Z-stack scanning is an emerging whole slide imaging technology that captures multiple focal planes alongside the z-axis of a glass slide. Because z-stacking can offer enhanced depth information compared to the single-layer whole slide imaging, this technology can be particularly useful in analyzing small-scaled histopathological patterns. However, its actual clinical impact remains debated with mixed results. To clarify this, we investigate the effect of z-stack scanning on artificial intelligence (AI) mitosis detection of meningiomas. With the same set of 22 Hematoxylin and Eosin meningioma glass slides scanned by three different digital pathology scanners, we tested the performance of three AI pipelines on both single-layer and z-stacked whole slide images (WSIs). Results showed that in all scanner-AI combinations, z-stacked WSIs significantly increased AI's sensitivity (+17.14%) on the mitosis detection with only a marginal impact on precision. Our findings provide quantitative evidence that highlights z-stack scanning as a promising technique for AI mitosis detection, paving the way for more reliable AI-assisted pathology workflows, which can ultimately benefit patient management.
The expansion of artificial intelligence (AI) in pathology tasks has intensified the demand for doctors' annotations in AI development. However, collecting high-quality annotations from doctors is costly and time-consuming, creating a bottleneck in AI progress. This study investigates eye-tracking as a cost-effective technology to collect doctors' behavioral data for AI training with a focus on the pathology task of mitosis detection. One major challenge in using eye-gaze data is the low signal-to-noise ratio, which hinders the extraction of meaningful information. We tackled this by levering the properties of inter-observer eye-gaze consistencies and creating eye-gaze labels from consistent eye-fixations shared by a group of observers. Our study involved 14 non-medical participants, from whom we collected eye-gaze data and generated eye-gaze labels based on varying group sizes. We assessed the efficacy of such eye-gaze labels by training Convolutional Neural Networks (CNNs) and comparing their performance to those trained with ground truth annotations and a heuristic-based baseline. Results indicated that CNNs trained with our eye-gaze labels closely followed the performance of ground-truth-based CNNs, and significantly outperformed the baseline. Although primarily focused on mitosis, we envision that insights from this study can be generalized to other medical imaging tasks.
Introduction: Nottingham grading system is a major prognostic factor for invasive breast carcinoma (IBC). Its determination requires the evaluation of the mitotic score (MS) which is subject to low intra- and inter-observer reproducibility. The MS shall be performed in the most proliferative area of the tumor, which determination is hard but critical. Artificial intelligence based tools could help pathologists to detect mitosis on whole slide images (WSI). Objective: The aim of this study was to evaluate the contribution of a mitosis detection algorithms pecifically developed to assist the pathologist during the evaluation of the MS on WSI. Methods: Algorithmic mitosis detection is a two-step process: first the algorithm detects candidate objects resembling mitosis, then the selection is refined by a classifier. The densest mitoticregions are shown to the pathologist, then he can establish the MS with algorithm results. For this study, three expert pathologists have determined a consensual ground truth for MS on fifty WSI of IBC. Those slides were also submitted to two readers pathologists who evaluated the MS of each slide twice, with and without the assistance of the algorithm, with a four week wash-out period. Interobserver reproducibility was measured by evaluating the scores obtained with, and without assistance between two readers pathologists and was also measured between each reader pathologist and the expert ground truth to determine the accuracy of the established score. Results:Baseline linearly weighted Cohen's Kappa for interobserver agreement of MS between two readers pathologists was 0.482. Using the algorithm generated mitotic detection in WSI, the agreement score increased to 0.672. Baseline linearly weighted Cohen's Kappa for interobserver agreement of MS between each reader pathologist and expert consensus was 0.378 and 0.457 for pathologist 1 and 2 respectively. Using the algorithm generated mitoticdetection in WSI, the agreement score increased respectively to 0.629 and 0.726. Conclusion:The use of the developed algorithm constitutes a viable approach to assist the pathologist for the evaluation of the MS of IBC on WSI. Its use makes it possible to improve interobserver reproducibility between pathologists and the accuracy of the score established by expert consensus. The use of such a tool constitutes a new approach in the evaluation of the mitoticscore which could lead to an evolution of practices.
In certain types of cancerous tissue, mitotic count has been shown to be associated with tumor proliferation, poor prognosis, and therapeutic resistance. Due to the high inter-rater variability of mitotic counting by pathologists, convolutional neural networks (CNNs) have been employed to reduce the subjectivity of mitosis detection in hematoxylin and eosin (H&E)-stained whole slide images. However, most existing models have performance that lags behind expert panel review and only incorporate visual information. In this work, we demonstrate that pre-trained large-scale vision-language models that leverage both visual features and natural language improve mitosis detection accuracy. We formulate the mitosis detection task as an image captioning task and a visual question answering (VQA) task by including metadata such as tumor and scanner types as context. The effectiveness of our pipeline is demonstrated via comparison with various baseline models using 9,501 mitotic figures and 11,051 hard negatives (non-mitotic figures that are difficult to characterize) from the publicly available Mitosis Domain Generalization Challenge (MIDOG22) dataset.
