosin-stained slides by calculating the Sorensen-Dice coefficient for fifteen predefined renal tissue components, including six tumor-related components. We trained the AI system using multiclass annotations from 72 whole-slide images of patients diagnosed with WT. (3) Results: The overall Dice coefficient for all fifteen tissue components was 0.85 and for the six tumor-related components was 0.79. Tumor segmentation worked best to reliably identify necrosis (Dice coefficient 0.98) and blastema (Dice coefficient 0.82). (4) Conclusions: Accurate histopathological classification of WT may be feasible using a digital pathology-based AI system in a national cohort of WT patients.

AimReliably diagnosing or safely excluding serous tubal intraepithelial carcinoma (STIC), a precursor lesion of tubo-ovarian high-grade serous carcinoma (HGSC), is crucial for individual patient care, for better understanding the oncogenesis of HGSC, and for safely investigating novel strategies to prevent tubo-ovarian carcinoma. To optimize STIC diagnosis and increase its reproducibility, we set up a three-round Delphi study. Methods and resultsIn round 1, an international expert panel of 34 gynecologic pathologists, from 11 countries, was assembled to provide input regarding STIC diagnosis, which was used to develop a set of statements. In round 2, the panel rated their level of agreement with those statements on a 9-point Likert scale. In round 3, statements without previous consensus were rated again by the panel while anonymously disclosing the responses of the other panel members. Finally, each expert was asked to approve or disapprove the complete set of consensus statements. The panel indicated their level of agreement with 64 statements. A total of 27 statements (42%) reached consensus after three rounds. These statements reflect the entire diagnostic work-up for pathologists, regarding processing and macroscopy (three statements); microscopy (eight statements); immunohistochemistry (nine statements); interpretation and reporting (four statements); and miscellaneous (three statements). The final set of consensus statements was approved by 85%. ConclusionThis study provides an overview of current clinical practice regarding STIC diagnosis amongst expert gynecopathologists. The experts consensus statements form the basis for a set of recommendations, which may help towards more consistent STIC diagnosis.

In colorectal cancer (CRC), artificial intelligence (AI) can alleviate the laborious task of characterization and reporting on resected biopsies, including polyps, the numbers of which are increasing as a result of CRC population screening programs ongoing in many countries all around the globe. Here, we present an approach to address two major challenges in the automated assessment of CRC histopathology whole-slide images. We present an AI-based method to segment multiple (n=14 ) tissue compartments in the H &E-stained whole-slide image, which provides a different, more perceptible picture of tissue morphology and composition. We test and compare a panel of state-of-the-art loss functions available for segmentation models, and provide indications about their use in histopathology image segmentation, based on the analysis of (a) a multi-centric cohort of CRC cases from five medical centers in the Netherlands and Germany, and (b) two publicly available datasets on segmentation in CRC. We used the best performing AI model as the basis for a computer-aided diagnosis system that classifies colon biopsies into four main categories that are relevant pathologically. We report the performance of this system on an independent cohort of more than 1000 patients. The results show that with a good segmentation network as a base, a tool can be developed which can support pathologists in the risk stratification of colorectal cancer patients, among other possible uses. We have made the segmentation model available for research use on .

Tumor budding (TB), the presence of single cells or small clusters of up to 4 tumor cells at the invasive front of colorectal cancer (CRC), is a proven risk factor for adverse outcomes. International definitions are necessary to reduce interobserver variability. According to the current international guidelines, hotspots at the invasive front should be counted in hematoxylin and eosin (H & E)-stained slides. This is time-consuming and prone to interobserver variability; therefore, there is a need for computer-aided diagnosis solutions. In this study, we report an artificial intelligence-based method for detecting TB in H & E-stained whole slide images. We propose a fully automated pipeline to identify the tumor border, detect tumor buds, characterize them based on the number of tumor cells, and produce a TB density map to identify the TB hotspot. The method outputs the TB count in the hotspot as a computational biomarker. We show that the proposed automated TB detection workflow performs on par with a panel of 5 pathologists at detecting tumor buds and that the hotspot-based TB count is an independent prognosticator in both the univariate and the multivariate analysis, validated on a cohort of n 1/4 981 patients with CRC. Computer-aided detection of tumor buds based on deep learning can perform on par with expert pathologists for the detection and quantification of tumor buds in H & E-stained CRC histopathology slides, strongly facilitating the introduction of budding as an independent prognosticator in clinical routine and clinical trials. & COPY; 2023 THE AUTHORS. Published by Elsevier Inc. on behalf of the United States & Canadian Academy of Pathology. This is an open access article under the CC BY license (http://creativecommons.org/ licenses/by/4.0/).

Current hardware limitations make it impossible to train convolutional neural networks on gigapixel image inputs directly. Recent developments in weakly supervised learning, such as attention-gated multiple instance learning, have shown promising results, but often use multi-stage or patch-wise training strategies risking suboptimal feature extraction, which can negatively impact performance. In this paper, we propose to train a ResNet-34 encoder with an attention-gated classification head in an end-to-end fashion, which we call StreamingCLAM, using a streaming implementation of convolutional layers. This allows us to train end-to-end on 4-gigapixel microscopic images using only slide-level labels.We achieve a mean area under the receiver operating characteristic curve of 0.9757 for metastatic breast cancer detection (CAMELYON16), close to fully supervised approaches using pixel-level annotations. Our model can also detect MYC-gene translocation in histologic slides of diffuse large B-cell lymphoma, achieving a mean area under the ROC curve of 0.8259. Furthermore, we show that our model offers a degree of interpretability through the attention mechanism.

