Hitchhiker's guide to cancer-associated lymphoid aggregates in histology images: manual and deep learning-based quantification approaches

Quantification of lymphoid aggregates including tertiary lymphoid structures with germinal centers in histology images of cancer is a promising approach for developing prognostic and predictive tissue biomarkers. In this article, we provide recommendations for identifying lymphoid aggregates in tissue sections from routine pathology workflows such as hematoxylin and eosin staining. To overcome the intrinsic variability associated with manual image analysis (such as subjective decision making, attention span), we recently developed a deep learning-based algorithm called HookNet-TLS to detect lymphoid aggregates and germinal centers in various tissues. Here, we additionally provide a guideline for using manually annotated images for training and implementing HookNet-TLS for automated and objective quantification of lymphoid aggregates in various cancer types.

HoVer-UNet: Accelerating HoVerNet with UNet-based multi-class nuclei segmentation via knowledge distillation

We present HoVer-UNet, an approach to distill the knowledge of the multi-branch HoVerNet framework for nuclei instance segmentation and classification in histopathology. We propose a compact, streamlined single UNet network with a Mix Vision Transformer backbone, and equip it with a custom loss function to optimally encode the distilled knowledge of HoVerNet, reducing computational requirements without compromising performances. We show that our model achieved results comparable to HoVerNet on the public PanNuke and Consep datasets with a three-fold reduction in inference time. We make the code of our model publicly available at https://github.com/DIAGNijmegen/HoVer-UNet.

"HoVer-UNet": Accelerating HoVerNet with UNet-based multi-class nuclei segmentation via knowledge distillation

We present "HoVer-UNet", an approach to distill the knowledge of the multi-branch HoVerNet framework for nuclei instance segmentation and classification in histopathology. We propose a compact, streamlined single UNet network with a Mix Vision Transformer backbone, and equip it with a custom loss function to optimally encode the distilled knowledge of HoVerNet, reducing computational requirements without compromising performances. We show that our model achieved results comparable to HoVerNet on the public PanNuke and Consep datasets with a three-fold reduction in inference time. We make the code of our model publicly available at https://github.com/DIAGNijmegen/HoVer-UNet.

LYSTO: The Lymphocyte Assessment Hackathon and Benchmark Dataset

We introduce LYSTO, the Lymphocyte Assessment Hackathon, which was held in conjunction with the MICCAI 2019 Conference in Shenzen (China). The competition required participants to automatically assess the number of lymphocytes, in particular T-cells, in histopathological images of colon, breast, and prostate cancer stained with CD3 and CD8 immunohistochemistry. Differently from other challenges setup in medical image analysis, LYSTO participants were solely given a few hours to address this problem. In this paper, we describe the goal and the multi-phase organization of the hackathon; we describe the proposed methods and the on-site results. Additionally, we present post-competition results where we show how the presented methods perform on an independent set of lung cancer slides, which was not part of the initial competition, as well as a comparison on lymphocyte assessment between presented methods and a panel of pathologists. We show that some of the participants were capable to achieve pathologist-level performance at lymphocyte assessment. After the hackathon, LYSTO was left as a lightweight plug-and-play benchmark dataset on grand-challenge website, together with an automatic evaluation platform. LYSTO has supported a number of research in lymphocyte assessment in oncology. LYSTO will be a long-lasting educational challenge for deep learning and digital pathology, it is available at https://lysto.grand-challenge.org/.

Seeded iterative clustering for histology region identification

Annotations are necessary to develop computer vision algorithms for histopathology, but dense annotations at a high resolution are often time-consuming to make. Deep learning models for segmentation are a way to alleviate the process, but require large amounts of training data, training times and computing power. To address these issues, we present seeded iterative clustering to produce a coarse segmentation densely and at the whole slide level. The algorithm uses precomputed representations as the clustering space and a limited amount of sparse interactive annotations as seeds to iteratively classify image patches. We obtain a fast and effective way of generating dense annotations for whole slide images and a framework that allows the comparison of neural network latent representations in the context of transfer learning.

Mitosis domain generalization in histopathology images -- The MIDOG challenge

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.

Automated risk classification of colon biopsies based on semantic segmentation of histopathology images

Artificial Intelligence (AI) can potentially support histopathologists in the diagnosis of a broad spectrum of cancer types. In colorectal cancer (CRC), 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 automated assessment of CRC histopathology whole-slide images. First, we present an AI-based method to segment multiple 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. Second, we use the best performing AI model as the basis for a computer-aided diagnosis system (CAD) 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 1,000 patients. The results show the potential of such an AI-based system to assist pathologists in diagnosis of CRC in the context of population screening. We have made the segmentation model available for research use on https://grand-challenge.org/algorithms/colon-tissue-segmentation/.

Quantifying the Scanner-Induced Domain Gap in Mitosis Detection

Automated detection of mitotic figures in histopathology images has seen vast improvements, thanks to modern deep learning-based pipelines. Application of these methods, however, is in practice limited by strong variability of images between labs. This results in a domain shift of the images, which causes a performance drop of the models. Hypothesizing that the scanner device plays a decisive role in this effect, we evaluated the susceptibility of a standard mitosis detection approach to the domain shift introduced by using a different whole slide scanner. Our work is based on the MICCAI-MIDOG challenge 2021 data set, which includes 200 tumor cases of human breast cancer and four scanners. Our work indicates that the domain shift induced not by biochemical variability but purely by the choice of acquisition device is underestimated so far. Models trained on images of the same scanner yielded an average F1 score of 0.683, while models trained on a single other scanner only yielded an average F1 score of 0.325. Training on another multi-domain mitosis dataset led to mean F1 scores of 0.52. We found this not to be reflected by domain-shifts measured as proxy A distance-derived metric.

Automated Scoring of Nuclear Pleomorphism Spectrum with Pathologist-level Performance in Breast Cancer

Nuclear pleomorphism, defined herein as the extent of abnormalities in the overall appearance of tumor nuclei, is one of the components of the three-tiered breast cancer grading. Given that nuclear pleomorphism reflects a continuous spectrum of variation, we trained a deep neural network on a large variety of tumor regions from the collective knowledge of several pathologists, without constraining the network to the traditional three-category classification. We also motivate an additional approach in which we discuss the additional benefit of normal epithelium as baseline, following the routine clinical practice where pathologists are trained to score nuclear pleomorphism in tumor, having the normal breast epithelium for comparison. In multiple experiments, our fully-automated approach could achieve top pathologist-level performance in select regions of interest as well as at whole slide images, compared to ten and four pathologists, respectively.