Mitosis detection is one of the fundamental tasks in computational pathology, which is extremely challenging due to the heterogeneity of mitotic cell. Most of the current studies solve the heterogeneity in the technical aspect by increasing the model complexity. However, lacking consideration of the biological knowledge and the complex model design may lead to the overfitting problem while limited the generalizability of the detection model. In this paper, we systematically study the morphological appearances in different mitotic phases as well as the ambiguous non-mitotic cells and identify that balancing the data and feature diversity can achieve better generalizability. Based on this observation, we propose a novel generalizable framework (MitDet) for mitosis detection. The data diversity is considered by the proposed diversity-guided sample balancing (DGSB). And the feature diversity is preserved by inter- and intra- class feature diversity-preserved module (InCDP). Stain enhancement (SE) module is introduced to enhance the domain-relevant diversity of both data and features simultaneously. Extensive experiments have demonstrated that our proposed model outperforms all the SOTA approaches in several popular mitosis detection datasets in both internal and external test sets using minimal annotation efforts with point annotations only. Comprehensive ablation studies have also proven the effectiveness of the rethinking of data and feature diversity balancing. By analyzing the results quantitatively and qualitatively, we believe that our proposed model not only achieves SOTA performance but also might inspire the future studies in new perspectives. Source code is at https://github.com/Onehour0108/MitDet.
Detection of mitosis events plays an important role in biomedical research. Deep-learning-based mitosis detection methods have achieved outstanding performance with a certain amount of labeled data. However, these methods require annotations for each imaging condition. Collecting labeled data involves time-consuming human labor. In this paper, we propose a mitosis detection method that can be trained with partially annotated sequences. The base idea is to generate a fully labeled dataset from the partial labels and train a mitosis detection model with the generated dataset. First, we generate an image pair not containing mitosis events by frame-order flipping. Then, we paste mitosis events to the image pair by alpha-blending pasting and generate a fully labeled dataset. We demonstrate the performance of our method on four datasets, and we confirm that our method outperforms other comparisons which use partially labeled sequences.
Mitosis detection is one of the challenging problems in computational pathology, and mitotic count is an important index of cancer grading for pathologists. However, current counts of mitotic nuclei rely on pathologists looking microscopically at the number of mitotic nuclei in hot spots, which is subjective and time-consuming. In this paper, we propose a two-stage cascaded network, named FoCasNet, for mitosis detection. In the first stage, a detection network named M_det is proposed to detect as many mitoses as possible. In the second stage, a classification network M_class is proposed to refine the results of the first stage. In addition, the attention mechanism, normalization method, and hybrid anchor branch classification subnet are introduced to improve the overall detection performance. Our method achieves the current highest F1-score of 0.888 on the public dataset ICPR 2012. We also evaluated our method on the GZMH dataset released by our research team for the first time and reached the highest F1-score of 0.563, which is also better than multiple classic detection networks widely used at present. It confirmed the effectiveness and generalization of our method. The code will be available at: https://github.com/antifen/mitosis-nuclei-detection.
Making histopathology image classifiers robust to a wide range of real-world variability is a challenging task. Here, we describe a candidate deep learning solution for the Mitosis Domain Generalization Challenge 2022 (MIDOG) to address the problem of generalization for mitosis detection in images of hematoxylin-eosin-stained histology slides under high variability (scanner, tissue type and species variability). Our approach consists in training a rotation-invariant deep learning model using aggressive data augmentation with a training set enriched with hard negative examples and automatically selected negative examples from the unlabeled part of the challenge dataset. To optimize the performance of our models, we investigated a hard negative mining regime search procedure that lead us to train our best model using a subset of image patches representing 19.6% of our training partition of the challenge dataset. Our candidate model ensemble achieved a F1-score of .697 on the final test set after automated evaluation on the challenge platform, achieving the third best overall score in the MIDOG 2022 Challenge.