Computational pathology (CPath) algorithms detect, segment or classify cancer in whole slide images, approaching or even exceeding the accuracy of pathologists. Challenges have to be overcome before these algorithms can be used in practice. We therefore aim to explore international perspectives on the future role of CPath in oncological pathology by focusing on opinions and first experiences regarding barriers and facilitators. We conducted an international explorative eSurvey and semi-structured interviews with pathologists utilizing an implementation framework to classify potential influencing factors. The eSurvey results showed remarkable variation in opinions regarding attitude, understandability and validation of CPath. Interview results showed that barriers focused on the quality of available evidence, while most facilitators concerned strengths of CPath. A lack of consensus was present for multiple factors, such as the determination of sufficient validation using CPath, the preferred function of CPath within the digital workflow and the timing of CPath introduction in pathology education. The diversity in opinions illustrates variety in influencing factors in CPath adoption. A next step would be to quantitatively determine important factors for adoption and initiate validation studies. Both should include clear case descriptions and be conducted among a more homogenous panel of pathologists based on sub specialization.

Machine learning model deployment in clinical practice demands real-time risk assessment to identify situations in which the model is uncertain. Once deployed, models should be accurate for classes seen during training while providing informative estimates of uncertainty to flag abnormalities and unseen classes for further analysis. Although recent developments in uncertainty estimation have resulted in an increasing number of methods, a rigorous empirical evaluation of their performance on large-scale digital pathology datasets is lacking. This work provides a benchmark for evaluating prevalent methods on multiple datasets by comparing the uncertainty estimates on both in-distribution and realistic near and far out-of-distribution (OOD) data on a whole-slide level. To this end, we aggregate uncertainty values from patch-based classifiers to whole-slide level uncertainty scores. We show that results found in classical computer vision benchmarks do not always translate to the medical imaging setting. Specifically, we demonstrate that deep ensembles perform best at detecting far-OOD data but can be outperformed on a more challenging near-OOD detection task by multi-head ensembles trained for optimal ensemble diversity. Furthermore, we demonstrate the harmful impact OOD data can have on the performance of deployed machine learning models. Overall, we show that uncertainty estimates can be used to discriminate in-distribution from OOD data with high AUC scores. Still, model deployment might require careful tuning based on prior knowledge of prospective OOD data.

Tumor budding is a histopathological biomarker associated with metastases and adverse survival outcomes in colorectal carcinoma (CRC) patients. It is characterized by the presence of single tumor cells or small clusters of cells within the tumor or at the tumor-invasion front. In order to obtain a tumor budding score for a patient, the region with the highest tumor bud density must first be visually identified by a pathologist, after which buds will be counted in the chosen hotspot field. The automation of this process will expectedly increase efficiency and reproducibility. Here, we present a deep learning convolutional neural network model that automates the above procedure. For model training, we used a semi-supervised learning method, to maximize the detection performance despite the limited amount of labeled training data. The model was tested on an independent dataset in which human- and machine-selected hotspots were mapped in relation to each other and manual and machine detected tumor bud numbers in the manually selected fields were compared. We report the results of the proposed method in comparison with visual assessment by pathologists. We show that the automated tumor bud count achieves a prognostic value comparable with visual estimation, while based on an objective and reproducible quantification. We also explore novel metrics to quantify buds such as density and dispersion and report their prognostic value. We have made the model available for research use on the grand-challenge platform.

In the last decade, the field of computational pathology has advanced at a rapid pace because of the availability of deep neural networks, which achieved their first successes in computer vision tasks in 2012. An important driver for the progress of the field were public competitions, so called Grand Challenges, in which increasingly large data sets were offered to the public to solve clinically relevant tasks. Going from the first Pathology challenges, which had data obtained from 23 patients, to current challenges sharing data of thousands of patients, performance of developed deep learning solutions has reached (and sometimes surpassed) the level of experienced pathologists for specific tasks. We expect future challenges to broaden the horizon, for instance by combining data from radiology, pathology and tumor genetics, and to extract prognostic and predictive information independent of currently used grading schemes.

Through a community-driven competition, the PANDA challenge provides a curated diverse dataset and a catalog of models for prostate cancer pathology, and represents a blueprint for evaluating AI algorithms in digital pathology. Artificial intelligence (AI) has shown promise for diagnosing prostate cancer in biopsies. However, results have been limited to individual studies, lacking validation in multinational settings. Competitions have been shown to be accelerators for medical imaging innovations, but their impact is hindered by lack of reproducibility and independent validation. With this in mind, we organized the PANDA challenge-the largest histopathology competition to date, joined by 1,290 developers-to catalyze development of reproducible AI algorithms for Gleason grading using 10,616 digitized prostate biopsies. We validated that a diverse set of submitted algorithms reached pathologist-level performance on independent cross-continental cohorts, fully blinded to the algorithm developers. On United States and European external validation sets, the algorithms achieved agreements of 0.862 (quadratically weighted kappa, 95% confidence interval (CI), 0.840-0.884) and 0.868 (95% CI, 0.835-0.900) with expert uropathologists. Successful generalization across different patient populations, laboratories and reference standards, achieved by a variety of algorithmic approaches, warrants evaluating AI-based Gleason grading in prospective clinical trials.

Artificial Intelligence (AI) has become of increasing interest over the past decade. While digital image analysis (DIA) is already being used in radiology, it is still in its infancy in pathology. One of the reasons is that large-scale digitization of glass slides has only recently become available. With the advent of digital slide scanners, that digitize glass slides into whole slide images, many labs are now in a transition phase towards digital pathology. However, only few departments worldwide are currently fully digital. Digital pathology provides the ability to annotate large datasets and train computers to develop and validate robust algorithms, similar to radiology. In this opinionated overview, we will give a brief introduction into AI in pathology, discuss the potential positive and negative implications and speculate about the future role of AI in the field of pediatric pathology.

Convolutional neural networks (CNNs) offer the potential to generate comprehensive quantitative analysis of histologic features. Diagnostic reporting of benign breast disease (BBD) biopsies is usually limited to subjective assessment of the most severe lesion in a sample, while ignoring the vast majority of tissue features, including involution of background terminal duct lobular units (TDLUs), the structures from which breast cancers arise. Studies indicate that increased levels of age-related TDLU involution in BBD biopsies predict lower breast cancer risk, and therefore its assessment may have potential value in risk assessment and management. However, assessment of TDLU involution is time-consuming and difficult to standardize and quantitate. Accordingly, we developed a CNN to enable automated quantitative measurement of TDLU involution and tested its performance in 174 specimens selected from the pathology archives at Mayo Clinic, Rochester, MN. The CNN was trained and tested on a subset of 33 biopsies, delineating important tissue types. Nine quantitative features were extracted from delineated TDLU regions. Our CNN reached an overall dice-score of 0.871 (+/- 0.049) for tissue classes versus reference standard annotation. Consensus of four reviewers scoring 705 images for TDLU involution demonstrated substantial agreement with the CNN method (unweighted kappa = 0.747 +/- 0.01). Quantitative involution measures showed anticipated associations with BBD histology, breast cancer risk, breast density, menopausal status, and breast cancer risk prediction scores (p < 0.05). Our work demonstrates the potential to improve risk prediction for women with BBD biopsies by applying CNN approaches to generate automated quantitative evaluation of TDLU involution.

An increasing number of pathology laboratories are now fully digitised, using whole slide imaging (WSI) for routine diagnostics. WSI paves the road to use artificial intelligence (AI) that will play an increasing role in computer-aided diagnosis (CAD). In melanocytic skin lesions, the presence of a dermal mitosis may be an important clue for an intermediate or a malignant lesion and may indicate worse prognosis. In this study a mitosis algorithm primarily developed for breast carcinoma is applied to melanocytic skin lesions. This study aimed to assess whether the algorithm could be used in diagnosing melanocytic lesions, and to study the added value in diagnosing melanocytic lesions in a practical setting. WSIs of a set of hematoxylin and eosin (H&E) stained slides of 99 melanocytic lesions (35 nevi, 4 intermediate melanocytic lesions, and 60 malignant melanomas, including 10 nevoid melanomas), for which a consensus diagnosis was reached by three academic pathologists, were subjected to a mitosis algorithm based on AI. Two academic and six general pathologists specialized in dermatopathology examined the WSI cases two times, first without mitosis annotations and after a washout period of at least 2 months with mitosis annotations based on the algorithm. The algorithm indicated true mitosis in lesional cells, i.e., melanocytes, and non-lesional cells, i.e., mainly keratinocytes and inflammatory cells. A high number of false positive mitosis was indicated as well, comprising melanin pigment, sebaceous glands nuclei, and spindle cell nuclei such as stromal cells and neuroid differentiated melanocytes. All but one pathologist reported more often a dermal mitosis with the mitosis algorithm, which on a regular basis, was incorrectly attributed to mitoses from mainly inflammatory cells. The overall concordance of the pathologists with the consensus diagnosis for all cases excluding nevoid melanoma (n = 89) appeared to be comparable with and without the use of AI (89% vs. 90%). However, the concordance increased by using AI in nevoid melanoma cases (n = 10) (75% vs. 68%). This study showed that in general cases, pathologists perform similarly with the aid of a mitosis algorithm developed primarily for breast cancer. In nevoid melanoma cases, pathologists perform better with the algorithm. From this study, it can be learned that pathologists need to be aware of potential pitfalls using CAD on H&E slides, e.g., misinterpreting dermal mitoses in non-melanotic cells.

In kidney transplant biopsies, both inflammation and chronic changes are important features that predict long-term graft survival. Quantitative scoring of these features is important for transplant diagnostics and kidney research. However, visual scoring is poorly reproducible and labor intensive. The goal of this study was to investigate the potential of convolutional neural networks (CNNs) to quantify inflammation and chronic features in kidney transplant biopsies. A structure segmentation CNN and a lymphocyte detection CNN were applied on 125 whole-slide image pairs of periodic acid-Schiff- and CD3-stained slides. The CNN results were used to quantify healthy and sclerotic glomeruli, interstitial fibrosis, tubular atrophy, and inflammation within both nonatrophic and atrophic tubuli, and in areas of interstitial fibrosis. The computed tissue features showed high correlation with Banff lesion scores of five pathologists (A.A., A.Dend., J.H.B., J.K., and T.N.). Analyses on a small subset showed a moderate correlation toward higher CD3+ cell density within scarred regions and higher CD3+ cell count inside atrophic tubuli correlated with long-term change of estimated glomerular filtration rate. The presented CNNs are valid tools to yield objective quantitative information on glomeruli number, fibrotic tissue, and inflammation within scarred and non-scarred kidney parenchyma in a reproducible manner. CNNs have the potential to improve kidney transplant diagnostics and will benefit the community as a novel method to generate surrogate end points for large-scale clinical studies. (Am J Pathol 2022, 192: 1418-1432; https://doi.org/10.1016/j.ajpath.2022.06.009)

To guide the choice of treatment, every new breast cancer is assessed for aggressiveness (i.e., graded) by an experienced histopathologist. Typically, this tumor grade consists of three components, one of which is the nuclear pleomorphism score (the extent of abnormalities in the overall appearance of tumor nuclei). The degree of nuclear pleomorphism is subjectively classified from 1 to 3, where a score of 1 most closely resembles epithelial cells of normal breast epithelium and 3 shows the greatest abnormalities. Establishing numerical criteria for grading nuclear pleomorphism is challenging, and inter-observer agreement is poor. Therefore, we studied the use of deep learning to develop fully automated nuclear pleomorphism scoring in breast cancer. The reference standard used for training the algorithm consisted of the collective knowledge of an international panel of 10 pathologists on a curated set of regions of interest covering the entire spectrum of tumor morphology in breast cancer. To fully exploit the information provided by the pathologists, a first-of-its-kind deep regression model was trained to yield a continuous scoring rather than limiting the pleomorphism scoring to the standard three-tiered system. Our approach preserves the continuum of nuclear pleomorphism without necessitating a large data set with explicit annotations of tumor nuclei. Once translated to the traditional system, our approach achieves top pathologist-level performance in multiple experiments on regions of interest and whole-slide images, compared to a panel of 10 and 4 pathologists, respectively.