Mitotic activity is a crucial proliferation biomarker for the diagnosis and prognosis of different types of cancers. Nevertheless, mitosis counting is a cumbersome process for pathologists, prone to low reproducibility, due to the large size of augmented biopsy slides, the low density of mitotic cells, and pattern heterogeneity. To improve reproducibility, deep learning methods have been proposed in the last years using convolutional neural networks. However, these methods have been hindered by the process of data labelling, which usually solely consist of the mitosis centroids. Therefore, current literature proposes complex algorithms with multiple stages to refine the labels at pixel level, and to reduce the number of false positives. In this work, we propose to avoid complex scenarios, and we perform the localization task in a weakly supervised manner, using only image-level labels on patches. The results obtained on the publicly available TUPAC16 dataset are competitive with state-of-the-art methods, using only one training phase. Our method achieves an F1-score of 0.729 and challenges the efficiency of previous methods, which required multiple stages and strong mitosis location information.
The effective localization of mitosis is a critical precursory task for deciding tumor prognosis and grade. Automated mitosis detection through deep learning-oriented image analysis often fails on unseen patient data due to inherent domain biases. This paper proposes a domain homogenizer for mitosis detection that attempts to alleviate domain differences in histology images via adversarial reconstruction of input images. The proposed homogenizer is based on a U-Net architecture and can effectively reduce domain differences commonly seen with histology imaging data. We demonstrate our domain homogenizer's effectiveness by observing the reduction in domain differences between the preprocessed images. Using this homogenizer, along with a subsequent retina-net object detector, we were able to outperform the baselines of the 2021 MIDOG challenge in terms of average precision of the detected mitotic figures.
The account of mitotic cells is a key feature in tumor diagnosis. However, due to the variability of mitotic cell morphology, it is a highly challenging task to detect mitotic cells in tumor tissues. At the same time, although advanced deep learning method have achieved great success in cell detection, the performance is often unsatisfactory when tested data from another domain (i.e. the different tumor types and different scanners). Therefore, it is necessary to develop algorithms for detecting mitotic cells with robustness in domain shifts scenarios. Our work further proposes a foreground detection and tumor classification task based on the baseline(Retinanet), and utilizes data augmentation to improve the domain generalization performance of our model. We achieve the state-of-the-art performance (F1 score: 0.5809) on the challenging premilary test dataset.
Counting of mitotic figures is a fundamental step in grading and prognostication of several cancers. However, manual mitosis counting is tedious and time-consuming. In addition, variation in the appearance of mitotic figures causes a high degree of discordance among pathologists. With advances in deep learning models, several automatic mitosis detection algorithms have been proposed but they are sensitive to {\em domain shift} often seen in histology images. We propose a robust and efficient two-stage mitosis detection framework, which comprises mitosis candidate segmentation ({\em Detecting Fast}) and candidate refinement ({\em Detecting Slow}) stages. The proposed candidate segmentation model, termed \textit{EUNet}, is fast and accurate due to its architectural design. EUNet can precisely segment candidates at a lower resolution to considerably speed up candidate detection. Candidates are then refined using a deeper classifier network, EfficientNet-B7, in the second stage. We make sure both stages are robust against domain shift by incorporating domain generalization methods. We demonstrate state-of-the-art performance and generalizability of the proposed model on the three largest publicly available mitosis datasets, winning the two mitosis domain generalization challenge contests (MIDOG21 and MIDOG22). Finally, we showcase the utility of the proposed algorithm by processing the TCGA breast cancer cohort (1,125 whole-slide images) to generate and release a repository of more than 620K mitotic figures.
This work presents a mitosis detection method with only one vanilla Convolutional Neural Network (CNN). Our method consists of two steps: given an image, we first apply a CNN using a sliding window technique to extract patches that have mitoses; we then calculate each extracted patch's class activation map to obtain the mitosis's precise location. To increase the model performance on high-domain-variance pathology images, we train the CNN with a data augmentation pipeline, a noise-tolerant loss that copes with unlabeled images, and a multi-rounded active learning strategy. In the MIDOG 2022 challenge, our approach, with an EfficientNet-b3 CNN model, achieved an overall F1 score of 0.7323 in the preliminary test phase, and 0.6847 in the final test phase (task 1). Our approach sheds light on the broader applicability of class activation maps for object detections in pathology images.
The density of mitotic figures within tumor tissue is known to be highly correlated with tumor proliferation and thus is an important marker in tumor grading. Recognition of mitotic figures by pathologists is known to be subject to a strong inter-rater bias, which limits the prognostic value. State-of-the-art deep learning methods can support the expert in this assessment but are known to strongly deteriorate when applied in a different clinical environment than was used for training. One decisive component in the underlying domain shift has been identified as the variability caused by using different whole slide scanners. The goal of the MICCAI MIDOG 2021 challenge has been to propose and evaluate methods that counter this domain shift and derive scanner-agnostic mitosis detection algorithms. The challenge used a training set of 200 cases, split across four scanning systems. As a test set, an additional 100 cases split across four scanning systems, including two previously unseen scanners, were given. The best approaches performed on an expert level, with the winning algorithm yielding an F_1 score of 0.748 (CI95: 0.704-0.781). In this paper, we evaluate and compare the approaches that were submitted to the challenge and identify methodological factors contributing to better performance.