Simple Summary Pathology is a cornerstone in cancer diagnostics, and digital pathology and artificial intelligence-driven image analysis could potentially save time and enhance diagnostic accuracy. For clinical implementation of artificial intelligence, a major question is whether the computer models maintain high performance when applied to new settings. We tested the generalizability of a highly accurate deep learning model for breast cancer metastasis detection in sentinel lymph nodes from, firstly, unseen sentinel node data and, secondly, data with a small change in surgical indication, in this case lymph nodes from axillary dissections. Model performance dropped in both settings, particularly on axillary dissection nodes. Retraining of the model was needed to mitigate the performance drop. The study highlights the generalization challenge of clinical implementation of AI models, and the possibility that retraining might be necessary. Poor generalizability is a major barrier to clinical implementation of artificial intelligence in digital pathology. The aim of this study was to test the generalizability of a pretrained deep learning model to a new diagnostic setting and to a small change in surgical indication. A deep learning model for breast cancer metastases detection in sentinel lymph nodes, trained on CAMELYON multicenter data, was used as a base model, and achieved an AUC of 0.969 (95% CI 0.926-0.998) and FROC of 0.838 (95% CI 0.757-0.913) on CAMELYON16 test data. On local sentinel node data, the base model performance dropped to AUC 0.929 (95% CI 0.800-0.998) and FROC 0.744 (95% CI 0.566-0.912). On data with a change in surgical indication (axillary dissections) the base model performance indicated an even larger drop with a FROC of 0.503 (95%CI 0.201-0.911). The model was retrained with addition of local data, resulting in about a 4% increase for both AUC and FROC for sentinel nodes, and an increase of 11% in AUC and 49% in FROC for axillary nodes. Pathologist qualitative evaluation of the retrained model s output showed no missed positive slides. False positives, false negatives and one previously undetected micro-metastasis were observed. The study highlights the generalization challenge even when using a multicenter trained model, and that a small change in indication can considerably impact the model s performance.

Background: The first sign of metastatic prostate cancer after radical prostatectomy is rising PSA levels in the blood, termed biochemical recurrence. The prediction of recurrence relies mainly on the morphological assessment of prostate cancer using the Gleason grading system. However, in this system, within-grade morphological patterns and subtle histopathological features are currently omitted, leaving a significant amount of prognostic potential unexplored.

Methods: To discover additional prognostic information using artificial intelligence, we trained a deep learning system to predict biochemical recurrence from tissue in H&E-stained microarray cores directly. We developed a morphological biomarker using convolutional neural networks leveraging a nested case-control study of 685 patients and validated on an independent cohort of 204 patients. We use concept-based explainability methods to interpret the learned tissue patterns.

Results: The biomarker provides a strong correlation with biochemical recurrence in two sets (n = 182 and n = 204) from separate institutions. Concept-based explanations provided tissue patterns interpretable by pathologists.

Conclusions: These results show that the model finds predictive power in the tissue beyond the morphological ISUP grading.

Purpose Breast terminal duct lobular units (TDLUs) are the main source of breast cancer (BC) precursors. Higher serum concentrations of hormones and growth factors have been linked to increased TDLU numbers and to elevated BC risk, with variable effects by menopausal status. We assessed associations of circulating factors with breast histology among premenopausal women using artificial intelligence (AI) and preliminarily tested whether parity modifies associations.

Methods Pathology AI analysis was performed on 316 digital images of H&E-stained sections of normal breast tissues from Komen Tissue Bank donors ages ≤ 45 years to assess 11 quantitative metrics. Associations of circulating factors with AI metrics were assessed using regression analyses, with inclusion of interaction terms to assess effect modification.

Results Higher prolactin levels were related to larger TDLU area (p<0.001) and increased presence of adipose tissue proximate to TDLUs (p<0.001), with less significant positive associations for acini counts (p = 0.012), dilated acini (p = 0.043), capillary area (p = 0.014), epithelial area (p = 0.007), and mononuclear cell counts (p = 0.017). Testosterone levels were associated with increased TDLU counts (p<0.001), irrespective of parity, but associations differed by adipose tissue content. AI data for TDLU counts generally agreed with prior visual assessments.

Conclusion Among premenopausal women, serum hormone levels linked to BC risk were also associated with quantitative features of normal breast tissue. These relationships were suggestively modified by parity status and tissue composition. We conclude that the microanatomic features of normal breast tissue may represent a marker of BC risk.

Background Breast terminal duct lobular units (TDLUs), the source of most breast cancer (BC) precursors, are shaped by age-related involution, a gradual process, and postpartum involution (PPI), a dramatic inflammatory process that restores baseline microanatomy after weaning. Dysregulated PPI is implicated in the pathogenesis of postpartum BCs. We propose that assessment of TDLUs in the postpartum period may have value in risk estimation, but characteristics of these tissues in relation to epidemiological factors are incompletely described. Methods Using validated Artificial Intelligence and morphometric methods, we analyzed digitized images of tissue sections of normal breast tissues stained with hematoxylin and eosin from donors &lt;= 45 years from the Komen Tissue Bank (180 parous and 545 nulliparous). Metrics assessed by AI, included: TDLU count; adipose tissue fraction; mean acini count/TDLU; mean dilated acini; mean average acini area; mean "capillary" area; mean epithelial area; mean ratio of epithelial area versus intralobular stroma; mean mononuclear cell count (surrogate of immune cells); mean fat area proximate to TDLUs and TDLU area. We compared epidemiologic characteristics collected via questionnaire by parity status and race, using a Wilcoxon rank sum test or Fishers exact test. Histologic features were compared between nulliparous and parous women (overall and by time between last birth and donation [recent birth: &lt;= 5 years versus remote birth: &gt; 5 years]) using multivariable regression models. Results Normal breast tissues of parous women contained significantly higher TDLU counts and acini counts, more frequent dilated acini, higher mononuclear cell counts in TDLUs and smaller acini area per TDLU than nulliparas (all multivariable analyses p &lt; 0.001). Differences in TDLU counts and average acini size persisted for &gt; 5 years postpartum, whereas increases in immune cells were most marked &lt;= 5 years of a birth. Relationships were suggestively modified by several other factors, including demographic and reproductive characteristics, ethanol consumption and breastfeeding duration. Conclusions Our study identified sustained expansion of TDLU numbers and reduced average acini area among parous versus nulliparous women and notable increases in immune responses within five years following childbirth. Further, we show that quantitative characteristics of normal breast samples vary with demographic features and BC risk factors.

The digitalization of clinical workflows and the increasing performance of deep learning algorithms are paving the way towards new methods for tackling cancer diagnosis. However, the availability of medical specialists to annotate digitized images and free-text diagnostic reports does not scale with the need for large datasets required to train robust computer-aided diagnosis methods that can target the high variability of clinical cases and data produced. This work proposes and evaluates an approach to eliminate the need for manual annotations to train computer-aided diagnosis tools in digital pathology. The approach includes two components, to automatically extract semantically meaningful concepts from diagnostic reports and use them as weak labels to train convolutional neural networks (CNNs) for histopathology diagnosis. The approach is trained (through 10-fold cross-validation) on 3769 clinical images and reports, provided by two hospitals and tested on over 11000 images from private and publicly available datasets. The CNN, trained with automatically generated labels, is compared with the same architecture trained with manual labels. Results show that combining text analysis and end-to-end deep neural networks allows building computer-aided diagnosis tools that reach solid performance (micro-accuracy = 0.908 at image-level) based only on existing clinical data without the need for manual annotations.

The Gleason score is the most important prognostic marker for prostate cancer patients, but it suffers from significant observer variability. Artificial intelligence (AI) systems based on deep learning can achieve pathologist-level performance at Gleason grading. However, the performance of such systems can degrade in the presence of artifacts, foreign tissue, or other anomalies. Pathologists integrating their expertise with feedback from an AI system could result in a synergy that outperforms both the individual pathologist and the system. Despite the hype around AI assistance, existing literature on this topic within the pathology domain is limited. We investigated the value of AI assistance for grading prostate biopsies. A panel of 14 observers graded 160 biopsies with and without AI assistance. Using AI, the agreement of the panel with an expert reference standard increased significantly (quadratically weighted Cohens kappa, 0.799 vs. 0.872;p = 0.019). On an external validation set of 87 cases, the panel showed a significant increase in agreement with a panel of international experts in prostate pathology (quadratically weighted Cohens kappa, 0.733 vs. 0.786;p = 0.003). In both experiments, on a group-level, AI-assisted pathologists outperformed the unassisted pathologists and the standalone AI system. Our results show the potential of AI systems for Gleason grading, but more importantly, show the benefits of pathologist-AI synergy.

The global digital transformation enables computational audiology for advanced clinical applications that can reduce the global burden of hearing loss. In this article, we describe emerging hearing-related artificial intelligence applications and argue for their potential to improve access, precision, and efficiency of hearing health care services. Also, we raise awareness of risks that must be addressed to enable a safe digital transformation in audiology. We envision a future where computational audiology is implemented via interoperable systems using shared data and where health care providers adopt expanded roles within a network of distributed expertise. This effort should take place in a health care system where privacy, responsibility of each stakeholder, and patients safety and autonomy are all guarded by design.

Recent advances in machine learning techniques have created opportunities to improve medical diagnostics, but implementing these advances in the clinic will not be without challenge. Machine learning techniques have great potential to improve medical diagnostics, offering ways to improve accuracy, reproducibility and speed, and to ease workloads for clinicians. In the field of histopathology, deep learning algorithms have been developed that perform similarly to trained pathologists for tasks such as tumor detection and grading. However, despite these promising results, very few algorithms have reached clinical implementation, challenging the balance between hope and hype for these new techniques. This Review provides an overview of the current state of the field, as well as describing the challenges that still need to be addressed before artificial intelligence in histopathology can achieve clinical value.

Prostate cancer is the most prevalent cancer among men in Western countries, with 1.1 million new diagnoses every year. The gold standard for the diagnosis of prostate cancer is a pathologists evaluation of prostate tissue. To potentially assist pathologists deep/learning/based cancer detection systems have been developed. Many of the state-of-the- art models are patch/based convolutional neural networks, as the use of entire scanned slides is hampered by memory limitations on accelerator cards. Patch-based systems typically require detailed, pixel-level annotations for effective training. However, such annotations are seldom readily available, in contrast to the clinical reports of pathologists, which contain slide-level labels. As such, developing algorithms which do not require manual pixel-wise annotations, but can learn using only the clinical report would be a significant advancement for the field. In this paper, we propose to use a streaming implementation of convolutional layers, to train a modern CNN (ResNet/34) with 21 million parameters end-to-end on 4712 prostate biopsies. Themethod enables the use of entire biopsy images at high-resolution directly by reducing the GPUmemory requirements by 2.4 TB. We show thatmodern CNNs, trained using our streaming approach, can extract meaningful features from high-resolution images without additional heuristics, reaching similar performance as state-of-the-art patch-based and multiple-instance learning methods. By circumventing the need for manual annotations, this approach can function as a blueprint for other tasks in histopathological diagnosis. The source code to reproduce the streaming models is available at https://github.com/DIAGNijmegen/ pathology-streaming-pipeline.

In this work, we propose a deep learning system for weakly supervised object detection in digital pathology whole slide images. We designed the system to be organ- and object-agnostic, and to be adapted on-the-fly to detect novel objects based on a few examples provided by the user. We tested our method on detection of healthy glands in colon biopsies and ductal carcinoma in situ (DCIS) of the breast, showing that (1) the same system is capable of adapting to detect requested objects with high accuracy, namely 87% accuracy assessed on 582 detections in colon tissue, and 93% accuracy assessed on 163 DCIS detections in breast tissue; (2) in some settings, the system is capable of retrieving similar cases with little to none false positives (i.e., precision equal to 1.00); (3) the performance of the system can benefit from previously detected objects with high confidence that can be reused in new searches in an iterative fashion.