Mitotic count (MC) is an important histological parameter for cancer diagnosis and grading, but the manual process for obtaining MC from whole-slide histopathological images is very time-consuming and prone to error. Therefore, deep learning models have been proposed to facilitate this process. Existing approaches utilize a two-stage pipeline: the detection stage for identifying the locations of potential mitotic cells and the classification stage for refining prediction confidences. However, this pipeline formulation can lead to inconsistencies in the classification stage due to the poor prediction quality of the detection stage and the mismatches in training data distributions between the two stages. In this study, we propose a Refine Cascade Network (ReCasNet), an enhanced deep learning pipeline that mitigates the aforementioned problems with three improvements. First, window relocation was used to reduce the number of poor quality false positives generated during the detection stage. Second, object re-cropping was performed with another deep learning model to adjust poorly centered objects. Third, improved data selection strategies were introduced during the classification stage to reduce the mismatches in training data distributions. ReCasNet was evaluated on two large-scale mitotic figure recognition datasets, canine cutaneous mast cell tumor (CCMCT) and canine mammary carcinoma (CMC), which resulted in up to 4.8% percentage point improvements in the F1 scores for mitotic cell detection and 44.1% reductions in mean absolute percentage error (MAPE) for MC prediction. Techniques that underlie ReCasNet can be generalized to other two-stage object detection networks and should contribute to improving the performances of deep learning models in broad digital pathology applications.
Domain variability is a common bottle neck in developing generalisable algorithms for various medical applications. Motivated by the observation that the domain variability of the medical images is to some extent compact, we propose to learn a target representative feature space through unpaired image to image translation (CycleGAN). We comprehensively evaluate the performanceand usefulness by utilising the transformation to mitosis detection with candidate proposal and classification. This work presents a simple yet effective multi-step mitotic figure detection algorithm developed as a baseline for the MIDOG challenge. On the preliminary test set, the algorithm scoresan F1 score of 0.52.
For the MIDOG mitosis detection challenge, we created a cascade algorithm consisting of a Mask-RCNN detector, followed by a classification ensemble consisting of ResNet50 and DenseNet201 to refine detected mitotic candidates. The MIDOG training data consists of 200 frames originating from four scanners, three of which are annotated for mitotic instances with centroid annotations. Our main algorithmic choices are as follows: first, to enhance the generalizability of our detector and classification networks, we use a state-of-the-art residual Cycle-GAN to transform each scanner domain to every other scanner domain. During training, we then randomly load, for each image, one of the four domains. In this way, our networks can learn from the fourth non-annotated scanner domain even if we don't have annotations for it. Second, for training the detector network, rather than using centroid-based fixed-size bounding boxes, we create mitosis-specific bounding boxes. We do this by manually annotating a small selection of mitoses, training a Mask-RCNN on this small dataset, and applying it to the rest of the data to obtain full annotations. We trained the follow-up classification ensemble using only the challenge-provided positive and hard-negative examples. On the preliminary test set, the algorithm scores an F1 score of 0.7578, putting us as the second-place team on the leaderboard.
The difficulty of detecting mitosis and its similarity to non-mitosis objects has remained a challenge in computational pathology. The lack of publicly available data has added more complexity. Deep learning algorithms have shown potentials in mitosis detection tasks. However, they face challenges when applied to pathology images with dense medium and diverse dataset. This paper introduces an optimized UV-Net architecture, developed to focus on mitosis details with high-resolution through feature preservation. Stain normalization methods are used to generalize the trained network. An F1 score of 0.6721 is achieved using this network.
Mitotic figure detection is a challenging task in digital pathology that has a direct impact on therapeutic decisions. While automated methods often achieve acceptable results under laboratory conditions, they frequently fail in the clinical deployment phase. This problem can be mainly attributed to a phenomenon called domain shift. An important source of a domain shift is introduced by different microscopes and their camera systems, which noticeably change the color representation of digitized images. In this method description we present our submitted algorithm for the Mitosis Domain Generalization Challenge, which employs a RetinaNet trained with strong data augmentation and achieves an F1 score of 0.7138 on the preliminary test set.
We present a summary of the domain adaptive cascade R-CNN method for mitosis detection of digital histopathology images. By comprehensive data augmentation and adapting existing popular detection architecture, our proposed method has achieved an F1 score of 0.7500 on the preliminary test set in MItosis DOmain Generalization (MIDOG) Challenge at MICCAI 2021.