We propose HookNet, a semantic segmentation model for histopathology whole-slide images, which combines context and details via multiple branches of encoder-decoder convolutional neural networks. Concentric patches at multiple resolutions with different fields of view, feed different branches of HookNet, and intermediate representations are combined via a hooking mechanism. We describe a framework to design and train HookNet for achieving high-resolution semantic segmentation and introduce constraints to guarantee pixel-wise alignment in feature maps during hooking. We show the advantages of using HookNet in two histopathology image segmentation tasks where tissue type prediction accuracy strongly depends on contextual information, namely (1) multi-class tissue segmentation in breast cancer and, (2) segmentation of tertiary lymphoid structures and germinal centers in lung cancer. We show the superiority of HookNet when compared with single-resolution U-Net models working at different resolutions as well as with a recently published multi-resolution model for histopathology image segmentation. We have made HookNet publicly available by releasing the source coder as well as in the form of web-based applications) :3 based on the grand-challenge.org platform. (C) 2020 The Authors. Published by Elsevier B.V.

Tumor budding is a long-established independent adverse prognostic marker in colorectal cancer, yet methods for its assessment have varied widely. In an effort to standardize its reporting, a group of experts met in Bern, Switzerland, in 2016 to reach consensus on a single, international, evidence-based method for tumor budding assessment and reporting (International Tumor Budding Consensus Conference [ITBCC]). Tumor budding assessment using the ITBCC criteria has been validated in large cohorts of cancer patients and incorporated into several international colorectal cancer pathology and clinical guidelines. With the wider reporting of tumor budding, new issues have emerged that require further clarification. To better inform researchers and health-care professionals on these issues, an international group of experts in gastrointestinal pathology participated in a modified Delphi process to generate consensus and highlight areas requiring further research. This effort serves to re-affirm the importance of tumor budding in colorectal cancer and support its continued use in routine clinical practice.

The tumour microenvironment has been shown to be a valuable source of prognostic information for different cancer types. This holds in particular for triple negative breast cancer (TNBC), a breast cancer subtype for which currently no prognostic biomarkers are established. Although different methods to assess tumour infiltrating lymphocytes (TILs) have been published, it remains unclear which method (marker, region) yields the most optimal prognostic information. In addition, to date, no objective TILs assessment methods are available. For this proof of concept study, a subset of our previously described TNBC cohort (n = 94) was stained for CD3, CD8 and FOXP3 using multiplex immunohistochemistry and subsequently imaged by a multispectral imaging system. Advanced whole-slide image analysis algorithms, including convolutional neural networks (CNN) were used to register unmixed multispectral images and corresponding H&E sections, to segment the different tissue compartments (tumour, stroma) and to detect all individual positive lymphocytes. Densities of positive lymphocytes were analysed in different regions within the tumour and its neighbouring environment and correlated to relapse free survival (RFS) and overall survival (OS). We found that for all TILs markers the presence of a high density of positive cells correlated with an improved survival. None of the TILs markers was superior to the others. The results of TILs assessment in the various regions did not show marked differences between each other. The negative correlation between TILs and survival in our cohort are in line with previous studies. Our results provide directions for optimizing TILs assessment methodology. (C) 2021 The Author(s). Published by Elsevier Ltd.

Delayed graft function (DGF) is a strong risk factor for development of interstitial fibrosis and tubular atrophy (IFTA) in kidney transplants. Quantitative assessment of inflammatory infiltrates in kidney biopsies of DGF patients can reveal predictive markers for IFTA development. In this study, we combined multiplex tyramide signal amplification (mTSA) and convolutional neural networks (CNNs) to assess the inflammatory microenvironment in kidney biopsies of DGF patients (n = 22) taken at 6 weeks post-transplantation. Patients were stratified for IFTA development (&lt;10% versus &gt;= 10%) from 6 weeks to 6 months post-transplantation, based on histopathological assessment by three kidney pathologists. One mTSA panel was developed for visualization of capillaries, T- and B-lymphocytes and macrophages and a second mTSA panel for T-helper cell and macrophage subsets. The slides were multi spectrally imaged and custom-made python scripts enabled conversion to artificial brightfield whole-slide images (WSI). We used an existing CNN for the detection of lymphocytes with cytoplasmatic staining patterns in immunohistochemistry and developed two new CNNs for the detection of macrophages and nuclear-stained lymphocytes. F1-scores were 0.77 (nuclear-stained lymphocytes), 0.81 (cytoplasmatic-stained lymphocytes), and 0.82 (macrophages) on a test set of artificial brightfield WSI. The CNNs were used to detect inflammatory cells, after which we assessed the peritubular capillary extent, cell density, cell ratios, and cell distance in the two patient groups. In this cohort, distance of macrophages to other immune cells and peritubular capillary extent did not vary significantly at 6 weeks post-transplantation between patient groups. CD163(+) cell density was higher in patients with &gt;= 10% IFTA development 6 months post-transplantation (p &lt; 0.05). CD3(+)CD8(-)/CD3(+)CD8(+) ratios were higher in patients with &lt;10% IFTA development (p &lt; 0.05). We observed a high correlation between CD163(+) and CD4(+)GATA3(+) cell density (R = 0.74, p &lt; 0.001). Our study demonstrates that CNNs can be used to leverage reliable, quantitative results from mTSA-stained, multi spectrally imaged slides of kidney transplant biopsies. This study describes a methodology to assess the microenvironment in sparse tissue samples. Deep learning, multiplex immunohistochemistry, and mathematical image processing techniques were incorporated to quantify lymphocytes, macrophages, and capillaries in kidney transplant biopsies of delayed graft function patients. The quantitative results were used to assess correlations with development of interstitial fibrosis and tubular atrophy.

Variation between stains in histopathology is commonplace across different medical centers. This can have a significant effect on the reliability of machine learning algorithms. In this paper, we propose to reduce performance variability by using-consistent generative adversarial (CycleGAN) networks to remove staining variation. We improve upon the regular CycleGAN by incorporating residual learning. We comprehensively evaluate the performance of our stain transformation method and compare its usefulness in addition to extensive data augmentation to enhance the robustness of tissue segmentation algorithms. Our steps are as follows: first, we train a model to perform segmentation on tissue slides from a single source center, while heavily applying augmentations to increase robustness to unseen data. Second, we evaluate and compare the segmentation performance on data from other centers, both with and without applying our CycleGAN stain transformation. We compare segmentation performances in a colon tissue segmentation and kidney tissue segmentation task, covering data from 6 different centers. We show that our transformation method improves the overall Dice coefficient by 9% over the non-normalized target data and by 4% over traditional stain transformation in our colon tissue segmentation task. For kidney segmentation, our residual CycleGAN increases performance by 10% over no transformation and around 2% compared to the non-residual CycleGAN. (c) 2021 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license ( http://creativecommons.org/licenses/by/4.0/ )

Tumor budding is a promising and cost-effective biomarker with strong prognostic value in colorectal cancer. However, challenges related to interobserver variability persist. Such variability may be reduced by immunohistochemistry and computer-aided tumor bud selection. Development of computer algorithms for this purpose requires unequivocal examples of individual tumor buds. As such, we undertook a large-scale, international, and digital observer study on individual tumor bud assessment. From a pool of 46 colorectal cancer cases with tumor budding, 3000 tumor bud candidates were selected, largely based on digital image analysis algorithms. For each candidate bud, an image patch (size 256 x 256 mu m) was extracted from a pan cytokeratin-stained whole-slide image. Members of an International Tumor Budding Consortium (n = 7) were asked to categorize each candidate as either (1) tumor bud, (2) poorly differentiated cluster, or (3) neither, based on current definitions. Agreement was assessed with Cohens and Fleiss Kappa statistics. Fleiss Kappa showed moderate overall agreement between observers (0.42 and 0.51), while Cohens Kappas ranged from 0.25 to 0.63. Complete agreement by all seven observers was present for only 34% of the 3000 tumor bud candidates, while 59% of the candidates were agreed on by at least five of the seven observers. Despite reports of moderate-to-substantial agreement with respect to tumor budding grade, agreement with respect to individual pan cytokeratin-stained tumor buds is moderate at most. A machine learning approach may prove especially useful for a more robust assessment of individual tumor buds.

Much research has focused on finding novel prognostic biomarkers for triple negative breast cancer (TNBC), whereas only scattered information about the relation between histopathological features and survival in TNBC is available. This study aims to explore the prognostic value of histological subtypes in TNBC. A multicenter retrospective TNBC cohort was established from five Dutch hospitals. All non-neoadjuvantly treated, stage I-III patients with estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 negative breast cancer diagnosed between 2006 and 2014 were included. Clinical and follow-up data (overall survival; OS, relapse free survival; RFS) were retrieved and a central histopathological review was performed. Of 597 patients included (median follow up 62.8 months, median age at diagnosis 56.0 years), 19.4% developed a recurrence. The most prevalent histological subtypes were carcinoma of no special type (NST) (88.4%), metaplastic carcinoma (4.4%) and lobular carcinoma (3.4%). Collectively, tumors of special type were associated with a worse RFS and OS compared to carcinoma NST (RFS HR 1.89; 95% CI 1.18-3.03; p = 0.008; OS HR 1.94; 95% CI 1.28-2.92; p = 0.002). Substantial differences in survival, however, were present between the different histological subtypes. In the presented TNBC cohort, special histological subtype was in general associated with less favorable survival. However, within the group of tumors of special type there were differences in survival between the different subtypes. Accurate histological examination can provide specific prognostic information that may potentially enable more personalized treatment and surveillance regimes for TNBC patients.

Algorithms can improve the objectivity and efficiency of histopathologic slide analysis. In this paper, we investigated the impact of scanning systems (scanners) and cycle-GAN-based normalization on algorithm performance, by comparing different deep learning models to automatically detect prostate cancer in whole-slide images. Specifically, we compare U-Net, DenseNet and EfficientNet. Models were developed on a multi-center cohort with 582 WSIs and subsequently evaluated on two independent test sets including 85 and 50 WSIs, respectively, to show the robustness of the proposed method to differing staining protocols and scanner types. We also investigated the application of normalization as a pre-processing step by two techniques, the whole-slide image color standardizer (WSICS) algorithm, and a cycle-GAN based method. For the two independent datasets we obtained an AUC of 0.92 and 0.83 respectively. After rescanning the AUC improves to 0.91/0.88 and after style normalization to 0.98/0.97. In the future our algorithm could be used to automatically pre-screen prostate biopsies to alleviate the workload of pathologists.

Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring.

The introduction of digital pathology is changing the practice of diagnostic anatomic pathology. Digital pathology offers numerous advantages over using a physical slide on a physical microscope, including more discriminative tools to render a more precise diagnostic report. The development of these tools is being facilitated by public challenges related to specific diagnostic tasks within anatomic pathology. To date, 24 public challenges related to pathology tasks have been published. This article discusses these public challenges and briefly reviews the underlying characteristics of public challenges and why they are helpful to the development of digital tools.

In this white paper, experts from the Digital Pathology Association (DPA) define terminology and concepts in the emerging field of computational pathology, with a focus on its application to histology images analyzed together with their associated patient data to extract information. This review offers a historical perspective and describes the potential clinical benefits from research and applications in this field, as well as significant obstacles to adoption. Best practices for implementing computational pathology workflows are presented. These include infrastructure considerations, acquisition of training data, quality assessments, as well as regulatory, ethical, and cyber-security concerns. Recommendations are provided for regulators, vendors, and computational pathology practitioners in order to facilitate progress in the field. (c) 2019 The Authors. The Journal of Pathology published by John Wiley amp; Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

PurposeTumor-stroma ratio (TSR) serves as an independent prognostic factor in colorectal cancer and other solid malignancies. The recent introduction of digital pathology in routine tissue diagnostics holds opportunities for automated TSR analysis. We investigated the potential of computer-aided quantification of intratumoral stroma in rectal cancer whole-slide images.MethodsHistological slides from 129 rectal adenocarcinoma patients were analyzed by two experts who selected a suitable stroma hot-spot and visually assessed TSR. A semi-automatic method based on deep learning was trained to segment all relevant tissue types in rectal cancer histology and subsequently applied to the hot-spots provided by the experts. Patients were assigned to a stroma-high or stroma-low group by both TSR methods (visual and automated). This allowed for prognostic comparison between the two methods in terms of disease-specific and disease-free survival times.ResultsWith stroma-low as baseline, automated TSR was found to be prognostic independent of age, gender, pT-stage, lymph node status, tumor grade, and whether adjuvant therapy was given, both for disease-specific survival (hazard ratio=2.48 (95% confidence interval 1.29-4.78)) and for disease-free survival (hazard ratio=2.05 (95% confidence interval 1.11-3.78)). Visually assessed TSR did not serve as an independent prognostic factor in multivariate analysis.ConclusionsThis work shows that TSR is an independent prognosticator in rectal cancer when assessed automatically in user-provided stroma hot-spots. The deep learning-based technology presented here may be a significant aid to pathologists in routine diagnostics.

As part of routine histological grading, for every invasive breast cancer the mitotic count is assessed by counting mitoses in the (visually selected) region with the highest proliferative activity. Because this procedure is prone to subjectivity, the present study compares visual mitotic counting with deep learning based automated mitotic counting and fully automated hotspot selection. Two cohorts were used in this study. Cohort A comprised 90 prospectively included tumors which were selected based on the mitotic frequency scores given during routine glass slide diagnostics. This pathologist additionally assessed the mitotic count in these tumors in whole slide images (WSI) within a preselected hotspot. A second observer performed the same procedures on this cohort. The preselected hotspot was generated by a convolutional neural network (CNN) trained to detect all mitotic figures in digitized hematoxylin and eosin (Hamp;E) sections. The second cohort comprised a multicenter, retrospective TNBC cohort (n = 298), of which the mitotic count was assessed by three independent observers on glass slides. The same CNN was applied on this cohort and the absolute number of mitotic figures in the hotspot was compared to the averaged mitotic count of the observers. Baseline interobserver agreement for glass slide assessment in cohort A was good (kappa 0.689; 95% CI 0.580-0.799). Using the CNN generated hotspot in WSI, the agreement score increased to 0.814 (95% CI 0.719-0.909). Automated counting by the CNN in comparison with observers counting in the predefined hotspot region yielded an average kappa of 0.724. We conclude that manual mitotic counting is not affected by assessment modality (glass slides, WSI) and that counting mitotic figures in WSI is feasible. Using a predefined hotspot area considerably improves reproducibility. Also, fully automated assessment of mitotic score appears to be feasible without introducing additional bias or variability.

Background The development of deep neural networks is facilitating more advanced digital analysis of histopathologic images. We trained a convolutional neural network for multiclass segmentation of digitized kidney tissue sections stained with periodic acid-Schiff (PAS). Methods We trained the network using multiclass annotations from 40 whole-slide images of stained kidney transplant biopsies and applied it to four independent data sets. We assessed multiclass segmentation performance by calculating Dice coefficients for ten tissue classes on ten transplant biopsies from the Radboud University Medical Center in Nijmegen, The Netherlands, and on ten transplant biopsies from an external center for validation. We also fully segmented 15 nephrectomy samples and calculated the networks glomerular detection rates and compared network-based measures with visually scored histologic components (Banff classification) in 82 kidney transplant biopsies. Results The weighted mean Dice coefficients of all classes were 0.80 and 0.84 in ten kidney transplant biopsies from the Radboud center and the external center, respectively. The best segmented class was "glomeruli" in both data sets (Dice coefficients, 0.95 and 0.94, respectively), followed by "tubuli combined" and "interstitium." The network detected 92.7% of all glomeruli in nephrectomy samples, with 10.4% false positives. In whole transplant biopsies, the mean intraclass correlation coefficient for glomerular counting performed by pathologists versus the network was 0.94. We found significant correlations between visually scored histologic components and network-based measures. Conclusions This study presents the first convolutional neural network for multiclass segmentation of PAS-stained nephrectomy samples and transplant biopsies. Our network may have utility for quantitative studies involving kidney histopathology across centers and provide opportunities for deep learning applications in routine diagnostics.

The immune system is of critical importance in the development of cancer. The evasion of destruction by the immune system is one of the emerging hallmarks of cancer. We have built a dataset of 171,166 manually annotated CD3(+) and CD8(+) cells, which we used to train deep learning algorithms for automatic detection of lymphocytes in histopathology images to better quantify immune response. Moreover, we investigate the effectiveness of four deep learning based methods when different subcompartments of the whole-slide image are considered: normal tissue areas, areas with immune cell clusters, and areas containing artifacts. We have compared the proposed methods in breast, colon and prostate cancer tissue slides collected from nine different medical centers. Finally, we report the results of an observer study on lymphocyte quantification, which involved four pathologists from different medical centers, and compare their performance with the automatic detection. The results give insights on the applicability of the proposed methods for clinical use. U-Net obtained the highest performance with an F1-score of 0.78 and the highest agreement with manual evaluation (kappa = 0.72), whereas the average pathologists agreement with reference standard was kappa = 0.64. The test set and the automatic evaluation procedure are publicly available at lyon19.grand-challenge.org. (C) 2019 Elsevier B.V. All rights reserved.

A deep-learning model for cancer detection trained on a large number of scanned pathology slides and associated diagnosis labels enables model development without the need for pixel-level annotations.

Stain variation is a phenomenon observed when distinct pathology laboratories stain tissue slides that exhibit similar but not identical color appearance. Due to this color shift between laboratories, convolutional neural networks (CNNs) trained with images from one lab often underperform on unseen images from the other lab. Several techniques have been proposed to reduce the generalization error, mainly grouped into two categories: stain color augmentation and stain color normalization. The former simulates a wide variety of realistic stain variations during training, producing stain-invariant CNNs. The latter aims to match training and test color distributions in order to reduce stain variation. For the first time, we compared some of these techniques and quantified their effect on CNN classification performance using a heterogeneous dataset of hematoxylin and eosin histopathology images from 4 organs and 9 pathology laboratories. Additionally, we propose a novel unsupervised method to perform stain color normalization using a neural network. Based on our experimental results, we provide practical guidelines on how to use stain color augmentation and stain color normalization in future computational pathology applications. (C) 2019 Elsevier B.V. All rights reserved.